The Aryl Hydrocarbon Receptor, Epigenetics and the Aging Process.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor, classically associated with the regulation of xenobiotic metabolism in response to environmental toxins. In recent years, transgenic rodent models have implicated AhR in aging and longevity. Moreover, several AhR ligands, such as resveratrol and quercetin, are compounds proven to extend the lifespan of model organisms. In this paper, we first review AhR biology with a focus on aging and highlight several AhR ligands with potential anti-aging properties. We outline how AhR-driven expression of xenobiotic metabolism genes into old age may be a key mechanism through which moderate induction of AhR elicits positive benefits on longevity and healthspan. Furthermore, via integration of publicly available datasets, we show that liver-specific AhR target genes are enriched among genes subject to epigenetic aging. Changes to epigenetic states can profoundly affect transcription factor binding and are a hallmark of the aging process. We suggest that the interplay between AhR and epigenetic aging should be the subject of future research and outline several key gaps in the current literature. Finally, we recommend that a broad range of non-toxic AhR ligands should be investigated for their potential to promote healthspan and longevity.

The impact of domain knowledge on structured data collection and templated note design.

OBJECTIVE: The objective of this case report is to evaluate the importance of specialized domain knowledge when designing and using structured templated notes in a clinical environment. METHODS: To analyze the impact of specialization on structured note generation we compared notes generated for three scenarios: 1) We compared the templated history of present illness (HPI) for patients presenting with a dermatology concern to the dermatologist versus the emergency department. 2) We compared the evaluation of chest pain by ED physicians versus cardiologists. 3) Finally, we compared the data elements asked for in the evaluation of the gastrointestinal system between cardiologists and the liver transplant service (LTS). We used the SNOMED CT representation via BioPortal to evaluate specificity and grouping between data elements and specialized physician groups. RESULTS: We found few similarities in structured data elements designed by and for the specific physician groups. The distinctness represented both differences in granularity as well as fundamental differences in data elements requested. When compared to ED physicians, dermatologists had different and more granular elements while cardiologists requested much more granular data. Comparing cardiologists and LTS, there were differences in the data elements requested. CONCLUSION: This case study supports the importance of domain knowledge in EHR design and implementation. That different specialities should want and use different information is well supported by cognitive science literature. Despite this, it is rare for domain knowledge to be considered in EHR implementation. Physicians with correct domain knowledge should be involved in the design process of templated notes.

Behavioral metabolomics analysis identifies novel neurochemical signatures in methamphetamine sensitization.

Behavioral sensitization has been widely studied in animal models and is theorized to reflect neural modifications associated with human psychostimulant addiction. While the mesolimbic dopaminergic pathway is known to play a role, the neurochemical mechanisms underlying behavioral sensitization remain incompletely understood. In this study, we conducted the first metabolomics analysis to globally characterize neurochemical differences associated with behavioral sensitization. Methamphetamine (MA)-induced sensitization measures were generated by statistically modeling longitudinal activity data for eight inbred strains of mice. Subsequent to behavioral testing, nontargeted liquid and gas chromatography-mass spectrometry profiling was performed on 48 brain samples, yielding 301 metabolite levels per sample after quality control. Association testing between metabolite levels and three primary dimensions of behavioral sensitization (total distance, stereotypy and margin time) showed four robust, significant associations at a stringent metabolome-wide significance threshold (false discovery rate, FDR <0.05). Results implicated homocarnosine, a dipeptide of GABA and histidine, in total distance sensitization, GABA metabolite 4-guanidinobutanoate and pantothenate in stereotypy sensitization, and myo-inositol in margin time sensitization. Secondary analyses indicated that these associations were independent of concurrent MA levels and, with the exception of the myo-inositol association, suggest a mechanism whereby strain-based genetic variation produces specific baseline neurochemical differences that substantially influence the magnitude of MA-induced sensitization. These findings demonstrate the utility of mouse metabolomics for identifying novel biomarkers, and developing more comprehensive neurochemical models, of psychostimulant sensitization.

Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D.

Affecting about 1 in 12 Americans annually, depression is a leading cause of the global disease burden. While a range of effective antidepressants are now available, failure and relapse rates remain substantial, with intolerable side effect burden the most commonly cited reason for discontinuation. Thus, understanding individual differences in susceptibility to antidepressant therapy side effects will be essential to optimize depression treatment. Here we perform genome-wide association studies (GWAS) to identify genetic variation influencing susceptibility to citalopram-induced side effects. The analysis sample consisted of 1762 depression patients, successfully genotyped for 421K single-nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study. Outcomes included five indicators of citalopram side effects: general side effect burden, overall tolerability, sexual side effects, dizziness and vision/hearing side effects. Two SNPs met our genome-wide significance criterion (q<0.1), ensuring that, on average, only 10% of significant findings are false discoveries. In total, 12 additional SNPs demonstrated suggestive associations (q<0.5). The top finding was rs17135437, an intronic SNP within EMID2, mediating the effects of citalopram on vision/hearing side effects (P=3.27 × 10(-8), q=0.026). The second genome-wide significant finding, representing a haplotype spanning ∼30 kb and eight genotyped SNPs in a gene desert on chromosome 13, was associated with general side effect burden (P=3.22 × 10(-7), q=0.096). Suggestive findings were also found for SNPs at LAMA1, AOX2P, EGFLAM, FHIT and RTP2. Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antidepressant medications.

Genome-wide association study of antipsychotic-induced QTc interval prolongation.

QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic-induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug-specific genome-wide association studies (GWASs) with 492K single-nucleotide polymorphisms to search for genetic variation mediating antipsychotic-induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness study. Our candidate gene study suggests the involvement of NOS1AP and NUBPL (P-values=1.45 × 10(-05) and 2.66 × 10(-13), respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a Q-value <0.10 (P-value=1.54 × 10(-7), Q-value=0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds, including drugs, environmental toxins and endogenous metabolites, across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic-induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug-induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic-induced QT prolongation.

Pharmacogenomic study of side-effects for antidepressant treatment options in STAR*D.

BACKGROUND: Understanding individual differences in susceptibility to antidepressant therapy side-effects is essential to optimize the treatment of depression. METHOD: We performed genome-wide association studies (GWAS) to search for genetic variation affecting the susceptibility to side-effects. The analysis sample consisted of 1439 depression patients, successfully genotyped for 421K single nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Outcomes included four indicators of side-effects: general side-effect burden, sexual side-effects, dizziness and vision/hearing-related side-effects. Our criterion for genome-wide significance was a prespecified threshold ensuring that, on average, only 10% of the significant findings are false discoveries. RESULTS: Thirty-four SNPs satisfied this criterion. The top finding indicated that 10 SNPs in SACM1L mediated the effects of bupropion on sexual side-effects (p = 4.98 × 10(-7), q = 0.023). Suggestive findings were also found for SNPs in MAGI2, DTWD1, WDFY4 and CHL1. CONCLUSIONS: Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that could mediate adverse effects of antidepressant medication.

Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs.

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.

Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics.

Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel diagnostic tests to match individual schizophrenia patients to the most effective and safe medication. In this study, we use a genome-wide approach to detect genetic variation underlying individual differences in response to treatment with the antipsychotics olanzapine, quetiapine, risperidone, ziprasidone and perphenazine. Our sample consisted of 738 subjects with DSM-IV schizophrenia who took part in the Clinical Antipsychotic Trials of Intervention Effectiveness. Subjects were genotyped using the Affymetrix 500 K genotyping platform plus a custom 164 K chip to improve genome-wide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale. Our criterion for genome-wide significance was a prespecified threshold that ensures that, on an average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our prespecified threshold and involved a single-nucleotide polymorphism (SNP) in an intergenic region on chromosome 4p15. In addition, SNPs in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing Protein 1B (ANKS1B) and in the Contactin-Associated Protein-Like 5 gene (CNTNAP5), which mediated the effects of olanzapine and risperidone on Negative symptoms, were very close to our threshold for declaring significance. The most significant SNP in CNTNAP5 is nonsynonymous, giving rise to an amino-acid substitution. In addition to highlighting our top results, we provide all P-values for download as a resource for investigators with the requisite samples to carry out replication. This study demonstrates the potential of genome-wide association studies to discover novel genes that mediate the effects of antipsychotics, which could eventually help to tailor drug treatment to schizophrenic patients.

Adoption of electronic health records: a qualitative study of academic and private physicians and health administrators.

OBJECTIVE: Less than 20% of hospitals in the US have an electronic health record (EHR). In this qualitative study, we examine the perspectives of both academic and private physicians and administrators as stakeholders, and their alignment, to explore their perspectives on the use of technology in the clinical environment. METHODS: Focus groups were conducted with 74 participants who were asked a series of open-ended questions. Grounded theory was used to analyze the transcribed data and build convergent themes. The relevance and importance of themes was constructed by examining frequency, convergence, and intensity. A model was proposed that represents the interactions between themes. RESULTS: Six major themes emerged, which include the impact of EHR systems on workflow, patient care, communication, research/outcomes/billing, education/learning, and institutional culture. Academic and private physicians were confident of the future benefits of EHR systems, yet cautious about the current implementations of EHR, and its impact on interactions with other members of the healthcare team and with patients, and the amount of time necessary to use EHR's. Private physicians differed on education and were uneasy about the steep learning curve necessary for use of new systems. In contrast to physicians, university and hospital administrators are optimistic, and value the availability of data for use in reporting. CONCLUSION: The results of our study indicate that both private and academic physicians concur on the need for features that maintain and enhance the relationship with the patient and the healthcare team. Resistance to adoption is related to insufficient functionality and its potential negative impact on patient care. Integration of data collection into clinical workflows must consider the unexpected costs of data acquisition.

A region of 35 kb containing the trace amine associate receptor 6 (TAAR6) gene is associated with schizophrenia in the Irish study of high-density schizophrenia families.

The TAAR6 gene has been previously associated with schizophrenia in 192 pedigrees of European and African ancestry. To replicate these findings we performed an association study of TAAR6 in 265 pedigrees of the Irish Study of High-Density Schizophrenia Families (ISHDSF). Of the 24 genotyped single-nucleotide polymorphisms only rs12189813 and rs9389011 provided single-marker evidence for association (0.0094

Catechol-O-methyltransferase and the clinical features of psychosis.

A functional polymorphism (Val-158-Met) at the Catechol-O-methyltransferase (COMT) locus has been identified as a potential etiological factor in schizophrenia. Yet the association has not been convincingly replicated across independent samples. We hypothesized that phenotypic heterogeneity might be diluting the COMT effect. To clarify the putative association, we performed an exploratory analysis to test for association between COMT and five psychosis symptom scales. These were derived through factor analysis of the Operational Criteria Checklist for Psychiatric Illness. Our sample was the Irish Study of High Density Schizophrenia Families, a large collection consisting of 268 multiplex families. This sample has previously shown a small but significant effect of the COMT Val allele in conferring risk for schizophrenia. We tested for preferential transmission of COMT alleles from parent to affected offspring (n = 749) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression). Significant overtransmission of the Val allele was found for mania (P < 0.05) and depression (P = 0.01) scales. Examination of odds ratios (ORs) revealed a heterogeneous effect of COMT, whereby it had no effect on Negative Symptoms, but largest impact on Depression (OR = 1.4). These results suggest a modest affective vulnerability conferred by this allele in psychosis, but will require replication.

The dopamine D4 receptor and the hyperactivity phenotype: a developmental-epidemiological study.

Attention-deficit hyperactivity disorder (ADHD) affects 2-6% of school-age children and is a precursor of behavioural problems in adolescence and adulthood. Underlying the categorical definition of ADHD are the quantitative traits of activity, impulsivity, and inattention which vary continuously in the population. Both ADHD and quantitative measures of hyperactivity are heritable, and influenced by multiple genes of small effect. Several studies have reported an association between clinically defined ADHD and the seven-repeat allele of a 48-bp tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene (DRD4). We tested this association in a large, unselected birth cohort (n = 1037) using multiple measures of the hyperactivity phenotype taken at multiple assessment ages across 20 years. This longitudinal approach allowed us to ascertain whether or not DRD4 has a general effect on the diagnosed (n = 49) or continuously distributed hyperactivity phenotype, and related personality traits. We found no evidence to support this association.

The effectiveness of tonsillectomy in diagnosing lymphoproliferative disease in pediatric patients after liver transplantation.

OBJECTIVE: To determine the effectiveness of diagnosing forms of lymphoproliferative disease by performing tonsillectomy in pediatric patients who develop symptomatic or asymptomatic tonsillar hypertrophy during immunosuppressive therapy after liver transplantation. DESIGN: Retrospective chart and pathological review. SETTING: Urban tertiary referral children's hospital. MAIN OUTCOME MEASURES: The presence of a pathological stage of lymphoproliferative disease or Epstein-Barr virus (EBV) diagnosed using tonsillar specimens, resulting in a change in therapy. RESULTS: Of 275 pediatric patients who underwent liver transplantation, 13 had tonsillectomy performed with histopathological review of the tonsillar specimens. The specimens from 5 patients (39%) demonstrated pathological changes thought to be consistent with EBV-related changes or a form of lymphoproliferative disease. Histological changes ranged from tonsillar hyperplasia associated with EBV infection to large cell lymphoma. Immunosuppressive therapy was reduced or discontinued, and antiviral therapy was initiated. CONCLUSION: Children who have undergone liver transplantation and develop tonsillar hypertrophy should undergo a diagnostic tonsillectomy, regardless of the clinical presentation, to rule out a form of posttransplant lymphoproliferative disease. Arch Otolaryngol Head Neck Surg. 2000;126:1444-1447

Allele association studies with SSR and SNP markers at known physical distances within a 1 Mb region embracing the ALDH2 locus in the Japanese, demonstrates linkage disequilibrium extending up to 400 kb.

There has been considerable recent debate concerning the distances over which levels of allelic association useful for genomic quantitative trait locus (QTL) scans can be detected. We have examined simple sequence repeat (SSR) polymorphisms and two single nucleotide polymorphisms (SNPs) in the region flanking the aldehyde dehydrogenase 2 locus, ALDH2, in populations of Japanese alcoholics and controls. These groups differ significantly in the allele frequencies for the functional SNP in exon XII of this gene located on chromosome 12. The results obtained with SSR markers complement recent investigations with SNPs over similar distances at the TCR alpha/delta locus. Significant allelic association with this marker could be detected for SSRs over distances up to 400 kb and over 37 kb for the SNP thereby extending the distance over which LD at this locus could be detected by an order of magnitude. Furthermore, as a proof of principle, we show that comparisons of allele frequency differences for the SSR markers in the case (alcoholics) and control populations would have detected the ALDH2 marker as a putative QTL. Extending the tests to include alleles at two or three flanking loci suggests that the power to detect QTLs through association can be enhanced significantly.

Chloroma of the masseteric muscle.

Chloroma (leukemic infiltrate or granulocytic sarcoma) is a localized extramedullary mass of immature granulocytic cells. They are uncommon tumors that usually occur in patients with leukemia, mostly of the myeloid type. Involvement in the head and neck region is rare. Granulocytic sarcomas of the face, maxilla, paranasal sinuses, temporal bone, and pharynx have all been documented in the past. We present the first reported case of a granulocytic sarcoma involving the masseteric muscle in an 8-month-old white male diagnosed with acute myeloid leukemia (AML). The lesion resolved with chemotherapy but the patient subsequently died. This case reaffirms the importance of including chloroma in the differential diagnosis of lesions in patients with AML and the prognostic value they hold.

Lingual tonsillectomy for refractory paroxysmal cough.

Historically, the lingual tonsils are the most neglected members of Waldeyer's ring. They are often overlooked even in a thorough head and neck exam because of their anatomic location and the ambiguous constellation of symptoms which they produce when they are diseased or enlarged. The lingual tonsils have been reported to be associated with a variety of upper aerodigestive tract symptoms including odynophagia, dysphagia, otalgia, globus, halitosis, chronic cough, and dyspnea. Many patients with lingual tonsillar pathology may undergo extensive work-up for some of these non-specific upper airway complaints by their primary physician before referral to an otolaryngologist. Consequently, the diagnosis of lingual tonsillar disease requires a high index of suspicion and a thorough physical exam including evaluation of the tongue base and hypophaynx with indirect mirror or fiberoptic exam. In order to draw attention to this frequently unrecognized entity, we present a case report of a child with chronic cough resulting from lingual tonsillar hypertrophy.

Resistant bacteria in the adenoids: a preliminary report.

OBJECTIVE: To determine the incidence of resistant bacteria in adenoid cultures from children with and without middle ear disease and rhinosinusitis symptoms. DESIGN: Children meeting the requirement for tympanostomy tube placement underwent an adjuvant adenoidectomy for symptoms of adenoid hypertrophy or recurrent rhinosinusitis. Adenoid tissue and coexisting middle ear fluid, if present, were cultured. SETTING: Tertiary referral children's hospital with community-based satellite clinics. PATIENTS: Forty-six patients ranging in age from 1 to 11 years (68% <3 years) with recurrent or persistent otitis media and symptoms of adenoid hypertrophy or rhinosinusitis (study patients) underwent tympanostomy tube placement and adenoidectomy with culture of the adenoids and middle ear effusions. Eighteen patients with adenoid hypertrophy without ear disease or rhinosinusitis were used as controls. INTERVENTIONS: Tympanostomy tube placement and adenoidectomy. MAIN OUTCOME MEASURES: Presence or absence of resistant bacteria. RESULTS: Resistant bacteria were found in cultures of the adenoids in 56% (26/46) of the study group compared with 22% (4/18) of the control patients (P<.02). Also, strains of Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis were found in cultures from 78% (36/ 46) of the study group, compared with 44% (8/18) of those from the control group (P<.01). Resistant isolates were found in 65% (23/35) of the S. pneumoniae, 37% (18/49) of the H. influenzae, and 100% (19/19) of the M. catarrhalis cultures from the adenoids or middle ear spaces. CONCLUSION: Resistant bacteria are present in significant amounts in the adenoids of children with middle ear disease and rhinosinusitis symptoms compared with patients without those diseases or symptoms.

Chasing behaviour genes into the next millennium.

Both linkage and association strategies are appropriate for the characterization of genes implicated in human behavioural dimensions and disorders. For the foreseeable future, association studies involving whole-genome scanning will combine strategies using both single-nucleotide and simple-sequence-repeat polymorphisms.