CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3⁺ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4^−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3⁺ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3⁺ regulatory T cell function in vivo.     

Consumers of natural health products: natural-born pharmacovigilantes?

Background  

Natural health products (NHPs), such as herbal medicines and vitamins, are widely available over-the-counter and are often purchased by consumers without advice from a healthcare provider. This study examined how consumers respond when they believe they have experienced NHP-related adverse drug reactions (ADRs) in order to determine how to improve current safety monitoring strategies.     

Targeted 2D/3D registration using ray normalization and a hybrid optimizer

X-ray images are often used to guide minimally invasive procedures in interventional radiology. The use of a preoperatively obtained 3D volume can enhance the visualization needed for guiding catheters and other surgical devices. However, for intraoperative usefulness, the 3D dataset needs to be registered to the 2D x-ray images of the patient. We investigated the effect of targeting subvolumes of interest in the 3D datasets and registering the projections with C-arm x-ray images. We developed an intensity-based 2D/3D rigid-body registration using a Monte Carlo-based hybrid algorithm as the optimizer, using a single view for registration. Pattern intensity (PI) and mutual information (MI) were two metrics tested. We used normalization of the rays to address the problems due to truncation in 3D necessary for targeting. We tested the algorithm on a C-arm x-ray image of a pig's head and a 3D dataset reconstructed from multiple views of the C-arm. PI and MI were comparable in performance. For two subvolumes starting with a set of initial poses from +/-15 mm in x, from +/-3 mm (random), in y and z and +/-4 deg in the three angles, the robustness was 94% for PI and 91% for MI, with accuracy of 2.4 mm (PI) and 2.6 mm (MI), using the hybrid algorithm. The hybrid optimizer, when compared with a standard Powell's direction set method, increased the robustness from 59% (Powell) to 94% (hybrid). Another set of 50 random initial conditions from [+/-20] mm in x,y,z and [+/-10] deg in the three angles, yielded robustness of 84% (hybrid) versus 38% (Powell) using PI as metric, with accuracies 2.1 mm (hybrid) versus 2.0 mm (Powell).     

Dating, sexual activity, and well-being in Italian adolescents.

Associations among dating, sexual activity, gender, and adjustment were investigated in 2,273 Italian adolescents (54% female, ages 14 to 19 years) attending public high schools. After controlling for age and type of school attended, both being in a dating relationship and being male were associated with less alienation, more positive views of the self, and higher general expectations for success. Sexual activity interacted with both gender and dating status in predicting feelings of depression. For boys, there were no differences between youth who were sexually active and youth who were not; however, sexually active girls had higher levels of depressive symptoms than girls who were not sexually active. Among youth who were not sexually active, there were small differences between daters and nondaters; among sexually active youth, daters had lower levels of depression than nondaters. Gender differences in adolescents' experience of dating and sexual relationships and implications for adjustment are discussed.     

Prostate cancer derived prostatic acid phosphatase promotes an osteoblastic response in the bone microenvironment

Approximately 90 % of patients who die of prostate cancer (PCa) have bone metastases, often promoting osteoblastic lesions. We observed that 88 % of castration-resistant PCa (CRPC) bone metastases express prostatic acid phosphatase (PAP), a soluble secreted protein expressed by prostate epithelial cells in predominately osteoblastic (n = 18) or osteolytic (n = 15) lesions. Additionally, conditioned media (CM) of an osteoblastic PCa xenograft LuCaP 23.1 contained significant levels of PAP and promoted mineralization in mouse and human calvaria-derived cells (MC3T3-E1 and HCO). To demonstrate that PAP promotes mineralization, we stimulated MC3T3-E1 cells with PAP and observed increased mineralization, which could be blocked with the specific PAP inhibitor, phosphonic acid. Furthermore, the mineralization promoted by LuCaP 23.1 CM was also blocked by phosphonic acid, suggesting PAP is responsible for the mineralization promoting activity of LuCaP 23.1. In addition, gene expression arrays comparing osteoblastic to osteolytic CRPC (n = 14) identified betacellulin (BTC) as a gene upregulated during the osteoblastic response in osteoblasts during new bone formation. Moreover, BTC levels were increased in bone marrow stromal cells in response to LuCaP 23.1 CM in vitro. Because new bone formation does occur in osteoblastic and can occur in osteolytic CRPC bone metastases, we confirmed by immunohistochemistry (n = 36) that BTC was highly expressed in osteoblasts involved in new bone formation occurring in both osteoblastic and osteolytic sites. These studies suggest a role for PAP in promoting the osteoblastic reaction in CRPC bone metastases and identify BTC as a novel downstream protein expressed in osteoblasts during new bone formation.     

Effects of Parkinson’s disease on optic flow perception for heading direction during navigation

Visuoperceptual disorders have been identified in individuals with Parkinson’s disease (PD) and may affect the perception of optic flow for heading direction during navigation. Studies in healthy subjects have confirmed that heading direction can be determined by equalizing the optic flow speed (OS) between visual fields. The present study investigated the effects of PD on the use of optic flow for heading direction, walking parameters, and interlimb coordination during navigation, examining the contributions of OS and spatial frequency (dot density). Twelve individuals with PD without dementia, 18 age-matched normal control adults (NC), and 23 young control adults (YC) walked through a virtual hallway at about 0.8 m/s. The hallway was created by random dots on side walls. Three levels of OS (0.8, 1.2, and 1.8 m/s) and dot density (1, 2, and 3 dots/m²) were presented on one wall while on the other wall, OS and dot density were fixed at 0.8 m/s and 3 dots/m², respectively. Three-dimensional kinematic data were collected, and lateral drift, walking speed, stride frequency and length, and frequency, and phase relations between arms and legs were calculated. A significant linear effect was observed on lateral drift to the wall with lower OS for YC and NC, but not for PD. Compared to YC and NC, PD veered more to the left under OS and dot density conditions. The results suggest that healthy adults perceive optic flow for heading direction. Heading direction in PD may be more affected by the asymmetry of dopamine levels between the hemispheres and by motor lateralization as indexed by handedness.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.     

Pregnancy and delivery with an intrauterine device in situ: outcomes in the National Inpatient Sample Database

Background: Pregnancy with intrauterine device in place is rare and there are limited data that exist regarding associated perinatal outcomes.

Objective: The objective of this study is to determine the association between presence of an intrauterine device during pregnancy and spontaneous abortion, induced abortion, and preterm or small for gestational age delivery outcomes.

Study design: The National Inpatient Sample database was analyzed for the years 2010 and 2011. Maternal records with an intrauterine device in situ during delivery were identified using International Classification of Diseases, Ninth Revision, diagnostic codes. Primary outcome was incidence of spontaneous abortion. Secondary outcomes were incidence of induced abortion, preterm delivery, and small for gestational age. Data were analyzed using Chi-square and Fisher’s exact tests to calculate odds ratios (ORs) of abortion in association with intrauterine device in situ during pregnancy. Maternal birth records were further analyzed for adverse neonatal outcomes using logistic regression models, controlling for possible confounding variables.

Results: The data included 8,597,284 maternal birth records; 0.02% with an intrauterine device in situ. Patients with an intrauterine device in situ experienced a higher frequency of the pregnancy ending in spontaneous abortion (OR: 7.15; 95% confidence interval (CI): 5.06–10.09; p?p?in situ was 2.04 (95% CI: 1.71–2.43; p?p?=?.022), after controlling for associated demographic and clinical variables.

Conclusion: The presence of an intrauterine device in situ during pregnancy was associated with increased spontaneous and induced abortions, and increased incidence of delivery of a preterm, but not small for gestational age infant.     

Effect of aging on treadmill exercise induced theta power in the rat

The effects of aging on the electroencephalogram (EEG) power spectra of 8- and 60-week-old Wistar–Kyoto rats were examined during the waking baseline and treadmill exercise. Using continuous and simultaneous recordings of EEG and electromyogram signals, this study demonstrated that the alpha (10–13 Hz), theta (6–10 Hz), and delta (0.5–4 Hz) powers of the EEG were significantly lower in older rats as compared with young rats during the waking baseline. In the young rats, treadmill exercise resulted promptly in a higher alpha power, higher theta power, and higher theta power percentage as compared with the waking baseline. In the aged rats, treadmill exercise only resulted in a higher theta power and higher theta power percentage. During the treadmill exercise, however, the aged rats still showed a significantly lower exercise-evoked theta power change than the young rats. These results suggested that aging is accompanied by lower EEG activities during waking and this also is accompanied by an attenuated response of the brain to exercise in the rat.