Janice Husted

Clinical features of 78 adults with 22q11 Deletion Syndrome.

22q11 Deletion Syndrome (22q11DS) is a common microdeletion syndrome with multisystem expression. Phenotypic features vary with age, ascertainment, and assessment. We systematically assessed 78 adults (36 M, 42 F; mean age 31.5, SD 10.5 years) with a 22q11.2 deletion ascertained through an adult congenital cardiac clinic (n = 35), psychiatric‐related sources (n = 39), or as affected parents of subjects (n = 4). We recorded the lifetime prevalence of features requiring attention, with 95% confidence intervals (CI) not overlapping zero. Subtle learning difficulties, hypernasality and facial gestalt were not included. We investigated ascertainment effects using non‐overlapping subgroups ascertained with tetralogy of Fallot (n = 31) or schizophrenia (n = 31). Forty‐three features met inclusion criteria and were present in 5% or more patients, including several of later onset (e.g., hypothyroidism, cholelithiasis). Number of features per patient (median 9, range 3–22) correlated with hospitalizations (P = 0.0002) and, when congenital features were excluded, with age (P = 0.02). Adjusting for ascertainment, 25.8% (95% CI, 9.5–42.1%) of patients had cardiac anomalies and 22.6% (95% CI, 7.0–38.2%) had schizophrenia. Ascertainment subgroups were otherwise similar in median number and prevalence of features. Non‐characteristic features are common in 22q11DS. Adjusting for ascertainment effects is important. Many treatable conditions may be anticipated and features may accumulate over time. The results have implications for clinical assessment and management, genetic counseling and research into pathophysiological mechanisms.

Mortality studies in psoriatic arthritis: results from a single outpatient center. II. Prognostic indicators for death.

OBJECTIVE To investigate prognostic factors associated with mortality in patients with psoriatic arthritis (PsA). METHODS Patients followed up at the Toronto PsA Clinic between 1978 and 1994 were included. Patients were reviewed at initial clinic entry and at 6-month intervals using a standard protocol. Data on deaths were collected in a prospective manner, and death certificates were used to identify the primary and antecedent cause(s) of death. All death information was recorded in the clinics computerized database. Only factors that represented standard clinical measures of disease activity and progression were studied. The relationship between potential prognostic factors recorded at the time of the first clinic visit and the mortality rate was determined using the Cox relative risk regression model. RESULTS There were 428 patients (234 men and 194 women), of whom 68% were known to be alive on September 1, 1994, 20% were lost to followup but assumed to be alive, and 12% had died. Multivariate analysis revealed that an erythrocyte sedimentation rate (ESR) > 15 mm/hour, medications used prior to initial clinic visit, radiologic damage, and the absence of nail lesions were associated with an increased overall mortality rate. There is some suggestion that prior medication use was least important for deaths associated with the circulatory system, while radiologic damage was particularly important for such deaths. A marked sex-associated effect was noted among deaths caused by injuries/poisoning, since 6 of the deaths occurred in men and only 1 was in a woman. CONCLUSION Patients with PsA are at an increased risk of death compared with the general population. Evidence of previously active and severe disease, as manifested by the prior use of medications and by radiologic changes as well as an elevated ESR at presentation, are prognostic indicators for death. The presence of nail lesions appears to be a protective factor that has the most clinical importance in the context of previously active and severe disease.

Health-related quality of life of patients with psoriatic arthritis : A comparison with patients with rheumatoid arthritis

OBJECTIVE To compare health-related quality of life (QOL) between patients with psoriatic arthritis (PsA) and patients with rheumatoid arthritis (RA), using the Medical Outcomes Study Short Form health survey (SF-36) and the Health Assessment Questionnaire (HAQ). METHODS Both the SF-36 and the HAQ were administered to 107 PsA patients attending the University of Toronto Psoriatic Arthritis Clinic between January 1 and December 31, 1994, and to 43 RA patients attending a University of Toronto-affiliated RA clinic during the same period. Standardized assessments of disease activity and severity were also performed at each clinic visit. Logistic regression analysis was used to compare health-related QOL between PsA and RA. RESULTS Both patient populations experienced lower physical health compared with that of a general population sample. The RA patients demonstrated more active inflammatory disease at the time of assessment than the PsA patients. The PsA patients were younger, and more were men. Logistic regression analyses showed that patients with PsA reported higher levels of vitality than patients with RA, even after adjusting for the observed differences in clinical and demographic characteristics. PsA patients, however, reported more role limitations due to emotional problems and more bodily pain after adjusting for the difference in vitality and other covariates. CONCLUSIONS Although both patient populations experienced reduced QOL, there were some meaningful differences in how the 2 conditions affect health-related QOL. Further, it appeared that there may be unique disabilities associated with the psoriasis dimension of PsA.

Cardiovascular and other comorbidities in patients with psoriatic arthritis: A comparison with patients with psoriasis

To determine whether the presence of psoriatic arthritis (PsA) is associated with greater comorbidity, in particular cardiovascular morbidity, compared to psoriasis without arthritis.

Self-reported dietary energy intake of normal weight, overweight and obese adolescents.

OBJECTIVE The purpose of the present paper was to assess dietary energy reporting as a function of sex and weight status among Ontario and Alberta adolescents, using the ratio of energy intake (EI) to estimated BMR (BMRest). DESIGN Data were collected using the FBQ, a validated web-based dietary assessment tool (including a 24 h dietary recall, FFQ, and food and physical activity behavioural questions). BMI was calculated from self-reported height and weight and participants were classified as normal weight, overweight or obese. BMR was calculated using the WHO equations (based on weight). Reporting status was identified using the ratio EI:BMRest. SETTING Data were collected in public, Catholic and private schools in Ontario and Alberta, Canada. SUBJECTS A total of 1917 (n 876 male and n 1041 female) students (n 934 grade 9 and n 984 grade 10) participated. RESULTS The mean EI:BMRest ratio across all participants was 1.4 (sd 0.6), providing evidence of under-reporting for the total sample. Females under-reported more than males (t = 6.27, P < 0.001), and under-reporting increased with increasing weight status for both males (F = 33.21, P < 0.001) and females (F = 14.28, P < 0.001). After removing those who reported eating less to lose weight, the EI:BMRest was 1.56 (sd 0.6) for males and 1.4 (sd 0.6) for females. CONCLUSION The present study highlights methodological challenges associated with self-reported dietary data. Systematic differences in under-reporting of dietary intake by gender and weight status were observed using a web-based survey, similar to observations made using paper-based 24 h recalls and dietitian interviews.

Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays

Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high-resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. A blinded review by two independent clinical cytogenetic laboratory directors of all large (>500 kb) rare CNVs in cases and well-matched controls showed that those deemed to be clinically significant were highly enriched in schizophrenia (16.4-fold increase, P < 0.0001). In a single community catchment area, the prevalence of individuals with these CNVs was 8.1%. Rare 1.7 Mb CNVs at 2q13 were found to be significantly associated with schizophrenia for the first time, compared with the prevalence in 23 838 population-based controls (42.9-fold increase, P = 0.0002). Additional novel findings that will facilitate the future clinical interpretation of smaller CNVs in schizophrenia include: (i) a greater proportion of individuals with two or more rare exonic CNVs >10 kb in size (1.5-fold increase, P = 0.0109) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and, (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, P = 0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism.

Premature death in adults with 22q11.2 Deletion Syndrome

Background: 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disease with a prevalence of 1/4000. Variable expression of congenital and later onset features contributes to its under-recognition. Longevity in those surviving childhood is believed to be normal but data are limited. Methods: We prospectively followed 264 subjects; 102 adults (>17 years) with 22q11.2DS (44 male (M), 58 female (F); mean (SD) age 33.6 (10.9) years) and their 162 unaffected siblings (77 M, 85 F; mean age 36.1 (12.2) years). We compared survival between groups using Kaplan–Meier estimates. Results: Twelve (11.8%; 4 M, 8 F) individuals with 22q11.2DS and no siblings died (p<0.0001). Survival to ages 40 and 50 years was 89.9% and 73.9%, respectively. Median age at death was 41.5 (range 18.1–68.6) years. Deaths included two (7.7%) of 26 subjects with neither major congenital heart disease (CHD) nor schizophrenia. Four of six sudden and unexpected deaths occurred in individuals with no major CHD. There was no evidence of cancer or coronary artery disease or family history of sudden death in the 12 patients who died, six of whom had autopsies. Discussion: Individuals with 22q11.2DS who survive childhood have diminished life expectancy and increased risk of sudden death not attributable to any single factor. Some sudden and/or premature deaths observed in the general population may represent undiagnosed 22q11.2DS. Increased recognition of the syndrome by family doctors, specialists and coroners will be essential to facilitate the tissue studies needed to determine underlying mechanisms.

Heritability of neurocognitive traits in familial schizophrenia

Neurocognitive deficits are considered promising endophenotypes for gene discovery in schizophrenia. Understanding the heritability and genetic inter‐relationships of neurocognitive traits could support their use as alternatives to diagnosis. Participants were 85 adults from 17 multiplex Canadian families with familial schizophrenia linked to 1q23 who had neurocognitive testing results available. Heritability of 13 standard measures assessing motor skills, processing speed, verbal, and visuospatial memory, attention/working memory, executive functioning, and IQ was estimated using variance component models and SOLAR software. We then investigated bivariate relationships between those variables found to be heritable. IQ showed the highest heritability (h2 = 0.64–0.74) and seven other neurocognitive measures, reflecting immediate and delayed verbal memory, attention/working memory, delayed visual memory, processing speed and motor skills, showed significant heritability (h2 = 0.31–0.62) under one or more of the models assessed. A schizophrenia diagnostic covariate was significant (P < 0.0001) for all heritable variables. Bivariate analyses suggested that memory‐IQ and visuomotor‐processing speed formed two groups of heritable traits. The results provide further evidence of the heritability of selected neurocognitive measures, and their relationship to schizophrenia and underlying genetic architecture. Composite measures of memory or processing speed may be heritable phenotypes useful for studies of neurocognition.

Longitudinal study of the bidirectional association between pain and depressive symptoms in patients with psoriatic arthritis.

To test the bidirectional hypothesis that depressive symptoms influence changes in pain over time, and pain influences changes in depressive symptoms.

Comparison of hemodynamic responses to social and nonsocial stress: evaluation of an anger interview.

Hemodynamic responses to an anger interview and cognitive and physical stressors were compared, and the stability of associated hemodynamic reactions examined. Participants experienced control, handgrip, counting, and mental arithmetic tests and an anger interview on two occasions. Systolic and diastolic blood pressure, heart rate, stroke volume, and cardiac output were measured. Total peripheral resistance was also derived. The anger interview produced larger, more sustained changes in blood pressure in both sessions than the other stressors. These changes were largely a consequence of increased peripheral resistance. Consistent with previous findings, handgrip was associated with a resistance-type reaction whereas arithmetic was associated with a cardiac output-type reaction. There was low-to-modest stability of hemodynamic reactions to the interview. Further research is necessary to optimize its utility in studies of cardiovascular function. Nevertheless, the findings underscore the ability of ecologically relevant stressors to provoke unique configurations of cardiovascular activity.