Transgenic Overexpression of Aryl Hydrocarbon Receptor Repressor (AhRR) and AhR-Mediated Induction of CYP1A1, Cytokines,and Acute Toxicity

Background:

The aryl hydrocarbon receptor repressor (AhRR) is known to repress aryl hydrocarbon receptor (AhR) signaling, but very little is known regarding the role of the AhRR in vivo.

Objective:

This study tested the role of AhRR in vivo in AhRR overexpressing mice on molecular and toxic end points mediated through a prototypical AhR ligand.

Methods:

We generated AhRR-transgenic mice (AhRR Tg) based on the genetic background of C57BL/6J wild type (wt) mice. We tested the effect of the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the expression of cytochrome P450 (CYP)1A1 and cytokines in various tissues of mice. We next analyzed the infiltration of immune cells in adipose tissue of mice after treatment with TCDD using flow cytometry.

Results:

AhRR Tg mice express significantly higher levels of AhRR compared to wt mice. Activation of AhR by TCDD caused a significant increase of the inflammatory cytokines Interleukin (IL)-1β, IL-6 and IL-10, and CXCL chemokines in white epididymal adipose tissue from both wt and AhRR Tg mice. However, the expression of IL-1β, CXCL2 and CXCL3 were significantly lower in AhRR Tg versus wt mice following TCDD treatment. Exposure to TCDD caused a rapid accumulation of neutrophils and macrophages in white adipose tissue of wt and AhRR Tg mice. Furthermore we found that male AhRR Tg mice were protected from high-dose TCDD-induced lethality associated with a reduced inflammatory response and liver damage as indicated by lower levels of TCDD-induced alanine aminotransferase and hepatic triglycerides. Females from both wt and AhRR Tg mice were less sensitive than male mice to acute toxicity induced by TCDD.

Conclusion:

In conclusion, the current study identifies AhRR as a previously uncharacterized regulator of specific inflammatory cytokines, which may protect from acute toxicity induced by TCDD.

Citation:

Vogel CF, Chang WL, Kado S, McCulloh K, Vogel H, Wu D, Haarmann-Stemmann T, Yang GX, Leung PS, Matsumura F, Gershwin ME. 2016. Transgenic overexpression of aryl hydrocarbon receptor repressor (AhRR) and AhR-mediated induction of CYP1A1, cytokines, and acute toxicity. Environ Health Perspect 124:1071–1083; http://dx.doi.org/10.1289/ehp.1510194     

Clinical results of mitral valve surgery in children

The clinical results of mitral valve surgery in children were evaluated. Fifty children (age ranged between 1 month and 12 years) with mitral valve regurgitation have undergone valve surgery with low operative mortality (2%). Valve plasty using several techniques including annuloplasty have been performed with quite high success rate (92%), while valve replacement was required in four patients who had the prolapse of the anterior mitral leaflet (8%). Reoperation was required in 5 patients (10%), and there were 4 late deaths. Introduction of the reconstructive technique of the chordae tendinae using artificial chordae resulted 100% success rate of mitral repair for the prolapse of the anterior mitral leaflet without death and reoperation. The reoperation free rate and the actuarial survival rate at 15 years of the patients with mitral regurgitation were 70 +/- 12% and 85 +/- 7%, respectively. In ten patients with mitral valve stenosis (age ranged between 1 month and 5 years), 5 patients required valve replacement (50%), and 2 patients died (20%). The clinical results of the surgery for the mitral stenosis were still unsatisfactory, and the reoperation free rate at 2 years was 42 +/- 30% and the actuarial survival rate at 13 years were 32 +/- 18%.     

The low resistance strategy for the perioperative management of the Norwood procedure

BACKGROUND: Postoperative course of the Norwood procedure is fragile because of an unstable pulmonary to systemic blood flow ratio caused by fluctuation of systemic and pulmonary vascular resistance. METHODS: Twenty-seven patients with hypoplastic left heart syndrome who underwent the Norwood procedure from June 1998 to February 2002 were managed with the following low-resistance strategy. Intraoperative high-flow and low-resistance cardiopulmonary bypass was achieved with total avoidance of circulatory arrest and a large dose of chlorpromazine. In weaning from the bypass, pulmonary vascular resistance was maximally decreased by inspired oxygen fraction (100%), inhaled nitric oxide (20 ppm), and nitroglycerin (2 to 4 microg/kg/min). Then pulmonary blood flow was determined by adjusting the systemic to pulmonary shunt. Postoperatively, with continuous infusion of chlorpromazine and nitroglycerin as a systemic and pulmonary vasodilator, the inspired oxygen fraction and inhaled nitric oxide were tapered as the arterial oxygen saturation improved. RESULTS: In most patients, inhaled nitrous oxide and inspired oxygen fraction were weaned within 3 days. The postoperative course was stable with minimum changes in circulatory and respiratory status for the survivors. Patients were extubated on a median of 6 postoperative days. Early mortality was 11.1% (3 of 27), and none of the patients died of hemodynamic deterioration. CONCLUSIONS: The low resistance strategy is a simple and useful method for perioperative management of the Norwood procedure, minimizing fluctuation in both pulmonary and systemic vascular resistance and maintaining stable circulatory and respiratory status.     

Differential diagnosis in patients with ring-like thallium-201 uptake in brain SPECT

This study was performed to investigate lesions with ring-like thallium-201 (201Tl) uptake and to determine whether SPECT provides any information in differential diagnosis. METHODS: A total of 244 201Tl SPECT images were reviewed. In each study, early (15 min postinjection) and late (3 hr) brain SPECT images were obtained with 111 MBq of 201Tl. The early uptake ratio (ER; lesion to normal brain average count ratio) and the late uptake ratio (LR) and the L/E ratio (ratio of LR to ER) were calculated. RESULTS: Ring-like uptake was observed in pre-therapeutic 26 SPECT images, including ten glioblastoma multiformes (ER, 3.45 +/- 0.64; LR, 2.74 +/- 0.54; L/E ratio 0.80 +/- 0.13), five meningiomas (6.48 +/- 2.34; 4.41 +/- 1.41; 0.72 +/- 0.19), four metastatic lung cancers (3.47 +/- 1.23; 2.40 +/- 0.98; 0.70 +/- 0.14), four brain abscesses (2.48 +/- 1.06; 1.59 +/- 0.30; 0.78 +/- 0.15), one invasive lesion of squamous cell carcinoma from the ethmoid sinus (1.54; 1.52; 0.99), one medulloblastoma (3.53; 3.52; 1.00) and one hematoma (3.32; 2.36; 0.71). The ER of meningioma was significantly higher than those of glioblastoma multiforme (p < 0.0005), metastatic lung cancer (p < 0.005) and brain abscess (p < 0.0005). There were no significant differences among these three entities. The LR of meningioma was significantly higher than those of glioblastoma multiforme (p < 0.005), metastatic lung cancer (p < 0.005) and brain abscess (p < 0.0001). The LR of brain abscess was significantly lower than that of glioblastoma multiforme (p < 0.05). The L/E ratio could not differentiate these four entities. CONCLUSION: High ER and high LR in a lesion with ring-like uptake is likely an indicator of meningioma. The LR of brain abscess was significantly lower than that of glioblastoma multiforme, but 201T1 SPECT has still difficulty in differentiating abscess from brain tumor.     

Genetic contribution of the interleukin-10 promoter polymorphism in endometriosis susceptibility

PROBLEM: Interleukin-10 (IL-10) is an important immunomodulatory cytokine. The aim of this study was to investigate whether polymorphisms of the IL-10 gene promoter polymorphisms may be responsible in part for genetic susceptibility to endometriosis. METHODS OF STUDY: Polymorphisms at position -1082 and -592 in the IL-10 promoter region were determined in 196 patients with endometriosis and 160 fertile healthy women by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: There were no statistically significant differences in the genotype and allele frequencies of IL-10 promoter polymorphism between the endometriosis and control groups. However, when subgrouped according to clinical features, the frequencies of the -592*CC genotype and -592*C allele were significantly increased in patients with autoantibodies to carbonic anhydrase II (anti-CA II ab) compared with controls. CONCLUSION: IL-10 promoter polymorphisms were associated with the production of anti-CA II ab in patients with endometriosis, suggesting a role in the genetic susceptibility for endometriosis.     

MRI prior computation and parallel tempering algorithm: a probabilistic resolution of the MEG/EEG inverse problem

Since the MEG inverse problem is ill-posed and admits many possible solutions, it is not possible to give it a single " true" answer. Therefore, we propose here to use a specific probabilistic algorithm to map the full probability distribution of the MEG sources with Markov Chain Monte Carlo methods. Using a Bayesian approach, the probability of the MEG solutions is expressed as the product of the likelihood by the prior probability. To compute the prior and constrain the MEG inverse problem resolution, MRI data are also acquired and automatically processed to determine the brain position and volume. We then use Parallel Tempering algorithm to estimate the full posterior probability and determine the likely solutions of the inverse problem. We illustrate the method with results obtained from the analysis of somatosensory data. This illustrates both the MRI processing for the prior computation, and how the knowledge of the full posterior probability distribution can be used to estimate the position of the sources, as well as their likely extension.     

Tetrodotoxin induced calcium spikes: in vitro and in vivo studies of normal and deafferented Purkinje cells

Summary Tetrodotoxin (TTX) is widely used to block the sodium dependent action potential in excitable cells to study their other ionic properties. TTX applied outside, selectively blocks voltage dependent sodium channels and is thought to have no other effects. We report here that TTX, applied to slices of rat cerebellum, suppressed sodium spikes of the Purkinje cells and induced firing in bursts of slower spikes. This activity was blocked by cobalt (2 mM) or cadmium (0.2 mM) in the medium as well as by hyperpolarizing currents showing that the slow spikes were due to voltage dependent calcium channels. The membrane potential was not significantly changed by TTX and the spikes during the bursts had the same threshold potentials and peak spike amplitudes as the voltage and Ca²⁺ dependent dendritic spikes evoked by injected current before adding TTX. This indicated that no marked changes in the membrane conductances were produced by the TTX. Unlike the burst firing induced by removing extracellular sodium, the TTX induced bursts were not followed by a large hyperpolarization. The same kind of results were obtained with extracellular recording in the in-vivo preparation with TTX applied topically or by pressure near the recording sites. TTX induced burst firing was not due to blocking afferent inhibitory input to the PC, since bicuculline (10^-6 M) applied without TTX, produced only increased firing of fast action potentials and no bursts. The bursts could be arrested within 1 to 2 min by intravenously administering 2 mg/kg sodium pentobarbital, the blockage lasted from 5 to 15 min. These effects of TTX were not due to a contaminant as TTX from two different suppliers produced the same effects. A possible mechanism based on a decrease of intracellular free sodium is discussed.     

Light and electron microscopic immunocytochemical study on the innervation of the pineal gland of the tree shrew (Tupaia glis), with special reference to peptidergic synaptic junctions with pinealocytes.

Conventional and immunocytochemical, light- and electron-microscopic studies on the innervation of the pineal gland of the tree shrew (Tupaia glis) were made. Neuropeptide Y (NPY)-immunoreactive fibers, which were abundantly distributed in the gland, disappeared almost completely after superior cervical ganglionectomy, suggesting that these fibers are mostly postganglionic sympathetic fibers. By contrast, tyrosine hydroxylase (TH)-immunoreactive fibers, which were less numerous than NPY-fibers, remained in considerable numbers in ganglionectomized animals, indicating the innervation of TH-positive fibers from extrasympathetic sources. Bundles of substance P (SP)- or calcitonin gene-related peptide (CGRP)-immunoreactive fibers, entering the gland at its distal end, were left intact after ganglionectomy. SP-fibers were numerous, but CGRP-fibers were scarce in the gland. SP-immunoreactive fibers were myelinated and nonmyelinated, and were regarded as peripheral fibers because of the presence of a Schwann cell sheath. NPY- and SP-immunoreactive fibers and endings were mainly localized in the pineal parenchyma. NPY-immunoreactive endings synapsed frequently, and SP-positive ones did less frequently, with the cell bodies of pinealocytes. The results suggest that NPY and SP directly control the activity of pinealocytes. Sections stained for myelin showed that thick and less thick bundles of myelinated fibers entered the gland by way of the habenular and posterior commissures, respectively. Under the electron microscope, the bundles were found to contain also unmyelinated fibers. A considerable number of nerve endings synapsing with the cell bodies of pinealocytes remained in ganglionectomized animals; these endings were not immunoreactive for TH or SP. Such synaptic endings may be the terminals of commissural fibers.     

Age-related hyperkyphosis, independent of spinal osteoporosis, is associated with impaired mobility in older community-dwelling women

Summary  

While many assume hyperkyphosis reflects underlying spinal osteoporosis and vertebral fractures, our results suggest hyperkyphosis is independently associated with decreased mobility. Hyperyphosis is associated with slower Timed Up and Go performance times and may be a useful clinical marker signaling the need for evaluation of vertebral fracture and falling risk.     

Effect of development and aging on the modified Wisconsin Card Sorting Test in normal subjects

The Wisconsin card sorting test (WCST) is applied to various types of neurological disorders. Since WCST requires the examinee's sustained efforts, it is not readily applicable to children with developmental disorders. In order to overcome this weakness, Keio version WCST (KWCST) was developed by reducing the number of cards from 128 to 48 and presenting them in two steps separated by a short pause. During which a brief instruction was given. This study was performed to clarify the changes with age in indices of KWCST and to obtain the normative value. Three hundred thirty five normal subjects, ranging from 5 to 82 years of age were examined. A simple regression analysis showed a significant age-related changes. Subjects between the middle thirties and the middle forties showed the best score in such indices as the categories achieved, perseverative errors of Nelson, difficulties of maintaining set, numbers of response cards until the first category achieved, and total errors. Most of the scores were improved in the second step across the all age groups, which might have resulted from learning during the first step and the instruction provided before the second step. KWCST can be performed briefly, and is suitable for cases with attention deficit/hyperactivity disorder and pervasive developmental disorder.