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2.  A Variant in the BACH2 Gene Is Associated With Susceptibility to Autoimmune Addison's Disease in Humans 
Context:
Autoimmune Addison's disease (AAD) is a rare but highly heritable condition. The BACH2 protein plays a crucial role in T lymphocyte maturation, and allelic variation in its gene has been associated with a number of autoimmune conditions.
Objective:
We aimed to determine whether alleles of the rs3757247 single nucleotide polymorphism (SNP) in the BACH2 gene are associated with AAD.
Design, Setting, and Patients:
This case-control association study was performed in two phases using Taqman chemistry. In the first phase, the rs3757247 SNP was genotyped in 358 UK AAD subjects and 166 local control subjects. Genotype data were also available from 5154 healthy UK controls from the Wellcome Trust (WTCCC2) for comparison. In the second phase, the SNP was genotyped in a validation cohort comprising 317 Norwegian AAD subjects and 365 controls.
Results:
The frequency of the minor T allele was significantly higher in subjects with AAD from the United Kingdom compared to both the local and WTCCC2 control cohorts (58% vs 45 and 48%, respectively) (local controls, P = 1.1 × 10−4; odds ratio [OR], 1.68; 95% confidence interval [CI], 1.29–2.18; WTCCC2 controls, P = 1.4 × 10−6; OR, 1.44; 95% CI, 1.23–1.69). This finding was replicated in the Norwegian validation cohort (P = .0015; OR, 1.41; 95% CI, 1.14–1.75). Subgroup analysis showed that this association is present in subjects with both isolated AAD (OR, 1.53; 95% CI, 1.22–1.92) and autoimmune polyglandular syndrome type 2 (OR, 1.37; 95% CI, 1.12–1.69) in the UK cohort, and with autoimmune polyglandular syndrome type 2 in the Norwegian cohort (OR, 1.58; 95% CI, 1.22–2.06).
Conclusion:
We have demonstrated, for the first time, that allelic variability at the BACH2 locus is associated with susceptibility to AAD. Given its association with multiple autoimmune conditions, BACH2 can be considered a “universal” autoimmune susceptibility locus.
We performed a two-stage case control association study in UK and Norwegian cohorts and found that allelic variability in BACH2 locus confers susceptibility to autoimmune Addison's disease.
doi:10.1210/jc.2016-2368
PMCID: PMC5095240  PMID: 27680876
3.  Impact of Month of Birth on the Risk of Development of Autoimmune Addison's Disease 
Context:
The pathogenesis of autoimmune Addison's disease (AAD) is thought to be due to interplay of genetic, immune, and environmental factors. A month-of-birth effect, with increased risk for those born in autumn/winter months, has been described in autoimmune conditions such as type 1 diabetes and autoimmune thyroid disease.
Objective:
Month-of-birth effect was investigated in 2 independent cohorts of AAD subjects.
Design, Setting, and Patients:
The monthly distribution of birth in AAD patients was compared with that of the general population using the cosinor test. A total of 415 AAD subjects from the United Kingdom cohort were compared with 8 180 180 United Kingdom births, and 231 AAD subjects from the Polish cohort were compared with 2 421 384 Polish births.
Main Outcome Measures:
Association between month of birth and the susceptibility to AAD.
Results:
In the entire cohort of AAD subjects, month-of-birth distribution analysis showed significant periodicity with peak of births in December and trough in May (P = .028). Analysis of the odds ratio distribution based on month of birth in 2 cohorts of patients with AAD versus the general population revealed a December peak and May trough, and January peak and July trough, in the United Kingdom and Polish cohorts, respectively.
Conclusion:
For the first time, we demonstrate that month of birth exerts an effect on the risk of developing AAD, with excess risk in individuals born in winter months and a protective effect when born in the summer. Exposure to seasonal viral infections in the perinatal period, coupled with vitamin D deficiency, could lead to dysregulation of innate immunity affecting the risk of developing AAD.
We show for the first time that month of birth exerts an effect on the risk of developing AAD, with excess risk in individuals born in winter months and a protective effect when born in the summer.
doi:10.1210/jc.2016-2392
PMCID: PMC5095257  PMID: 27575942
4.  A Putative Multiple-Demand System in the Macaque Brain 
The Journal of Neuroscience  2016;36(33):8574-8585.
In humans, cognitively demanding tasks of many types recruit common frontoparietal brain areas. Pervasive activation of this “multiple-demand” (MD) network suggests a core function in supporting goal-oriented behavior. A similar network might therefore be predicted in nonhuman primates that readily perform similar tasks after training. However, an MD network in nonhuman primates has not been described. Single-cell recordings from macaque frontal and parietal cortex show some similar properties to human MD fMRI responses (e.g., adaptive coding of task-relevant information). Invasive recordings, however, come from limited prespecified locations, so they do not delineate a macaque homolog of the MD system and their positioning could benefit from knowledge of where MD foci lie. Challenges of scanning behaving animals mean that few macaque fMRI studies specifically contrast levels of cognitive demand, so we sought to identify a macaque counterpart to the human MD system using fMRI connectivity in 35 rhesus macaques. Putative macaque MD regions, mapped from frontoparietal MD regions defined in humans, were found to be functionally connected under anesthesia. To further refine these regions, an iterative process was used to maximize their connectivity cross-validated across animals. Finally, whole-brain connectivity analyses identified voxels that were robustly connected to MD regions, revealing seven clusters across frontoparietal and insular cortex comparable to human MD regions and one unexpected cluster in the lateral fissure. The proposed macaque MD regions can be used to guide future electrophysiological investigation of MD neural coding and in task-based fMRI to test predictions of similar functional properties to human MD cortex.
SIGNIFICANCE STATEMENT In humans, a frontoparietal “multiple-demand” (MD) brain network is recruited during a wide range of cognitively demanding tasks. Because this suggests a fundamental function, one might expect a similar network to exist in nonhuman primates, but this remains controversial. Here, we sought to identify a macaque counterpart to the human MD system using fMRI connectivity. Putative macaque MD regions were functionally connected under anesthesia and were further refined by iterative optimization. The result is a network including lateral frontal, dorsomedial frontal, and insular and inferior parietal regions closely similar to the human counterpart. The proposed macaque MD regions can be useful in guiding electrophysiological recordings or in task-based fMRI to test predictions of similar functional properties to human MD cortex.
doi:10.1523/JNEUROSCI.0810-16.2016
PMCID: PMC4987434  PMID: 27535906
connectivity; fMRI; frontoparietal; macaque; multiple demand; resting state
5.  Spontaneous and tetracosactide‐induced anti‐ACTH antibodies in man 
Clinical Endocrinology  2015;84(4):489-495.
Summary
Context
During a clinical trial of regular tetracosactide depot injections, four of 13 patients with autoimmune Addison's disease (AAD) developed adverse reactions immediately following tetracosactide injections. We wished to investigate whether these adverse effects could be due to the production of circulating antitetracosactide (ACTH1–24) antibodies.
Design
Anti‐ACTH binding activity was investigated using immunoblotting and ELISA on sera from participants in the trial (n = 13; baseline and after tetracosactide exposure), 131 unrelated patients with AAD, 92 patients with Graves’ disease (GD), 15 patients with isolated ACTH deficiency and 102 controls. Immunohistochemistry of human pituitary tissue sections was also performed using pooled sera.
Results
Bands at approximately 4 and 6 kDa, corresponding to ACTH1–24 and full‐length ACTH1–39, respectively, were found in 10 of 13 (77%) of sera from trial patients exposed to tetracosactide, including all those who had an adverse reaction. This is in contrast with healthy control sera, which showed no binding. The same 10 subjects also showed high levels of binding to tetracosactide by ELISA, along with 21% of patients with AAD, 14% of patients with GD (both P < 0·001 compared to controls) and 1 isolated ACTH deficiency patient (7% of 15). These sera also recognized native ACTH in human pituitary sections.
Conclusion
Our study demonstrates that repeated administration of depot tetracosactide can lead to anti‐ACTH1–24 autoreactivity. In addition, a significant number of patients with AAD and GD also had similar, spontaneous, anti‐ACTH reactivity. The presence of these antibodies could mediate some of the adverse effects or explain the well‐described phenomenon of resistance to chronic ACTH therapy.
doi:10.1111/cen.12795
PMCID: PMC4949547  PMID: 25880719
6.  Critical role for the mediodorsal thalamus in permitting rapid reward-guided updating in stochastic reward environments 
eLife  null;5:e13588.
Adaptive decision-making uses information gained when exploring alternative options to decide whether to update the current choice strategy. Magnocellular mediodorsal thalamus (MDmc) supports adaptive decision-making, but its causal contribution is not well understood. Monkeys with excitotoxic MDmc damage were tested on probabilistic three-choice decision-making tasks. They could learn and track the changing values in object-reward associations, but they were severely impaired at updating choices after reversals in reward contingencies or when there were multiple options associated with reward. These deficits were not caused by perseveration or insensitivity to negative feedback though. Instead, monkeys with MDmc lesions exhibited an inability to use reward to promote choice repetition after switching to an alternative option due to a diminished influence of recent past choices and the last outcome to guide future behavior. Together, these data suggest MDmc allows for the rapid discovery and persistence with rewarding options, particularly in uncertain or changing environments.
DOI: http://dx.doi.org/10.7554/eLife.13588.001
eLife digest
A small structure deep inside the brain, called the mediodorsal thalamus, is a critical part of a brain network that is important for learning new information and making decisions. However, the exact role of this brain area is still not understood, and there is little evidence showing that this area is actually needed to make the best choices.
To explore the role of this area further, Chakraborty et al. trained macaque monkeys to choose between three colorful objects displayed on a touchscreen that was controlled by a computer. Some of their choices resulted in the monkeys getting a tasty food pellet as a reward. However the probability of receiving a reward changed during testing, and in some cases, reversed, meaning that the highest rewarded object was no longer rewarded when chosen and vice versa. While at first the monkeys did not know which choice was the right one, they quickly learned and changed their choices during the test according to which option resulted in them receiving the most reward.
Next, the mediodorsal thalamus in each monkey was damaged and the tests were repeated. Previous research had suggested that such damage might result in animals repeatedly choosing the same option, even though it is clearly the wrong choice. However, Chakraborty et al. showed that it is not as simple as that. Instead monkeys with damage to the mediodorsal thalamus could make different choices but they struggled to use information from their most recent choices to best guide their future behavior. Specifically, the pattern of the monkeys’ choices suggests that the mediodorsal thalamus helps to quickly link recent choices that resulted in a reward in order to allow an individual to choose the best option as their next choice.
Further studies are now needed to understand the messages that are relayed between the mediodorsal thalamus and interconnected areas during this rapid linking of recent choices, rewards and upcoming decisions. This will help reveal how these brain areas support normal thought processes and how these processes might be altered in mental health disorders involving learning information and making decisions.
DOI: http://dx.doi.org/10.7554/eLife.13588.002
doi:10.7554/eLife.13588
PMCID: PMC4887209  PMID: 27136677
decision-making; object-reward association; thalamus; reward guided learning; reversals; explore-exploit; Rhesus Macaque
7.  High frequency of cytolytic 21-Hydroxylase specific CD8+ T cells in autoimmune Addison’s disease patients1 
The mechanisms behind the destruction of the adrenal glands in autoimmune Addison’s disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in over 90% of patients, but these autoantibodies are not thought to mediate the disease. Here we demonstrate highly frequent 21-hydroxylase specific T cells detectable in 20 patients with Addison’s disease. Using overlapping 18aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8+ and CD4+ T cell responses in a large proportion of Addison’s patients both ex-vivo and after in-vitro culture of peripheral blood lymphocytes up to 20 years after diagnosis. In a large proportion of patients, CD8+ 21-hydroxylase specific T cells and CD4+ 21-hydroxylase specific T cells were very abundant and detectable in ex-vivo assays. HLA class-I tetramer-guided isolation of 21-hydroxylase specific CD8+ T cells showed their ability to lyse 21-hydroxylase positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate strong cytotoxic T lymphocyte responses to 21-hydroxylase often occur in-vivo, and that reactive cytotoxic T lymphocytes have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.
doi:10.4049/jimmunol.1400056
PMCID: PMC4821366  PMID: 25063864
8.  Edema, Hyperpigmentation, Induration: 3 Skin Signs Heralding Danger in Patients on Maintenance Hemodialysis 
Medicine  2016;95(12):e3121.
Abstract
Skin changes are common in patients on dialysis. This study focused on putative associations of specific skin findings with comorbidities and mortality.
We performed a retrospective analysis of data from 508 patients on maintenance hemodialysis therapy in 7 centers in the German State of North Rhine Westphalia. Data had been collected by interview, from patient files, and from targeted physical examination in an earlier prospective study screening hemodialysis patients for the presence of nephrogenic systemic fibrosis. While on dialysis, patients’ extremities had been examined for any of the following: edematous skin at the lower extremities, hyperpigmentation, induration, and xerosis cutis. Our present data analyses focused on associated mortality and comorbidities.
Five hundred eight patients (median age 71 years, range 20.0–95.9; n = 292 men) had agreed to participate in the initial study: 48% (n = 243) were diabetics and 46% (n = 232) had been diagnosed with coronary heart disease. On examination, 86% of patients (n = 439) presented with at least 1 of the prespecified skin changes. Skin edema (n = 89; 18%), hyperpigmentation (n = 74; 15%), and induration (n = 9; 2%) were independently associated with increased mortality over 24 months (P < 0.002, P < 0.030, and P < 0.020, respectively).
In our study, prespecified skin changes indicated an increased mortality risk in patients on chronic hemodialysis. Routinely assessing the skin of dialysis patients represents a simple, reliable, and cost effective means of identifying those at greatest risk.
doi:10.1097/MD.0000000000003121
PMCID: PMC4998382  PMID: 27015187
9.  Retrosplenial Cortical Contributions to Anterograde and Retrograde Memory in the Monkey 
Cerebral Cortex (New York, NY)  2016;26(6):2905-2918.
Primate retrosplenial cortex (RSC) is important for memory but patient neuropathologies are diffuse so its key contributions to memory remain elusive. This study provides the first causal evidence that RSC in macaque monkeys is crucial for postoperative retention of preoperatively and postoperatively acquired memories. Preoperatively, monkeys learned 300 object-in-place scene discriminations across sessions. After RSC removal, one-trial postoperative retention tests revealed significant retrograde memory loss for these 300 discriminations relative to unoperated control monkeys. Less robust evidence was found for a deficit in anterograde memory (new postoperative learning) after RSC lesions as new learning to criterion measures failed to reveal any significant learning impairment. However, after achieving ≥90% learning criterion for the postoperatively presented novel 100 object-in-place scene discriminations, short-term retention (i.e., measured after 24 h delay) of this well-learnt set was impaired in the RSC monkeys relative to controls. A further experiment assessed rapid “within” session acquisition of novel object-in-place scene discriminations, again confirming that new learning per se was unimpaired by bilateral RSC removal. Primate RSC contributes critically to memory by supporting normal retention of information, even when this information does not involve an autobiographical component.
doi:10.1093/cercor/bhw054
PMCID: PMC4869821  PMID: 26946129
amnesia; cingulate cortex; learning; lesion; macaque; retention
10.  CTLA-4 as a genetic determinant in autoimmune Addison’s disease 
Genes and immunity  2015;16(6):430-436.
In common with several other autoimmune diseases, autoimmune Addison’s disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (OR=1.35 [CI 1.10-1.66], P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 [CI 1.13-1.66], P=0.002). A three marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 [CI 1.68-3.51], P= 0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.
doi:10.1038/gene.2015.27
PMCID: PMC4561510  PMID: 26204230
CTLA-4; Addison’s disease; autoimmunity
11.  Behavioral and cognitive changes after early postnatal lesions of the rat mediodorsal thalamus 
Behavioural Brain Research  2015;292:219-232.
Highlights
•Early insult of the mediodorsal thalamus (MD) disturbed cognitive behaviors.•Early MD damage decreased locomotor activity, and reduced social interactions.•Early insult of the MD disturbed postnatal maturation of affective behavior.•The MD is important for prefrontal cortex function during brain maturation.
Early insults to the thalamus result in functional and/or structural abnormalities in the cerebral cortex. However, differences in behavioral and cognitive changes after early insult are not well characterized. The present study assessed whether early postnatal damage to mediodorsal nucleus of the thalamus (MD), reciprocally interconnected with the prefrontal cortex, causes behavioral and cognitive alterations in young adult rats. Rat pups at postnatal day 4 received bilateral electrolytic lesion of MD, or a MD Sham lesion or were anesthetized controls; on recovery they were returned to their mothers until weaning. Seven weeks later, all rats were tested with the following behavioral and cognitive paradigms: T-maze test, open field test, actimetry, elevated plus maze test, social interactions test and passive avoidance test. Rats with bilateral MD damage presented with disrupted recognition memory, deficits in shifting response rules, significant hypoactivity, increased anxiety-like behavior, deficits in learning associations as well as decreased locomotor activity, and reduced social interactions compared to MD Sham lesion and anesthetized Control rats. The lesion also caused significant decreases in pyramidal cell density in three frontal cortex regions: medial infralimbic cortex, dorsolateral anterior cortex, and cingulate Cg1 cortex. The present findings suggest a functional role for MD in the postnatal maturation of affective behavior. Further some of the behavioral and cognitive alterations observed in these young adult rats after early MD lesion are reminiscent of those present in major psycho-affective disorders, such as schizophrenia in humans.
doi:10.1016/j.bbr.2015.06.017
PMCID: PMC4571833  PMID: 26079768
MD, mediodorsal nucleus of the thalamus; PFC, prefrontal cortex; ZT, Zeitgeber time; P4, postnatal day 4; AP, antero-posteriority; L, laterality; P, profoundness; US, unconditioned stimulus; CS, conditioned stimulus; R, Ratio; ATN, anterior thalamic nucleus; VTA, ventral tegmental area; SA, spontaneous activity; Lesion; Mediodorsal thalamus; Anxiety; Learning; Prefrontal cortex; Schizophrenia
13.  Microalbuminuria in non-diabetic patients with unstable angina/non ST-segment elevation myocardial infarction 
BMC Research Notes  2015;8:371.
Background
Microalbuminuria (MAU) is defined as an urinary albumin excretion rate between 20–200 mg/l or 30–300 mg/day. It is a surrogate marker for endothelial dysfunction and is independently associated with atherosclerotis in diabetic and in non-diabetic patients. We assessed the prevalence of MAU in non-diabetic patients who presented with UA/NSTEMI and the relation of MAU to the severity of coronary artery disease in patients at a cardiac care center in Iraq.
Methods
Seventy non-diabetic patients referred to the Iraqi Center for Heart Disease, Baghdad, between November 1st 2010 and June 1st 2011 with the diagnosis of UA/NSTEMI were included in this study. Physical examination, ECG and echocardiography were performed on all patients. TIMI (“Thrombolysis in Myocardial Infarction”) risk score was obtained. Urine samples were collected and sent for quantitative determination of MAU. All patients underwent diagnostic coronary angiography. Data are give as mean (quantitative and percent) ± SD.
Results
Fifty-three men (76 %) and 17 (24 %) women (mean age 56 ± 12 years) were investigated. Overall 37 (53 %) individuals presented with arterial hypertension and 41 (59 %) with a history of smoking. 58 patients (83 %) had ischemic ECG changes (defined as ST segment depression more than 1 mm from baseline, and/or T wave inversion), 52 (74 %) had echocardiographic findings indicative of ischemia (defined as segmental wall motion abnormalities). Twenty-one (30 %) patients tested positive for MAU. There was a significant correlation of echocardiographic signs of ischemia and MAU, (n = 20 (38 %), p < 0.01). There was a clear relationship between MAU and TIMI risk score. Additionally, MAU was more common in patients with multivessel coronary artery disease (CAD) (p < 0.001). There was no statistically significant correlation between MAU and mean age, sex, smoking, and blood pressure.
Conclusion
In this analysis of patients with UA/NSTEMI we found a strong correlation of microalbuminuria with echocardiographic changes and findings in coronary angiography.
doi:10.1186/s13104-015-1347-x
PMCID: PMC4567814  PMID: 26362770
Microalbuminuria; Acute coronary syndrome; Coronary artery disease
14.  Connectivity between the superior colliculus and the amygdala in humans and macaque monkeys: virtual dissection with probabilistic DTI tractography 
Journal of Neurophysiology  2015;114(3):1947-1962.
It has been suggested that some cortically blind patients can process the emotional valence of visual stimuli via a fast, subcortical pathway from the superior colliculus (SC) that reaches the amygdala via the pulvinar. We provide in vivo evidence for connectivity between the SC and the amygdala via the pulvinar in both humans and rhesus macaques. Probabilistic diffusion tensor imaging tractography revealed a streamlined path that passes dorsolaterally through the pulvinar before arcing rostrally to traverse above the temporal horn of the lateral ventricle and connect to the lateral amygdala. To obviate artifactual connectivity with crossing fibers of the stria terminalis, the stria was also dissected. The putative streamline between the SC and amygdala traverses above the temporal horn dorsal to the stria terminalis and is positioned medial to it in humans and lateral to it in monkeys. The topography of the streamline was examined in relation to lesion anatomy in five patients who had previously participated in behavioral experiments studying the processing of emotionally valenced visual stimuli. The pulvinar lesion interrupted the streamline in two patients who had exhibited contralesional processing deficits and spared the streamline in three patients who had no deficit. Although not definitive, this evidence supports the existence of a subcortical pathway linking the SC with the amygdala in primates. It also provides a necessary bridge between behavioral data obtained in future studies of neurological patients, and any forthcoming evidence from more invasive techniques, such as anatomical tracing studies and electrophysiological investigations only possible in nonhuman species.
doi:10.1152/jn.01016.2014
PMCID: PMC4579293  PMID: 26224780
threat; DTI tractography; superior colliculus; pulvinar; amygdala
15.  Isolated Skeletal Malformations in a Child With a Small Mosaic Ring Microduplication of 18 p11.21q11.2: Genotype–Phenotype Correlations 
We describe a developmentally normal Amish child who has a karyotype with 47 chromosomes, including a supernumerary ring-shaped chromosome 18 in each metaphase studied. The only phenotypic findings in the patient were hemivertebrae and rib anomalies. Further analysis of interphase cells revealed an additional, less frequent mosaic, apparently normal cell population. Genes in the triplicated region that possibly are contributing to her skeletal phenotype include GATA6, MC2R, MC5R, RBBP8, ESCO1, and ROCK1, among others. By studying such patients with abnormal genetic dosage, genotype–phenotype correlations can be used to refine gene function.
doi:10.1002/ajmg.a.33816
PMCID: PMC4467729  PMID: 21344631
trisomy 18; scoliosis; hemivertebrae; ring chromosome 18; Edwards syndrome
16.  Linkage Analysis in Autoimmune Addison’s Disease: NFATC1 as a Potential Novel Susceptibility Locus 
PLoS ONE  2015;10(6):e0123550.
Background
Autoimmune Addison’s disease (AAD) is a rare, highly heritable autoimmune endocrinopathy. It is possible that there may be some highly penetrant variants which confer disease susceptibility that have yet to be discovered.
Methods
DNA samples from 23 multiplex AAD pedigrees from the UK and Norway (50 cases, 67 controls) were genotyped on the Affymetrix SNP 6.0 array. Linkage analysis was performed using Merlin. EMMAX was used to carry out a genome-wide association analysis comparing the familial AAD cases to 2706 UK WTCCC controls. To explore some of the linkage findings further, a replication study was performed by genotyping 64 SNPs in two of the four linked regions (chromosomes 7 and 18), on the Sequenom iPlex platform in three European AAD case-control cohorts (1097 cases, 1117 controls). The data were analysed using a meta-analysis approach.
Results
In a parametric analysis, applying a rare dominant model, loci on chromosomes 7, 9 and 18 had LOD scores >2.8. In a non-parametric analysis, a locus corresponding to the HLA region on chromosome 6, known to be associated with AAD, had a LOD score >3.0. In the genome-wide association analysis, a SNP cluster on chromosome 2 and a pair of SNPs on chromosome 6 were associated with AAD (P <5x10-7). A meta-analysis of the replication study data demonstrated that three chromosome 18 SNPs were associated with AAD, including a non-synonymous variant in the NFATC1 gene.
Conclusion
This linkage study has implicated a number of novel chromosomal regions in the pathogenesis of AAD in multiplex AAD families and adds further support to the role of HLA in AAD. The genome-wide association analysis has also identified a region of interest on chromosome 2. A replication study has demonstrated that the NFATC1 gene is worthy of future investigation, however each of the regions identified require further, systematic analysis.
doi:10.1371/journal.pone.0123550
PMCID: PMC4456164  PMID: 26042420
17.  Evidence for Mediodorsal Thalamus and Prefrontal Cortex Interactions during Cognition in Macaques 
Cerebral Cortex (New York, NY)  2015;25(11):4519-4534.
It is proposed that mediodorsal thalamus contributes to cognition via interactions with prefrontal cortex. However, there is relatively little evidence detailing the interactions between mediodorsal thalamus and prefrontal cortex linked to cognition in primates. This study investigated these interactions during learning, memory, and decision-making tasks in rhesus monkeys using a disconnection lesion approach. Preoperatively, monkeys learned object-in-place scene discriminations embedded within colorful visual backgrounds. Unilateral neurotoxic lesions to magnocellular mediodorsal thalamus (MDmc) impaired the ability to learn new object-in-place scene discriminations. In contrast, unilateral ablations to ventrolateral and orbital prefrontal cortex (PFv+o) left learning intact. A second unilateral MDmc or PFv+o lesion in the contralateral hemisphere to the first operation, causing functional MDmc–PFv+o disconnection across hemispheres, further impaired learning object-in-place scene discriminations, although object discrimination learning remained intact. Adaptive decision-making after reward satiety devaluation was also reduced. These data highlight the functional importance of interactions between MDmc and PFv+o during learning object-in-place scene discriminations and adaptive decision-making but not object discrimination learning. Moreover, learning deficits observed after unilateral removal of MDmc but not PFv+o provide direct behavioral evidence of the MDmc role influencing more widespread regions of the frontal lobes in cognition.
doi:10.1093/cercor/bhv093
PMCID: PMC4816796  PMID: 25979086
amnesia; decision-making; dysfunction; learning; monkey; orbitofrontal cortex; prefrontal cortex
18.  Advances in Understanding Mechanisms of Thalamic Relays in Cognition and Behavior 
The Journal of Neuroscience  2014;34(46):15340-15346.
The main impetus for a mini-symposium on corticothalamic interrelationships was the recent number of studies highlighting the role of the thalamus in aspects of cognition beyond sensory processing. The thalamus contributes to a range of basic cognitive behaviors that include learning and memory, inhibitory control, decision-making, and the control of visual orienting responses. Its functions are deeply intertwined with those of the better studied cortex, although the principles governing its coordination with the cortex remain opaque, particularly in higher-level aspects of cognition. How should the thalamus be viewed in the context of the rest of the brain? Although its role extends well beyond relaying of sensory information from the periphery, the main function of many of its subdivisions does appear to be that of a relay station, transmitting neural signals primarily to the cerebral cortex from a number of brain areas. In cognition, its main contribution may thus be to coordinate signals between diverse regions of the telencephalon, including the neocortex, hippocampus, amygdala, and striatum. This central coordination is further subject to considerable extrinsic control, for example, inhibition from the basal ganglia, zona incerta, and pretectal regions, and chemical modulation from ascending neurotransmitter systems. What follows is a brief review on the role of the thalamus in aspects of cognition and behavior, focusing on a summary of the topics covered in a mini-symposium held at the Society for Neuroscience meeting, 2014.
doi:10.1523/JNEUROSCI.3289-14.2014
PMCID: PMC4228136  PMID: 25392501
19.  Demographic and Health Related Data of Users of a Mobile Application to Support Drug Adherence is Associated with Usage Duration and Intensity 
PLoS ONE  2015;10(1):e0116980.
Purpose
A wealth of mobile applications are designed to support users in their drug intake. When developing software for patients, it is important to understand the differences between individuals who have, who will or who might never adopt mobile interventions. This study analyzes demographic and health-related factors associated with real-life “longer usage” and the “usage-intensity per day” of the mobile application “Medication Plan”.
Methods
Between 2010-2012, the mobile application “Medication Plan” could be downloaded free of charge from the Apple-App-Store. It was aimed at supporting the regular and correct intake of medication. Demographic and health-related data were collected via an online questionnaire. This study analyzed captured data.
Results
App-related activities of 1799 users (1708 complete data sets) were recorded. 69% (1183/1708) applied “Medication Plan” for more than a day. 74% were male (872/1183), the median age 45 years. Variance analysis showed a significant effect of the users´ age with respect to duration of usage (p = 0.025). While the mean duration of use was only 23.3 days for users younger than 21 years, for older users, there was a substantial increase over all age cohorts up to users of 60 years and above (103.9 days). Sex and educational status had no effect. “Daily usage intensity” was directly associated with an increasing number of prescribed medications and increased from an average of 1.87 uses per day and 1 drug per day to on average 3.71 uses per day for users stating to be taking more than 7 different drugs a day (p<0.001). Demographic predictors (sex, age and educational attainment) did not affect usage intensity.
Conclusion
Users aged 60+ as well as those with complicated therapeutic drug regimens relied on the service we provided for more than three months on average. Mobile applications may be a promising approach to support the treatment of patients with chronic conditions.
doi:10.1371/journal.pone.0116980
PMCID: PMC4309600  PMID: 25629939
20.  A Neural Circuit Covarying with Social Hierarchy in Macaques 
PLoS Biology  2014;12(9):e1001940.
A neural circuit that covaries with social hierarchy A neuroimaging study reveals that individual variation in brain circuits in structures below the cerebral cortex of macaques is associated with experience at different ends of the social hierarchy.
Despite widespread interest in social dominance, little is known of its neural correlates in primates. We hypothesized that social status in primates might be related to individual variation in subcortical brain regions implicated in other aspects of social and emotional behavior in other mammals. To examine this possibility we used magnetic resonance imaging (MRI), which affords the taking of quantitative measurements noninvasively, both of brain structure and of brain function, across many regions simultaneously. We carried out a series of tests of structural and functional MRI (fMRI) data in 25 group-living macaques. First, a deformation-based morphometric (DBM) approach was used to show that gray matter in the amygdala, brainstem in the vicinity of the raphe nucleus, and reticular formation, hypothalamus, and septum/striatum of the left hemisphere was correlated with social status. Second, similar correlations were found in the same areas in the other hemisphere. Third, similar correlations were found in a second data set acquired several months later from a subset of the same animals. Fourth, the strength of coupling between fMRI-measured activity in the same areas was correlated with social status. The network of subcortical areas, however, had no relationship with the sizes of individuals' social networks, suggesting the areas had a simple and direct relationship with social status. By contrast a second circuit in cortex, comprising the midsuperior temporal sulcus and anterior and dorsal prefrontal cortex, covaried with both individuals' social statuses and the social network sizes they experienced. This cortical circuit may be linked to the social cognitive processes that are taxed by life in more complex social networks and that must also be used if an animal is to achieve a high social status.
Author Summary
Social status is an important feature of group life in many primates. Position in the dominance hierarchy influences access to food and mates and is correlated with both general and mental health. Discovering how the brain is organized with respect to individual social status is an important first step for understanding the neural mechanisms that might drive social status and mediate its consequences. We performed a neuroimaging study in non-human primates and our findings suggest that brain organization reflects at least two aspects of dominance. First, we identified neural circuits in brain regions that appear to have a relatively simple and direct relationship with social status—one circuit in which gray matter volume tended to be greater in socially dominant individuals and another in which gray matter volume was greater in those with a more subordinate social position. We also showed that the degree of connectivity within each circuit was associated with experiences at each end of the social hierarchy. Second, given that social status in male macaques depends not only on successful engagement in agonistic behavior but also on success in forming social bonds that promote coalitions, we explored regions where gray matter relates to both social status and social network size. This second neural circuit may mediate the way in which dominance is dependent on social bond formation, which is in turn dependent on social cognition.
doi:10.1371/journal.pbio.1001940
PMCID: PMC4151964  PMID: 25180883
21.  VENTILATORY PATTERN AND ENERGY EXPENDITURE ARE ALTERED IN CYSTIC FIBROSIS MICE 
Background
Altered ventilatory pattern and increased energy expenditure are facets of the complex cystic fibrosis (CF) phenotype. Whether these are inherent attributes of CF, secondary consequences of lung infection or other disease complications is not known.
Methods
Studies were performed in congenic C57BL/6J, F508del (Cftrtm1kth) and CF gut-corrected (F508del) mice. Ventilatory patterns were measured using whole-body plethysmography. Indirect calorimetry was used to determine oxygen consumption, carbon dioxide production and resting energy expenditure.
Results
CF mice (F508del and F508del gut-corrected) have a significantly faster respiratory rate and increased ventilatory pattern variability as compared to non-CF mice. F508del but not CF gut-corrected mice had significantly increased energy expenditure per gram body weight.
Conclusions
CF mice exhibit a faster, more variable ventilatory pattern. These changes were present in the absence of detectable infection or illness due to gastrointestinal obstruction. Increased resting energy expenditure does not completely account for these differences.
doi:10.1016/j.jcf.2012.11.008
PMCID: PMC3620718  PMID: 23290341
Cystic Fibrosis; Ventilatory Pattern; Energy Expenditure; Respiratory Rate
22.  Characterization of Tissue-Specific and Developmentally Regulated Alternative Splicing of Exon 64 in the COL5A1 Gene 
Connective tissue research  2011;53(3):267-276.
The COL5A1 gene, a member of the clade B fibrillar collagen gene family, was recently shown to contain two alternatively spliced exons (64A and 64B) that encode 23 amino acids in the carboxyl-terminal propeptide. The two are identical in length, very similar in sequence, and used in a mutually exclusive fashion because of the small intron that separates them. Each COL5A1 allele uses both exons, but a given transcript will contain only one of the two exons. The sequences in other species are highly conserved at the amino acid level. The expression profile of the two isoforms was determined from analysis of RNA levels in a panel of murine tissues. While both isoforms were found in all tissues studied, actively proliferating tissues (liver, lung) used isoform B more often, while a less mitotically-active tissue, brain, had a higher proportion of exon 64A. The high degree of conservation between the two exons is consistent with a regional genomic duplication. The presence of the two isoforms as far back as pufferfish (tetraodon) implies an important functional significance. The exact role determined by the two sequences is not known, but involvement in the determination of chain composition of mature type V collagen or regulation of cell activity are possible, given the differences in tissue distribution.
doi:10.3109/03008207.2011.636160
PMCID: PMC3999617  PMID: 22149965
Type V collagen; alternative splicing; tissue distribution; developmental profile
23.  Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts 
PLoS ONE  2014;9(3):e88991.
Background
Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.
Aim
To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.
Methods
A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.
Results
We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively.
Conclusions
Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
doi:10.1371/journal.pone.0088991
PMCID: PMC3948621  PMID: 24614117
24.  Molecular Mechanisms of Classical Ehlers-Danlos Syndrome 
Human mutation  2009;30(6):10.1002/humu.21000.
Classical Ehlers-Danlos syndrome (EDS) is a heritable disorder characterized by joint hypermobility, skin hyperextensibility, and abnormal wound healing. The majority of affected individuals have alterations in one of the two type V collagen genes, COL5A1 and COL5A2. The most common mechanism is COL5A1 haploinsufficiency due to instability of the transcript of one allele. In dermal fibroblasts from our population of 76 individuals with clinical features of classical EDS, there were 21 (29.5%) with decreased expression of one COL5A1 allele, consistent with published estimates of the frequency of null alleles. We identified the causative mutation in 9 of these cell strains (mutations for 7 others had been previously described), and found two nonsense mutations, five splice mutations, and two insertion/deletions. The same type of genomic change at splice sites can have different effects at the RNA level and the outcome could not be predicted from the primary genomic DNA alteration.
doi:10.1002/humu.21000
PMCID: PMC3827857  PMID: 19370768
classical Ehlers-Danlos syndrome; EDS; type V collagen; COL5A1; COL5A2; haploinsufficiency; G530S
25.  User Profiles of a Smartphone Application to Support Drug Adherence — Experiences from the iNephro Project 
PLoS ONE  2013;8(10):e78547.
Purpose
One of the key problems in the drug therapy of patients with chronic conditions is drug adherence. In 2010 the initiative iNephro was launched (www.inephro.de). A software to support regular and correct drug intake was developed for a smartphone platform (iOS). The study investigated whether and how smartphone users deployed such an application.
Methods
Together with cooperating partners the mobile application “Medikamentenplan” (“Medication Plan”) was developed. Users are able to keep and alter a list of their regular medication. A memory function supports regular intake. The application can be downloaded free of charge from the App Store™ by Apple™. After individual consent of users from December 2010 to April 2012 2042338 actions were recorded and analysed from the downloaded applications. Demographic data were collected from 2279 users with a questionnaire.
Results
Overall the application was used by 11688 smartphone users. 29% (3406/11688) used it at least once a week for at least four weeks. 27% (3209/11688) used the application for at least 84 days. 68% (1554/2279) of users surveyed were male, the stated age of all users was between 6–87 years (mean 44). 74% of individuals (1697) declared to be suffering from cardiovascular disease, 13% (292) had a previous history of transplantation, 9% (205) were suffering from cancer, 7% (168) reported an impaired renal function and 7% (161) suffered from diabetes mellitus. 69% (1568) of users were on <6 different medications, 9% (201) on 6 – 10 and 1% (26) on more than 10.
Conclusion
A new smartphone application, which supports drug adherence, was used regularly by chronically ill users with a wide range of diseases over a longer period of time. The majority of users so far were middle-aged and male.
doi:10.1371/journal.pone.0078547
PMCID: PMC3806829  PMID: 24194946

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