Genetic defects of human brain development

This review focuses on malformations of the central nervous system that have a genetic etiology. One can view each malformation as giving us unique details on a map entitled "how to make a human brain." The gene(s) that cause each malformation are being identified, allowing discovery of their specific role in neurodevelopment, and defining a "road" on the map. The malformation is then the developmental consequence of "taking a wrong turn." Assimilation of complementary data from other species with human malformation phenotype and genotype is revealing just how wonderful and complex the neurodevelopment map is. Here we highlight recent research on brain malformations and how this is illuminating the map of normal human brain formation.     

Choice of environmental components for a longitudinal birth cohort study

Various aspects of the environment of the mother and child may have major influences on the health and development of the child. Long-term influences can even affect chronic diseases of adulthood. Here we describe the major psychosocial and physical environmental factors that should be measured in longitudinal birth cohort studies.     

Quantitative image analysis of drug-induced lung fibrosis using laser scanning confocal microscopy.

Pulmonary fibrosis is a serious lung disorder that in certain cases may be difficult to quantify. It was our objective to evaluate the use of laser scanning confocal microscopy (LSCM) in quantifying fibrosis after exposure to amiodarone (AD) and bleomycin (BLM), two commonly used therapeutic drugs known to cause debilitating lung fibrosis in humans. Male F344 rats were intratracheally dosed with AD (6.25 mg/kg on days 0 and 2), BLM (0.25 and 1.0 mg/kg on day 0), or their respective vehicle controls. The right lung was assayed for hydroxyproline, a biochemical measure of collagen, at day 21 for the BLM groups and day 28 for the AD groups. The left lung was fixed, sectioned into blocks, dehydrated, stained with Lucifer yellow (LY, 0.1 mg/ml), and embedded in Spurr resin. The area of lung tissue stained by LY was quantified by LSCM. A fibrotic response in the AD and BLM groups was confirmed by histopathological assessment and a significant increase (p < 0.05) in total right lung hydroxyproline above control values. The area of connective tissue stained by LY of the two drug-treated groups appeared as bright linear bands in the alveolar septae and was significantly increased (p < 0.05) as measured by image analysis when compared with their respective controls. LSCM, with its advanced image analysis system, is an alternate method to quantify fibrotic lung disease. LSCM could be particularly useful when tissue quantity is limited, such as when tissue has been archived from previous studies, or when analyzing human lung biopsy samples for disease diagnosis, where biochemical analysis is difficult.     

In vivo analyses of UV-irradiation-induced p53 promoter binding using a novel quantitative real-time PCR assay

The p53 tumor suppressor protein mediates cell cycle arrest and apoptosis through transactivation of downstream target genes. While many target genes have been identified to date, the mechanisms and time course of their induction are still unclear. We investigated the kinetics of p53 binding to the p21CIP1, MDM2, BAX and PIG3 promoters in vivo using a novel quantitative real-time chromatin immunoprecipitation-PCR assay. Our results demonstrate distinct kinetics of p53 promoter binding dependent on the target gene promoters. The timed induction of target genes due to genotoxic stress is likely to play a pivotal role for the divergent functions of p53.     

Comparison of intra-aortic computed tomography angiography to conventional angiography in the presurgical visualization of the Adamkiewicz artery: first results in patients with thoracoabdominal aortic aneurysms

Introduction

The aim of this study was to compare the sensitivity of intra-aortic computed tomography angiography (IA-CTA) to that of regular spinal digital subtraction angiography for the presurgical location of the Adamkiewicz artery (AKA).

Methods

Thirty patients (21 males, 9 females; mean age 64 years) had an IA-CTA for the location of the AKA before surgery of aneurysm (n?=?24) or dissection (n?=?6) of the thoracoabdominal aorta. After femoral artery puncture, a pigtail catheter was positioned at the origin of the descending aorta. CT acquisition was performed with an intra-aortic iodinated contrast media injection (15 mL/s, 120 mL). The visualization of the AKA and the location of the feeder(s) to the AKA were independently evaluated by two observers. Interrater agreement was calculated using a kappa test. Spinal angiogram by selective catheterization was systematically performed to confirm the results of the IA-CTA.

Results

The AKA was visualized by the IA-CTA in 27/30 cases (90 %); in 26/31 (84 %) cases, the continuity with the aorta was satisfactorily seen. Interrater agreement was good for the visualization of the AKA and its feeder(s): 0.625 and 0.87, respectively. In 75 % of the cases for which the AKA was visualized, the selective catheterization confirmed the results of the IA-CTA. In the remaining 25 % of the cases, the selective catheterization could not be performed due to marked vessels’ tortuosity or ostium stenosis.

Conclusion

IA-CTA is a feasible technique in a daily practice that presents a good sensitivity for the location of the AKA.     

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens

We studied nine presumed nongenotoxic rodent carcinogens, as defined by the U.S. National Toxicology Program (NTP), to determine their ability to induce acute or subacute biochemical and tissue changes that may act as useful predictors of nongenotoxic rodent carcinogenesis. The chemicals selected included six liver carcinogens (two of which are peroxisome proliferators), three thyroid gland carcinogens, and four kidney carcinogens. We administered the chemicals (diethylhexyl phthalate, cinnamyl anthranilate, chlorendic acid, 1,4-dichlorobenzene, monuron, ethylene thiourea, diethyl thiourea, trimethyl thiourea, and d-limonene to the same strains of mice and rats used in the original NTP bioassays (nine chemicals to rats and seven to mice). Selected tissues (liver, thyroid gland, and kidney) were collected from groups of animals at 7, 28, and 90 days for evaluation. Tissue changes selected for study were monitored for all of the test groups, irrespective of the specificity of the carcinogenic responses observed in those tissues. This allowed us to assess both the carcinogen specificity and the carcinogen sensitivity of the events being monitored. We studied relative weight, cell labeling indices, and pathologic changes such as hypertrophy in all tissues; a range of cytochrome P450 enzymes and palmitoyl coenzyme A oxidase in the liver; changes in the levels of plasma total triiodothyronine, total thyroxine, and thyroid-stimulating hormone (TSH) as markers of thyroid gland function; and hyaline droplet formation, tubular basophilia, and the formation of granular casts in the kidney. There were no single measurements that alerted specifically to the carcinogenicity of the agents to the rodent liver, thyroid gland, or kidney. However, in the majority of cases, the chemical induction of cancer in a tissue was preceded by a range of biochemical/morphologic changes, most of which were moderately specific for a carcinogenic outcome, and some of which were highly specific for it (e.g., increases in TSH in the thyroid gland and increases in relative liver weight in the mouse). The only measurements that failed to correlate usefully with carcinogenicity were the induction of liver enzymes (with the exception of the enzymes associated with peroxisome proliferation). Most of the useful markers were evident at the early times studied (7 days and 28 days), but no overall best time for the measurement of all markers was identified. The judicious choice of markers and evaluation times can aid the detection of potential nongenotoxic rodent carcinogens.     

Utility of gram staining for evaluation of the quality of cystic fibrosis sputum samples

The microscopic examination of Gram-stained sputum specimens is very helpful in the evaluation of patients with community-acquired pneumonia and has also been recommended for use in cystic fibrosis (CF) patients. This study was undertaken to evaluate that recommendation. One hundred one sputum samples from CF patients were cultured for gram-negative bacilli and examined by Gram staining for both sputum adequacy (using the quality [Q] score) and bacterial morphology. Subjective evaluation of adequacy was also performed and categorized. Based on Q score evaluation, 41% of the samples would have been rejected despite a subjective appearance of purulence. Only three of these rejected samples were culture negative for gram-negative CF pathogens. Correlation between culture results and quantitative Gram stain examination was also poor. These data suggest that subjective evaluation combined with comprehensive bacteriology is superior to Gram staining in identifying pathogens in CF sputum.     

The association between mindfulness and emotional distress in adults with diabetes: Could mindfulness serve as a buffer? Results from Diabetes MILES: The Netherlands

People with diabetes have a higher risk of emotional distress (anxiety, depression) than non-diabetic or healthy controls. Therefore, identification of factors that can decrease emotional distress is relevant. The aim of the present study was to examine (1) the association between facets of mindfulness and emotional distress; and (2) whether mindfulness might moderate the association between potential adverse conditions (stressful life events and comorbidity) and emotional distress. Analyses were conducted using cross-sectional data (Management and Impact for Long-term Empowerment and Success—Netherlands): 666 participants with diabetes (type 1 or type 2) completed measures of mindfulness (Five Facet Mindfulness Questionnaire-Short Form; FFMQ-SF), depressive symptoms (Patient Health Questionnaire; PHQ-9), and anxiety symptoms (General Anxiety Disorder assessment; GAD-7). Hierarchical multiple regression analyses showed significant associations between mindfulness facets (acting with awareness, non-judging, and non-reacting) and symptoms of anxiety and depression (β = ?0.20 to ?0.33, all p < 0.001). These mindfulness facets appeared to have a moderating effect on the association between stressful life events and depression and anxiety (all p < 0.01). However, the association between co-morbidity and emotional distress was largely not moderated by mindfulness. In conclusion, mindfulness is negatively related to both depression and anxiety symptoms in people with diabetes and shows promise as a potentially protective characteristic against the influence of stressful events on emotional well-being.