Association of CHRM2 with IQ: Converging Evidence for a Gene Influencing Intelligence

The cholinergic neurotransmitter system is thought to be involved in many aspects of memory, attention, and higher cognition. In the Collaborative Study on the Genetics of Alcoholism (COGA) sample, we have previously reported linkage and association to the cholinergic muscarinic 2 receptor gene (CHRM2) on chromosome 7 with evoked EEG oscillations (Jones et al. 2004), providing evidence that this gene may be involved in human brain dynamics and cognition. In addition, a small number of genetic markers were genotyped in CHRM2 in the Minnesota Twin and Family Study (Comings et al. 2003) and a Dutch family study (Gosso et al. 2006, in press) and both research groups found evidence that this gene may be involved in intelligence. In the COGA sample, we have extensively genotyped SNPs within and flanking the CHRM2 gene. We find evidence of association with multiple SNPs across CHRM2 and Performance IQ, as measured by the Wechsler Adult Intelligence Scale-Revised (WAIS-R). These results remain significant after taking into account alcohol dependence and depression diagnoses in the sample. Edited by Danielle Posthuma Henri Begleiter—Deceased     

CT evaluation of an anterior urethral tear

A retrograde urethrogram is usually performed to evaluate the urethra in patients with suspected urethral injuries. A computed tomography (CT) scan is performed after the retrograde urethrogram to evaluate for further intrabdominal injuries. We present a case in which a CT scan performed after a retrograde urethrogram in a trauma patient identified a urethral tear.     

Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

Rationale

Mefloquine is used for the prevention and treatment of chloroquine-resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics.

Objectives

Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (?)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters.

Results

Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (K _i?=?0.71–341 nM) to serotonin (5-HT) _2A but not 5-HT_1A or 5-HT_2C receptors. Mefloquine but not chloroquine was a partial 5-HT_2A agonist and a full 5-HT_2C agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquine’s effects. Mefloquine had low or no affinity for dopamine D₁, D₂, D₃, and D_4.4 receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the D₃ receptor and mefloquine but not chloroquine or hallucinogens blocked [³H]5-HT uptake by the 5-HT transporter.

Conclusions

Mefloquine, but not chloroquine, shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines.     

Nonclinical safety of mavrilimumab,an anti-GMCSF receptor alpha monoclonal antibody,in cynomolgus monkeys: Relevance for human safety

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26 weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters other than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress.     

Detection of the hemoglobin E mutation using the color complementation assay: application to complex genotyping

The color complementation assay (CCA) is a method of allele-specific DNA amplification by which competitive priming and extension of fluorescently labeled oligonucleotide primers determine the color of DNA amplification product. This diagnostic method precludes the need for radioisotopes, electrophoresis, and multiple high-stringency reaction conditions. The multiplicity of mutant globin genes present in Southeast Asians complicates clinical diagnosis and underscores the importance of DNA-based diagnostic methods. We have applied CCA to distinguish beta A and beta E alleles. Competing 15mer primers were a fluorescein-labeled complement to beta A and a rhodamine-labeled complement to beta E, identical except for their central nucleotides. A common unlabeled primer was used to amplify DNA product, the color of which was determined by the perfectly complementary primer. Color photography and spectrofluorometry, as well as a method of black-white photography that we developed to distinguish fluorescein- and rhodamine- labeled DNA, were used to record results. We applied CCA to define the complex genotype of a Thai woman with thalassemia intermedia, 96% HbE, and 4% HbF whose possible genotypes included several permutations of alpha-thalassemia, beta-thalassemia, and beta E genes. zeta-Globin gene mapping of DNA doubly digested with Bg/II and Asp 718 showed the -alpha 3.7/--SEA genotype, and CCA confirmed homozygous beta E/beta E. The CCA is useful for diagnosing the compound hemoglobin genotypes of Southeast Asians and could be applied also to prenatal diagnosis in this population.     

Diagnostic role of an immunoassay-detected polymorphism of factor IX for potential carriers of hemophilia B

In hemophilia B, assays based on a monoclonal antifactor IX specific for the Thr-148 variant of an exonic polymorphism have diagnosed carriers in selected families by either establishing linkage or by indicating the presence or absence of a given normal factor IX. The sensitivity of the immunoassays for detecting heterozygous women was explored by comparing results from immunoassays with solid-phase polyclonal v the monoclonal antifactor IXs. Factor IX with the normal Ala-148 variant gave a flat dilution curve, qualitatively distinct from factor IX with the Thr-148 variant in the monoclonal assay. The two were indistinguishable in the polyclonal assay. Mixtures of equal amounts of the two types gave an intermediate result, about half as reactive in the monoclonal as compared with the polyclonal assay system. Whereas mixtures with 10% Ala-148 and 90% Thr-148 factor IXs could not readily be distinguished from Thr-148 factor IX plasma, as little as 1% of the Thr-148 protein was detected in Ala-148 factor IX plasma. The frequency of the Ala-148 variant varied in individuals with different ethnic backgrounds; it was found in 29% of white, 12% of black, and none of Asian blood donors' factor IX genes in Seattle. Only 4% of samples from South African black men were nonreactive (ie, Ala- 148). The Thr/Ala-148 dimorphism is in strong linkage disequilibrium with Taql restriction fragment length polymorphisms (RFLPs). Three recombinations were noted in normal white genes and one in a normal black factor IX gene (less than 2% of those examined). In 34 white families with at least one woman being a possible carrier, genetically, the immunoassay results were informative in 18. RFLP analyses were informative in eight of the 15 families tested. In five families each, assignment of carrier status was made to a woman by only DNA or only immunoassay results, whereas the other approach was noninformative. The immunoassays provide a rapid, inexpensive screening test and complement DNA analysis in white women who are potential carriers of hemophilia B.     

Extracting and summarizing white matter hyperintensities using supervised segmentation methods in Alzheimer's disease risk and aging studies

Precise detection and quantification of white matter hyperintensities (WMH) observed in T2‐weighted Fluid Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) is of substantial interest in aging, and age‐related neurological disorders such as Alzheimer's disease (AD). This is mainly because WMH may reflect co‐morbid neural injury or cerebral vascular disease burden. WMH in the older population may be small, diffuse, and irregular in shape, and sufficiently heterogeneous within and across subjects. Here, we pose hyperintensity detection as a supervised inference problem and adapt two learning models, specifically, Support Vector Machines and Random Forests, for this task. Using texture features engineered by texton filter banks, we provide a suite of effective segmentation methods for this problem. Through extensive evaluations on healthy middle‐aged and older adults who vary in AD risk, we show that our methods are reliable and robust in segmenting hyperintense regions. A measure of hyperintensity accumulation, referred to as normalized effective WMH volume, is shown to be associated with dementia in older adults and parental family history in cognitively normal subjects. We provide an open source library for hyperintensity detection and accumulation (interfaced with existing neuroimaging tools), that can be adapted for segmentation problems in other neuroimaging studies. Hum Brain Mapp 35:4219–4235, 2014. © 2014 Wiley Periodicals, Inc .     

T-cell vaccination prevents EAE effector cell development but does not inhibit priming of MBP responsive cells

Cell recipients which have recovered from adoptively transferred Experimental Allergic Encephalomyelitis (EAE) mediated by encephalitogenic T-cell lines do not develop clinical disease following subsequent challenge with myelin basic protein (MBP) emulsified in CFA (MBP-CFA), a recipient response termed vaccination. The immune mechanism(s), which accounts for the vaccination-induced resistance response, is not known. We have used an adoptive transfer system to investigate the point(s) of control within the pathway of EAE effector cell development from MBP-specific naive precursors that prevents clinical disease in T-cell line vaccinated, MBP-CFA challenged Lewis rats. Although EAE effector cells do not develop in T-cell line vaccinated recipients, our data shows that MBP precursor cells are primed in T-cell line vaccinated MBP-CFA challenged animals, and these MBP-specific precursor cells can be stimulated in culture to the EAE effector cell level. MBP-memory cells also arise in T-cell line vaccinated MBP-CFA challenged donors, as demonstrated by the early and rapid onset of EAE in MBP-CFA challenged recipients of lymphnode cells from T-cell line vaccinated MBP-CFA challenged donors. We also found that it was possible to adoptively transfer resistance to MBP-CFA challenge using spleen cells from donors previously vaccinated with encephalitogenic T-cells. These results show that although EAE effector cells do not develop in T-cell line vaccinated animals, T-cell vaccination does not inhibit the initial MBP precursor cell response and does not prevent the development of MBP memory cells. © 1996 Wiley-Liss, Inc.