Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites.

Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort.

Bupropion sustained release for panic disorder.

Despite anecdotal reports suggesting that bupropion may be effective for panic disorder, both clinical lore and the results of one small controlled study suggest otherwise. There remains a paucity of systematic prospective data addressing this issue. Twenty outpatients meeting criteria for panic disorder with or without agoraphobia were entered in an 8 week, two center open-label flexible dose trial of bupropion SR.

Citalopram for social anxiety disorder: an open-label pilot study in refractory and nonrefractory patients.

There is limited systematic data assessing alternate pharmacotherapy of social anxiety disorder in patients failing to tolerate or fully respond to initial treatment; no data specifically address the efficacy of citalopram in this scenario. We present a prospective open-label trial of citalopram in 10 patients with generalized social anxiety disorder, 6 of 10 of whom had not responded to or not tolerated a prior treatment intervention for the disorder. Citalopram, at a mean dose of 55 mg (SD+/-12.

Ottawa Hospital Patient Safety Study: incidence and timing of adverse events in patients admitted to a Canadian teaching hospital.

Background: Adverse events are poor patient outcomes that are due to medical care. Studies of hospital patients have demonstrated that adverse events are common, but few data describe the timing of them in relation to hospital admission. We evaluated characteristics of adverse events affecting patients admitted to a Canadian teaching hospital, paying particular attention to timing.

A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population.

Objective: In the era of postgenomic research, linkage- and association-based strategies are beginning to reveal novel complex disease genes. Using such an approach, a functional haplotype of the peptidylarginine deiminase 4 gene (PADI4) has recently been identified as a gene conferring susceptibility to rheumatoid arthritis (RA) in a Japanese population. In the present study, we investigated the association of single-nucleotide polymorphisms (SNPs) in the PADI4 gene with RA in a UK population.

Retrospective application of the NEXUS low-risk criteria for cervical spine radiography in Canadian emergency departments.

Study Objective: We evaluate the accuracy, reliability, and potential impact of the National Emergency X-Radiography Utilization Study (NEXUS) low-risk criteria for cervical spine radiography, when applied in Canadian emergency departments (EDs).

Methods: The Canadian C-Spine Rule derivation study was a prospective cohort study conducted in 10 Canadian EDs that recruited alert and stable adult trauma patients. Physicians completed a 20-item data form for each patient and performed interobserver assessments when feasible.

Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus.

Objective: Rheumatoid arthritis (RA) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope.

Haplotype analysis in simplex families and novel analytic approaches in a case-control cohort reveal no evidence of association of the CTLA-4 gene with rheumatoid arthritis.

Objective: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T cells and is, therefore, a strong candidate susceptibility gene for T cell-mediated autoimmune diseases. The association of CTLA-4 single-nucleotide polymorphisms (SNPs) with rheumatoid arthritis (RA) has been investigated previously, with inconsistent results. Recently, SNPs mapping to the gene (and not previously investigated in RA) have been associated with both type 1 diabetes mellitus and Graves' disease.

Investigation of susceptibility loci identified in the UK rheumatoid arthritis whole-genome scan in a further series of 217 UK affected sibling pairs.

Objective: A previous whole-genome scan (WGS) of 182 UK rheumatoid arthritis (RA) affected sibling pair (ASP) families suggested linkage to HLA and 11 other chromosome regions. Replication of such findings in an independent cohort can help to distinguish true linkages from false-positive linkages. Since RA is a heterogeneous disease, some loci may be linked only in subsets of patients.

Polymorphisms in the mannose binding lectin (MBL) gene are not associated with radiographic erosions in rheumatoid or inflammatory polyarthritis.

Objective: To investigate the association between the mannose binding lectin gene (MBL) promoter and structural single nucleotide polymorphisms (SNP) with development of erosions in a primary care inception cohort of patients with inflammatory polyarthritis (IP).

Methods: DNA was available from 438 patients with IP and radiographic data were available for all patients at 5 years. Four SNP [MBL-550*C/G (H/L), MBL-221*G/C (Y/X), MBL codon 52*C/T, and MBL codon 54*G/A] mapping to the MBL gene were genotyped using primer extension techniques.

Linkage analysis of cross-sectional and longitudinally derived phenotypic measures to identify loci influencing blood pressure.

Background: The design of appropriate strategies to analyze and interpret linkage results for complex human diseases constitutes a challenge. Parameters such as power, definition of phenotype, and replicability have to be taken into account in order to reach meaningful conclusions. Incorporating data on repeated phenotypic measures may increase the power to detect linkage but requires sophisticated analysis methods.

Polymorphisms in the tumour necrosis factor gene are not associated with severity of inflammatory polyarthritis.

Background: Tumour necrosis factor alpha (TNFalpha) is a powerful inflammatory mediator in rheumatoid and other types of inflammatory arthritis. Polymorphisms within the TNFalpha gene have previously been investigated to determine their role in the aetiopathogenesis of rheumatoid arthritis (RA), but it is unclear whether reported associations are with susceptibility to, or severity of, disease.

Objective: To examine the association between both individual TNFalpha single nucleotide polymorphisms (SNPs) and haplotypes with the development and severity of erosions by 5 years in patients with inflammatory polyarthritis (IP).

Treatment of antidepressant-induced sexual dysfunction.

This article reviews the prevalence of antidepressant-induced sexual dysfunction and the strategies available for managing sexual adverse events. A high incidence of sexual dysfunction has been observed in patients treated with antidepressants. In particular, it has been reported in more than half of the patients treated with selective serotonin reuptake inhibitors.

The Canadian C-spine rule versus the NEXUS low-risk criteria in patients with trauma.

Background: The Canadian C-Spine (cervical-spine) Rule (CCR) and the National Emergency X-Radiography Utilization Study (NEXUS) Low-Risk Criteria (NLC) are decision rules to guide the use of cervical-spine radiography in patients with trauma. It is unclear how the two decision rules compare in terms of clinical performance.

Methods: We conducted a prospective cohort study in nine Canadian emergency departments comparing the CCR and NLC as applied to alert patients with trauma who were in stable condition.

Association of PADI4 and rheumatoid arthritis: a successful multidisciplinary approach.

The identification of functionally relevant polymorphisms of peptidylarginine deiminase 4, an enzyme that catalyzes the post-translational citrullination of proteins, as a rheumatoid arthritis gene is one of the most convincing success stories of complex disease gene mapping to date. In addition to an extensive single nucleotide polymorphism-based association study in a Japanese cohort, a range of techniques have been used to validate this finding.

Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis.

The aim of the study was to investigate whether polymorphisms of macrophage migration inhibitory factor (MIF) determine susceptibility to or severity of inflammatory polyarthritis (IP). Genotypes for a single-nucleotide polymorphism (MIF-173*G/C) and a tetranucleotide (CATT)(n) repeat mapping to the promoter region of the MIF gene were compared between UK Caucasian IP cases (n=438) and controls (n=343). Both polymorphisms were also investigated for association with features of disease activity and severity at baseline and by 5 years.

Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder.

Despite the widespread application of combined selective serotonin reuptake inhibitors (SSRI) and benzodiazepine treatment for panic disorder, there has been relatively little systematic assessment of the safety and efficacy of this therapeutic strategy. Although the limited number of studies to date suggest a more rapid onset of benefit with combined treatment, this study is the first to address the critical question of whether continued combined treatment confers superior efficacy. This study is a randomized, double-blind, three-arm study in patients with panic disorder (n = 60), comparing the efficacy and safety of paroxetine and placebo (PP), paroxetine coadministered with clonazepam followed by a tapered benzodiazepine discontinuation phase (PC-D), and ongoing combination treatment (PC-M).

No evidence of association between HLA-DRB1 and attention deficit hyperactivity disorder.

Objectives: There has been a recent resurgence in interest in the role of autoimmunity in childhood neuropsychiatric disorders. Significant association between HLA-DRB1 and attention deficit hyperactivity disorder (ADHD) in a case-control study of 31 subjects has been reported but there have been no other published studies following up these results. We attempted to replicate these findings.

The Canadian C-spine rule performs better than unstructured physician judgment.

Study Objectives: We compare the predictive accuracy of emergency physicians' unstructured clinical judgment to the Canadian C-Spine rule.

Methods: This prospective multicenter cohort study was conducted at 10 Canadian urban academic emergency departments. Included in the study were alert, stable, adult patients with a Glasgow Coma Scale score of 15 and trauma to the head or neck.

A pilot, open study of sertraline in outpatients with treatment-resistant depression (TRD) or with a history of TRD who responded but later relapsed.

While most depressed patients are prescribed a selective serotonin reuptake inhibitor (SSRI) as an initial treatment, the use of SSRIs as a second or third-line treatment for depression is not as prevalent. This trial assessed the efficacy of sertraline for patients with treatment-resistant depression (TRD) or patients with a history of TRD who responded but later relapsed. Twelve patients with TRD who had not responded to a number of antidepressant trials (n=7), or had responded but subsequently suffered a relapse (n=5), were enrolled in an 8-week, open trial of sertraline.

No evidence of association of two 5HT transporter gene polymorphisms and attention deficit hyperactivity disorder.

Objectives: Three studies to date have found evidence (or a trend for evidence) of linkage and association between the long allele of the 44 base pair repeat insertion/deletion 5-HTT functional polymorphism (5-HTTLPR) and attention deficit hyperactivity disorder (ADHD). In an attempt to replicate these findings, we examined this polymorphism and a variable number tandem repeat in the second intron of 5-HTT for association with ADHD.

Methods: One hundred and fifty children who met diagnostic criteria for ADHD and their parents (where available) were genotyped for these polymorphisms.