A resource of induced pluripotent stem cell (iPSC) lines including clinical, genomic, and cellular data from genetically isolated families with mood and psychotic disorders.

Genome-wide (GWAS) and copy number variant (CNV) association studies have reproducibly identified numerous risk alleles associated with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ), but biological characterization of these alleles lags gene discovery, owing to the inaccessibility of live human brain cells and inadequate animal models for human psychiatric conditions. Human-derived induced pluripotent stem cells (iPSCs) provide a renewable cellular reagent that can be differentiated into living, disease-relevant cells and 3D brain organoids carrying the full complement of genetic variants present in the donor germline. Experimental studies of iPSC-derived cells allow functional characterization of risk alleles, establishment of causal relationships between genes and neurobiology, and screening for novel therapeutics. Here we report the creation and availability of an iPSC resource comprising clinical, genomic, and cellular data obtained from genetically isolated families with BD and related conditions. Results from the first 324 study participants, 61 of whom have validated pluripotent clones, show enrichment of rare single nucleotide variants and CNVs overlapping many known risk genes and pathogenic CNVs. This growing iPSC resource is available to scientists pursuing functional genomic studies of BD and related conditions.

The neurobiology of insulin-like growth factor I: From neuroprotection to modulation of brain states.

After decades of research in the neurobiology of IGF-I, its role as a prototypical neurotrophic factor is undisputed. However, many of its actions in the adult brain indicate that this growth factor is not only involved in brain development or in the response to injury. Following a three-layer assessment of its role in the central nervous system, we consider that at the cellular level, IGF-I is indeed a bona fide neurotrophic factor, modulating along ontogeny the generation and function of all the major types of brain cells, contributing to sculpt brain architecture and adaptive responses to damage. At the circuit level, IGF-I modulates neuronal excitability and synaptic plasticity at multiple sites, whereas at the system level, IGF-I intervenes in energy allocation, proteostasis, circadian cycles, mood, and cognition. Local and peripheral sources of brain IGF-I input contribute to a spatially restricted, compartmentalized, and timed modulation of brain activity. To better define these variety of actions, we consider IGF-I a modulator of brain states. This definition aims to reconcile all aspects of IGF-I neurobiology, and may provide a new conceptual framework in the design of future research on the actions of this multitasking neuromodulator in the brain.

Muscarinic Receptors, from Synaptic Plasticity to its Role in Network Activity.

Acetylcholine acting via metabotropic receptors plays a key role in learning and memory by regulating synaptic plasticity and circuit activity. However, a recent overall view of the effects of muscarinic acetylcholine receptors (mAChRs) on excitatory and inhibitory long-term synaptic plasticity and on circuit activity is lacking. This review focusses on specific aspects of the regulation of synaptic plasticity and circuit activity by mAChRs in the hippocampus and cortex. Acetylcholine increases the excitability of pyramidal neurons, facilitating the generation of dendritic Ca2+-spikes, NMDA-spikes and action potential bursts which provide the main source of Ca2+ influx necessary to induce synaptic plasticity. The activation of mAChRs induced Ca2+ release from intracellular IP3-sensitive stores is a major player in the induction of a NMDA independent long-term potentiation (LTP) caused by an increased expression of AMPA receptors in hippocampal pyramidal neuron dendritic spines. In the neocortex, activation of mAChRs also induces a long-term enhancement of excitatory postsynaptic currents. In addition to effects on excitatory synapses, a single brief activation of mAChRs together with short repeated membrane depolarization can induce a long-term enhancement of GABA A type (GABAA) inhibition through an increased expression of GABAA receptors in hippocampal pyramidal neurons. By contrast, a long term depression of GABAA inhibition (iLTD) is induced by muscarinic receptor activation in the absence of postsynaptic depolarizations. This iLTD is caused by an endocannabinoid-mediated presynaptic inhibition that reduces the GABA release probability at the terminals of inhibitory interneurons. This bidirectional long-term plasticity of inhibition may dynamically regulate the excitatory/inhibitory balance depending on the quiescent or active state of the postsynaptic pyramidal neurons. Therefore, acetylcholine can induce varied effects on neuronal activity and circuit behavior that can enhance sensory detection and processing through the modification of circuit activity leading to learning, memory and behavior.

Sodium valproate rescues expression of TRANK1 in iPSC-derived neural cells that carry a genetic variant associated with serious mental illness.

Biological characterization of genetic variants identified in genome-wide association studies (GWAS) remains a substantial challenge. Here we used human-induced pluripotent stem cells (iPSC) and their neural derivatives to characterize common variants on chromosome 3p22 that have been associated by GWAS with major mental illnesses. IPSC-derived neural progenitor cells carrying the risk allele of the single nucleotide polymorphism (SNP), rs9834970, displayed lower baseline TRANK1 expression that was rescued by chronic treatment with therapeutic dosages of valproic acid (VPA). VPA had the greatest effects on TRANK1 expression in iPSC, NPC, and astrocytes. Although rs9834970 has no known function, we demonstrated that a nearby SNP, rs906482, strongly affects binding by the transcription factor, CTCF, and that the high-affinity allele usually occurs on haplotypes carrying the rs9834970 risk allele. Decreased expression of TRANK1 perturbed expression of many genes involved in neural development and differentiation. These findings have important implications for the pathophysiology of major mental illnesses and the development of novel therapeutics.

Rare variants in neuronal excitability genes influence risk for bipolar disorder.

We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.

[Leptospirosis: case-series report in a prison of the coast in Ecuador]. / Leptospirosis: serie de casos en un centro penitenciario de la costa de Ecuador.

We describe the cases of two patients with fever initially diagnosed as dengue and urinary tract infection. The patients were inmates of the same prison and were in contact with stagnant drinking water, which is considered to be the likely site of contamination, about 2 weeks before the onset of the symptoms during the carnival celebrations. The time between the hospital admission and suspected leptospirosis (and starting specific treatment) was four days for the patient in case 1 and two days for case 2; between admission and laboratory diagnostic confirmation was ten days for case 1 and four days for case 2. We conclude that Leptospirosis is not considered as an option in the initial differential diagnosis but only after ruling out other pathologies.

Leptospirosis: serie de casos en un centro penitenciario de la costa de Ecuador / Leptospirosis: case-series report in a prison of the coast in Ecuador

Se describe los casos de dos pacientes inicialmente diagnosticados como dengue e infección urinaria. Los pacientes eran personas privadas de la libertad en la misma prisión y estuvieron en contacto con agua dulce estancada aproximadamente dos semanas antes del inicio de los síntomas durante las fiestas del carnaval, siendo el sitio probable de la contaminación. El tiempo transcurrido entre el ingreso al hospital y la sospecha de leptospirosis (y el inicio del tratamiento) fue de cuatro días para el paciente del caso 1 y dos días para el caso 2; entre el ingreso y la confirmación diagnóstica por laboratorio fue de diez días para el caso 1 y cuatro días para el caso 2. Se concluye que la leptospirosis no se considera como una opción dentro del diagnóstico diferencial inicial sino luego de descartar otras patologías (AU)

We describe the cases of two patients with fever initially diagnosed as dengue and urinary tract infection. The patients were inmates of the same prison and were in contact with stagnant drinking water, which is considered to be the likely site of contamination, about 2 weeks before the onset of the symptoms during the carnival celebrations. The time between the hospital admission and suspected leptospirosis (and starting specific treatment) was four days for the patient in case 1 and two days for case 2; between admission and laboratory diagnostic confirmation was ten days for case 1 and four days for case 2. We conclude that Leptospirosis is not considered as an option in the initial differential diagnosis but only after ruling out other pathologies (AU)

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report.

OBJECTIVE: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. MATERIALS AND METHODS: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. RESULTS: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). CONCLUSIONS: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Study of hyperglycemia in non critically-ill patients receiving parenteral nutrition; incidence and risk factors / Estudio de hiperglicemia en pacientes no críticos tratados con nutrición parenteral; incidencia y factores de riesgo

Background: The objectives of our study on non-critically ill patients receiving parenteral nutrition (PN) are to assess the incidence of hyperglycemia, the risk factors associated to its development and its influence in patient's evolution. Methods: A multicentric prospective observational study was performed in 9 hospitals. Four multivariate studies were developed to study the temporal risk in the occurrence of hyperglycemia (endpoint), intensive care unit (ICU) admission, length of stay (LOS) and death. Demographics, nutrients, drugs and clinical variables were collected. Independent variables studied as a possible risk factors were: sex, diabetes mellitus 2, baseline glycemia, albuminemia, pancreatitis, surgery in the 7 days prior to the end point, infection, insulin/somatostatin/corticoids administration during the study, glomerular filtration rate (GFR), and difference in the amount of glucose administration between the endpoint and one day before. Results: 119 patients were enrolled in the study, 25 cases of hyperglycemia were detected. In the clinical factors associated with PN hyperglycemia, significant variables were: surgery in the 7 days before the end point, GFR, glucose load in the 24 hours previous to the end point insulin administration and somatostatine/octreotide (AU)

Antecedentes y objetivo: El estudio está dirigido a pacientes no críticos tratados con nutrición parenteral (NP) y tiene como objetivo evaluar la incidencia de hiperglucemia, los factores de riesgo asociados a su aparición y su influencia sobre su evolución clínica. Métodos: Estudio multicéntrico prospectivo y observacional en 9 hospitales. Se construyeron 4 modelos multivariantes para estudiar el riesgo de aparición de hiperglucemia (evento final), el ingreso en cuidados intensivos (UCI), el tiempo de hospitalización y muerte. Se recogieron variables demográficas, de nutrientes aportados, medicación y variables clínicas. La variables independientes estudiadas como posibles factores de riesgo fueron: sexo, diabetes mellitus tipo 2, glucemia basal, pancreatitis, cirugía en los 7 días previos al evento final, infección, administración durante el estudio de insulina/somatostatina/corticoides, nivel de filtración glomerular (GFR) y las diferencias entre el aporte de glucosa administrada entre el evento final y el día previo. Resultados: Se incluyeron 119 pacientes, de los cuales 25 presentaron hiperglucemia. Entre los factores clínicos asociados a la aparición de hiperglucemia, las variables significativas fueron: la cirugía en los 7 días previos al evento final, GFR, carga de glucosa en las 24 horas previas al evento final, administración de insulina y de somatostatina/octreotido. La hiperglucemia se asoció significativamente al ingreso en UCI y a la estancia hospitalaria. Conclusión: La administración de glucosa en pacientes no críticos en tratamiento con NP debería ser reevaluada con criterios restrictivos, especialmente en el postoperatorio inmediato, en insuficiencia renal y en pacientes tratados con análogos de la somatostatina. Debería tenerse en cuenta que los incrementos del aporte de glucosa se asocian a hiperglucemia, y esta se correlaciona con un incremento de la estancia hospitalaria y a una mayor frecuencia de ingresos en UCI (AU)

Study of hyperglycemia in non critically-ill patients receiving parenteral nutrition: incidence and risk factors.

BACKGROUND: The objectives of our study on non-critically ill patients receiving parenteral nutrition (PN) are to assess the incidence of hyperglycemia, the risk factors associated to its development and its influence in patient's evolution. METHODS: A multicentric prospective observational study was performed in 9 hospitals. Four multivariate studies were developed to study the temporal risk in the occurrence of hyperglycemia (endpoint), intensive care unit (ICU) admission, length of stay (LOS) and death. Demographics, nutrients, drugs and clinical variables were collected. Independent variables studied as a possible risk factors were: sex, diabetes mellitus 2, baseline glycemia, albuminemia, pancreatitis, surgery in the 7 days prior to the end point, infection, insulin/somatostatin/corticoids administration during the study, glomerular filtration rate (GFR), and difference in the amount of glucose administration between the endpoint and one day before. RESULTS: 119 patients were enrolled in the study, 25 cases of hyperglycemia were detected. In the clinical factors associated with PN hyperglycemia, significant variables were: surgery in the 7 days before the end point, GFR, glucose load in the 24 hours previous to the end point insulin administration and somatostatine/octreotide administration during the study. Hyperglycemia was significantly associated with ICU admission and increased LOS. CONCLUSIONS: Glucose administration in non-critically ill patients receiving PN should be reassessed downwards, especially in the immediate postsurgery, renal impairment and in patients treated with somatostatin analogues. It should be taken into account that an increase in glucose dose may lead to hyperglycemia in these patients and hyperglycemia correlates with longer hospital stay and increased frequency of ICU admissions.

Ablation of Mrds1/Ofcc1 induces hyper-γ-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice.

Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as "the Japan Mouse Clinic". No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia.

The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts.

Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1.

The major mood disorders, which include bipolar disorder and major depressive disorder (MDD), are considered heritable traits, although previous genetic association studies have had limited success in robustly identifying risk loci. We performed a meta-analysis of five case-control cohorts for major mood disorder, including over 13,600 individuals genotyped on high-density SNP arrays. We identified SNPs at 3p21.1 associated with major mood disorders (rs2251219, P = 3.63 x 10(-8); odds ratio = 0.87; 95% confidence interval, 0.83-0.92), with supportive evidence for association observed in two out of three independent replication cohorts. These results provide an example of a shared genetic susceptibility locus for bipolar disorder and MDD.

Analysis of a t(18;21)(p11.1;p11.1) translocation in a family with schizophrenia.

It is suggested that chromosome 18p11 is a susceptibility region for both bipolar disorder and schizophrenia. Aiming to identify susceptibility gene(s), we investigated a family whose members have either schizophrenia or schizophrenia-spectrum psychosis and carried a t(18;21)(p11.1;p11.1) translocation. Fluorescence in situ hybridization showed that the breakpoint on chromosome 21 was localized to a bacterial artificial chromosome (BAC) clone RP11-2503J9, which contained coding sequences for transmembrane phosphatase with tensin homology, although this gene was not disrupted. On chromosome 18p, the break point was narrowed to BAC clone RP11-527H14. In silico sequence analysis of this clone identified possible pseudo genes and gene fragments but no intact genes. RP11-527H14 also showed sites of cross hybridization, including 21p11.1. To test for a position effect on 18p11 sequences translocated to 21p11, we performed quantitative RT-PCR to measure the expression of the candidate gene C18orf1 in translocation carriers, but found no significant differences from controls in lymphoblastoid cells.

[Grounds for a multi-component programme for counselling families with children with attention deficit hyperactivity disorder]. / Fundamentación de un programa multicomponencialde asesoramiento a familias con hijos con trastornopor déficit de atención/hiperactividad.

AIM: To analyse the change of perspective in the approach used in counselling programmes for parents of children with attention deficit hyperactivity disorder (ADHD). DEVELOPMENT: Research focused on analysing the familial context of people with ADHD has shown that parents experience higher levels of tension and feelings of low degrees of competence. Furthermore, the stress that occurs in parenting is significantly related to the application of discipline techniques that are inefficient, too lenient or too strict. CONCLUSIONS: We present a parent counselling programme that was designed in accordance with the latest guidelines and includes procedures for managing stress and communicative skills, as well as behavioural modification training.

Fundamentación de un programa multicomponencial de asesoramiento a familias con hijos con trastorno por déficit de atención/hiperactividad / Grounds for a multi-component programme for counselling families with children with attention déficit hyperactivity disorder

Objetivo. Analizar el cambio de perspectiva en el planteamiento de los programas de asesoramiento a padres de niños con trastorno por déficit de atención/hiperactividad (TDAH). Desarrollo. Las investigaciones que se han focalizado en el análisis del contexto familiar de personas con TDAH han revelado que los padres experimentan niveles más altos de tensión y sentimientos de baja competencia. Además, el estrés en el ejercicio de la paternidad está significativamente relacionado con la aplicación de técnicas de disciplina ineficaces, demasiado permisivas o impositivas. Conclusiones. Se presenta un programa de asesoramiento a padres siguiendo las directrices más actuales, que incluye, además del entrenamiento en modificación de conducta, procedimientos para el manejo del estrés y de la habilidad de comunicación (AU)

Aim. To analyse the change of perspective in the approach used in counselling programmes for parents of children with attention deficit hyperactivity disorder (ADHD). Development. Research focused on analysing the familial context of people with ADHD has shown that parents experience higher levels of tension and feelings of low degrees of competence. Furthermore, the stress that occurs in parenting is significantly related to the application of discipline techniques that are inefficient, too lenient or too strict. Conclusions. We present a parent counselling programme that was designed in accordance with the latest guidelines and includes procedures for managing stress and communicative skills, as well as behavioural modification training (AU)

Association study between the Down syndrome cell adhesion molecule (DSCAM) gene and bipolar disorder.

OBJECTIVES: Defects of neurodevelopmental processes are suggested to underlie the pathogenesis of bipolar disorder. Down syndrome cell adhesion molecule (DSCAM), a member of neural immunoglobulin superfamily playing a diverse role for neural development, is mapped to chromosome 21q22, a linkage locus for bipolar disorder, and is, therefore, an interesting candidate for the disease. METHODS: We performed a variation screening of the gene and association studies in 22 multiplex bipolar pedigrees of Caucasian descent and 119 Japanese patients with bipolar disorder and 140 controls. Expression levels of DSCAM were also examined in postmortem brains from the Stanley Medical Research Institute. RESULTS: We found 27 single nucleotide polymorphisms in DSCAM. Possible associations of SNP DC141 (IVS27-15A>G; P=0.042) and DC142 (IVS29+328C>A; P=0.036) were observed in pedigree samples, and G allele of DC141 was correlated with increased expression levels of DSCAM (P=0.038) in postmortem brains. Possible association of DC136 (4749C>T), which is in the same haplotype block with DC141 and DC142, was detected in Japanese populations (P=0.049). CONCLUSIONS: These results suggest the possible contribution of DSCAM gene in bipolar disorder, and warrant further investigations.

SERT Ileu425Val in autism, Asperger syndrome and obsessive-compulsive disorder.

BACKGROUND: SERT I425V, an uncommon missense single nucleotide polymorphism producing a gain-of-function of the serotonin transporter (SERT), was originally found to segregate with a primarily obsessive-compulsive disorder (OCD) but complexly comorbid phenotype in two unrelated families. OBJECTIVE: As two individuals with SERT I425V and OCD also had Asperger syndrome (AS), an autism spectrum disorder, and as other rare SERT variants have recently shown significant associations with autism, we set out to extend our original OCD study by genotyping additional autism/AS and OCD samples. METHODS: Case-control association study of SERT I425V in 210 AS/autism probands and 215 controls, plus 335 OCD probands and their family members. RESULTS: SERT I425V was not found in any of the individuals with AS/autism, OCD alone or OCD comorbid with AS and other disorders, or in controls. This results in new estimates of SERT I425V having a 1.5% prevalence in 530 individuals with OCD from five unrelated families genotyped by us and by one other group and a 0.23% frequency in four control populations totaling 1300 individuals, yielding a continuing significant OCD-control difference (Fisher's exact test corrected for family coefficient of identity P=0.004, odds ratio=6.54). CONCLUSION: As several other uncommon, less well quantitated genetic variations occur with an OCD phenotype, including chromosomal anomalies and some other rare gene variants (SGCE, GCH1 and SLITRK1), a tentative conclusion is that OCD resembles other complex disorders in being etiologically heterogeneous and in having both highly penetrant familial subtypes associated with rare alleles or chromosomal anomalies, as well as having a more common, polygenetic form that may involve polymorphisms in such genes as BDNF, COMT, GRIN2beta, TPH2, HTR2A and SLC1A1.

Gene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: association with HMG2L1 and TOM1.

Genetic linkage studies in both bipolar affective disorder (BPAD) and schizophrenia have implicated overlapping regions of chromosome 22q. We previously reported that BPAD pedigrees containing multiple members with psychotic symptoms showed suggestive linkage to chromosome 22q12.3. Now we have tested 189 single nucleotide polymorphisms (SNPs) spanning a 3 Mb region around the linkage peak for association with BPAD in 305 families, unrelated cases, and controls. SNPs were selected in or near genes, resulting in coverage at a density of 1 SNP per 6.7 kb across the 22 annotated genes in the region. The strongest signal emerged from family-based association analysis of an 11-SNP, 54 kb haplotype straddling the gene HMG2L1 and part of TOM1. A 3-marker haplotype of SNPs within TOM1 was associated with BPAD (allele-wise P = 0.0011) and with psychotic BPAD (allele-wise P = 0.00049). As hypothesized, the mean odds ratio for the risk alleles across the region was 1.39 in the psychotic but only 0.96 in the non-psychotic subset. Genotype-wise analyses yielded similar results, but the psychotic/non-psychotic distinction was more pronounced with mean odds ratios of 1.91 versus 0.8. Permutation of genotype-wise results for rs2413338 in HMG2L1 showed an empirical P = 0.037 for the difference between subsets. HMG2L1 is a negative regulator of Wnt signaling, a pathway of interest in psychotic BPAD as it is activated by both mood stabilizer and anti-psychotic medications. Further work is needed to confirm these results and uncover the functional variation underlying the association signal.

Rapid and deep control of inflammation in rheumatoid arthritis with infliximab and its correlation with acute-phase reactants.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with predominant joint involvement and possible systemic compromise, which leads to a handicapped status and poor quality of life. An optimal approach to treat RA requires early and intensive intervention with close monitoring of treatment response. Tumor necrosis factor (TNF) blockers are recommended in cases of active RA after the unsuccessful use of effective disease-modifying antirheumatic drugs (DMARDs); even adding them to treatment or replacing these drugs. Anti-TNF therapies have been demonstrated to reduce significant joint damage and to relieve symptoms during a prolonged time (see Scott and Kingsley, 2006). The efficacy of infliximab in an open-label trial is summarized with respect to speed of onset of action, durability of response, and its correlation between clinical and laboratory parameters. Safety for long-term treatment is also summarized. We studied 105 RA patients with more than 3 years' history of disease during 24 months on i.v. infliximab (75 completed study). We evaluated ACR responses at base line, and at 1, 6, 12, 16, 52, 77, and 104 weeks. Morning stiffness, swollen and tender joints, HAQ, SF-36% (PCS/MCS), polymerase chain reaction (PCR), erythrosedimentation rate (ESR), transaminases, rheumatoid factor (RF) levels, hemogram, and adverse events profile were all assessed. The treatment offered rapid and sustained clinical improvements as revealed by ACR responses and marked changes in the parameters previously described. Important changes were made in functional status and acute-phase reactants. Finally, infliximab was considered well tolerated and did not affect the safety profile of this trial.