Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Development and external validation study of a melanoma risk prediction model incorporating clinically assessed naevi and solar lentigines.

BACKGROUND: Melanoma risk prediction models could be useful for matching preventive interventions to patients' risk. OBJECTIVES: To develop and validate a model for incident first-primary cutaneous melanoma using clinically assessed risk factors. METHODS: We used unconditional logistic regression with backward selection from the Australian Melanoma Family Study (461 cases and 329 controls) in which age, sex and city of recruitment were kept in each step, and we externally validated it using the Leeds Melanoma Case-Control Study (960 cases and 513 controls). Candidate predictors included clinically assessed whole-body naevi and solar lentigines, and self-assessed pigmentation phenotype, sun exposure, family history and history of keratinocyte cancer. We evaluated the predictive strength and discrimination of the model risk factors using odds per age- and sex-adjusted SD (OPERA) and the area under curve (AUC), and calibration using the Hosmer-Lemeshow test. RESULTS: The final model included the number of naevi ≥ 2 mm in diameter on the whole body, solar lentigines on the upper back (a six-level scale), hair colour at age 18 years and personal history of keratinocyte cancer. Naevi was the strongest risk factor; the OPERA was 3·51 [95% confidence interval (CI) 2·71-4·54] in the Australian study and 2·56 (95% CI 2·23-2·95) in the Leeds study. The AUC was 0·79 (95% CI 0·76-0·83) in the Australian study and 0·73 (95% CI 0·70-0·75) in the Leeds study. The Hosmer-Lemeshow test P-value was 0·30 in the Australian study and < 0·001 in the Leeds study. CONCLUSIONS: This model had good discrimination and could be used by clinicians to stratify patients by melanoma risk for the targeting of preventive interventions. What's already known about this topic? Melanoma risk prediction models may be useful in prevention by tailoring interventions to personalized risk levels. For reasons of feasibility, time and cost many melanoma prediction models use self-assessed risk factors. However, individuals tend to underestimate their naevus numbers. What does this study add? We present a melanoma risk prediction model, which includes clinically-assessed whole-body naevi and solar lentigines, and self-assessed risk factors including pigmentation phenotype and history of keratinocyte cancer. This model performs well on discrimination, the model's ability to distinguish between individuals with and without melanoma, and may assist clinicians to stratify patients by melanoma risk for targeted preventive interventions.

Associations of pigmentary and naevus phenotype with melanoma risk in two populations with comparable ancestry but contrasting levels of ambient sun exposure.

BACKGROUND: People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes. OBJECTIVE: We examined whether associations of these phenotypes with melanoma risk differed by ambient sun exposure or participant characteristics in two population-based, case-control studies with comparable ancestry but different ambient sun exposure. METHODS: Data were analysed from 616 cases and 496 controls from the Australian Melanoma Family Study and 2012 cases and 504 controls from the Leeds (UK) case-control study. Questionnaire, interview and dermatological skin examination data were collected using the same measurement protocols. Relative risks were estimated as odds ratios using unconditional logistic regression, adjusted for potential confounders. RESULTS: Hair and skin colour were the strongest pigmentary phenotype risk factors. All associations of pigmentary phenotype with melanoma risk were similar across countries. The median number of clinically assessed naevi was approximately three times higher in Australia than Leeds, but the relative risks for melanoma associated with each additional common or dysplastic naevus were higher for Leeds than Australia, especially for naevi on the upper and lower limbs. Higher naevus counts on the head and neck were associated with a stronger relative risk for melanoma for women than men. The two countries had similar relative risks for melanoma based on self-reported naevus density categories, but personal perceptions of naevus number differed by country. There was no consistent evidence of interactions between phenotypes on risk. CONCLUSIONS: Classifying people at high risk of melanoma based on their number of naevi should ideally take into account their country of residence, type of counts (clinical or self-reported), body site on which the naevus counts are measured and sex. The presence of naevi may be a stronger indicator of a genetic predisposition in the UK than in Australia based on less opportunity for sun exposure to influence naevus development.

Recurrent and founder mutations in the PMS2 gene.

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.

Morphological predictors of BRCA1 germline mutations in young women with breast cancer.

BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data. METHODS: We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation. RESULTS: The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83-0.90). CONCLUSION: Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes.

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.

BACKGROUND: defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. METHODS: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. RESULTS: all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77). CONCLUSIONS: overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

The role of SMAD4 in early-onset colorectal cancer.

OBJECTIVE: Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied. METHOD: We analysed 109 tumours from a population-based case-family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early-onset colorectal cancer had been previously screened for germ-line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFbetaRII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR. RESULTS: Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFbetaR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade. CONCLUSION: Loss of SMAD4 expression is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age-groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early-onset colorectal cancer only explain a small proportion of the disease and require further exploration.

Adherence to asthma management guidelines by middle-aged adults with current asthma.

BACKGROUND: With the increasing burden of asthma worldwide, much effort has been given to developing and updating management guidelines. Using data from the Tasmanian Longitudinal Health Study (TAHS), the adequacy of asthma management for middle-aged adults with asthma was investigated. METHODS: Information about spirometry, medication history and current asthma status was collected by the most recent TAHS when participants were in their mid 40s. Only those who reported ever having asthma were eligible for analysis. RESULTS: Of the 702 participants who reported ever having asthma, 50% had current asthma (n = 351) of whom 71% were categorised as having persistent asthma (n = 98 mild, n = 92 moderate, n = 58 severe). The majority (85.2%) of participants with current asthma had used some form of asthma medication in the past 12 months, but the proportion of the use of minimally adequate preventer medication was low (26%). Post-bronchodilator airflow obstruction increased progressively from mild to severe persistent asthma for those inadequately managed, but not for those on adequate therapy. CONCLUSION: Appropriate use of asthma medication by this middle-aged group of adults with current asthma was inadequate, especially for those with adult-onset moderate or severe persistent disease and without a family history of asthma. These results suggest that proper use of preventer medication could protect against the progressive decline in lung function associated with increasing severity. This has implications not just for poor quality of life, but also for the development of fixed airflow obstruction.

Relevance of the hygiene hypothesis to early vs. late onset allergic rhinitis.

INTRODUCTION: The hygiene hypothesis proposes that reduced exposure to infections in early life increases the risk of developing allergic conditions including allergic rhinitis. We examined the association between markers of the hygiene hypothesis and allergic rhinitis that developed before 7 years of age and allergic rhinitis that developed after 7 years of age. METHODS: The Tasmanian Longitudinal Health Study (TAHS) is a population-based cohort (n=8583) study of respiratory disease. Participants have been followed from 7 to 44 years of age. Information on potential risk factors, allergies and respiratory symptoms was collected longitudinally. Using multi-nomial logistic regression, exposure to siblings, infections, tonsillectomy and farm residence during childhood were examined as risk factors for allergic rhinitis that developed before or after 7 years of age. All analyses were adjusted for gender, maternal and paternal atopy, mother's age at participant's birth, paternal socio-economic status in 1968 and personal socio-economic status in 2004. RESULTS: Greater cumulative exposure to siblings before the age of 2 years was strongly inversely associated with early onset allergic rhinitis (<1 year sib exposure: OR=0.6, 95% CI 0.3-1.0; 1-3 years sib exposure: OR=0.6, 95% CI 0.4-0.9; >3 years sib exposure: OR=0.4, 95% CI 0.3-0.8) less so with later onset allergic rhinitis. The risk of early onset allergic rhinitis decreased with increasing viral infections (OR=0.7, 95% CI 0.5-0.9) during childhood. Having a tonsillectomy before 7 years of age increased the risk of early onset allergic rhinitis (OR=1.7, 95% CI 1.2-2.5). None of these factors was associated with later onset allergic rhinitis. CONCLUSIONS: Exposures relevant to the hygiene hypothesis were important predictors for the development of early onset but less so for later onset allergic rhinitis. The exact mechanisms by which siblings and infections protect against allergic rhinitis are unclear. The stronger findings for earlier onset allergic rhinitis suggest that family structure and infections have most impact on disease risk in early life. Further research should focus on early onset allergic rhinitis when exploring causal explanations for any sibling effect.

Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families.

Genetic screening of women from multiple-case breast cancer families and other research-based endeavors have identified an extensive collection of germline variations of BRCA1 and BRCA2 that can be classified as deleterious and have clinical relevance. For some variants, such as those in the conserved intronic splice site regions which are highly likely to alter splicing, it is not possible to classify them based on the identified DNA sequence variation alone. We studied 11 multiple-case breast cancer families carrying seven distinct splice site region genetic alterations in BRCA1 or BRCA2 (BRCA1, c.IVS6-2delA, c.IVS9-2A>C, c.IVS4-1G>T, c.IVS20+1G>A and BRCA2, c.IVS17-1G>C, c.IVS20+1G>A, c.IVS7-1G>A) and applied SpliceSiteFinder to predict possible changes in efficiency of splice donor and acceptor sites, characterized the transcripts, and estimated the average age-specific cumulative risk (penetrance) using a modified segregation analysis. SpliceSiteFinder predicted and we identified transcipts that illustrated that all variants caused exon skipping, and all but two led to frameshifts. The risks of breast cancer to age 70 yrs, averaged over all variants, over BRCA1 variants alone, and over BRCA2 variants alone, were 73% (95% confidence interval 47-93), 64% (95%CI 28-96) and 79% (95%CI 48-98) respectively (all P<0.0001). Therefore five of these seven consensus splice site variants of BRCA1 and BRCA2 produce a transcript similar to that of other previously described deleterious exonic variants and are associated with similar high lifetime risks.

A specific GFP expression assay, penetrance estimate, and histological assessment for a putative splice site mutation in BRCA1.

Genetic testing for cancer predisposing mutations in BRCA1 and BRCA2 has been of benefit to many individuals from breast and ovarian cancer-prone kindreds. However, a function has not been assigned to many of the domains that make up these complex proteins and hence, the significance of many sequence variants, including missense mutations, splice-site mutations, and in-frame deletions/insertions, remains unclear. We identified a putative splice site mutation (IVS6-2delA) in BRCA1 in a family attending a Familial Cancer Centre that had a significant history of both breast and ovarian cancer. This sequence variant was not novel but the exact effect on mRNA splicing and hence the biological impact of this sequence variation was unclear and therefore the finding was unable to be used in genetic counseling of the family. Via the construction of novel GFP-based expression fusion constructs, we demonstrated that this sequence variation prevented normal splicing of the BRCA1 transcript. By combining these data with an assessment of the histopathological features of the breast carcinomas in this family and mutation penetrance estimate we were able to conclude that this BRCA1 variant conveyed an increased risk of breast cancer.

Design and analysis issues in a population-based, case-control-family study of the genetic epidemiology of breast cancer and the Co-operative Family Registry for Breast Cancer Studies (CFRBCS).

BACKGROUND: Historically, studies of the "genetic epidemiology" of cancer have used nonsystematically sampled kindreds with numerous cases of cancer across multiple generations. From the epidemiologic viewpoint, it is difficult to extrapolate findings to the population because of the ad hoc ascertainment of these atypical, ill-defined families. Since 1992, we have been conducting a population-based, case-control-family study of breast cancer. METHODS: Families are identified through a single, population-sampled proband, who is either affected or unaffected, making adjustment for ascertainment straightforward. Administered questionnaires and blood samples are sought from cases, controls, and specified sets of relatives. From 1996 through 1999, a further 1200 case families have been recruited as part of the Co-operative Family Registry for Breast Cancer Studies (CFRBCS). Issues relevant to the study design and analysis are discussed. RESULTS: Epidemiologic and genetic findings published to date are summarized. In particular, this population-based study has shown that the so-called "high-risk" families containing multiple cases of breast cancer are not typical of families in the general population in which BRCA1 or BRCA2 mutations are segregating. Most "hereditary" cancers are "sporadic." CONCLUSION: The collection of DNA, as well as data on disease status and risk factors, from population-sampled sets of relatives provides a powerful resource for addressing genetic and environmental determinants of cancer. A population-based multicenter, multidisciplinary enterprise, such as has been developed by the CFRBCS, may become a model for future research in cancer epidemiology, allowing genetic and environmental risk factors to be put into a proper population perspective.

The abnormality of normal comparison groups: the identification of psychosis proneness and substance abuse in putatively normal research subjects.

OBJECTIVE: Careful assessment of research subjects is important because the inclusion of subjects who manifest psychopathology and significant substance abuse in normal comparison groups will decrease statistical and experimental power. The current study evaluated the usefulness of an MMPI-derived algorithm in identifying tendencies toward psychosis and substance abuse in putatively normal research volunteers. METHOD: Ninety-eight adults who were recruited as normal comparison research subjects completed the MMPI, psychiatric interviews, questionnaires, and selected neuropsychological tests. The MMPI classified 81 presumed normal subjects into four subgroups: 1) not psychosis prone/substance abuse not likely, 2) not psychosis prone/substance abuse likely, 3) psychosis prone/substance abuse not likely, and 4) psychosis prone/substance abuse likely. RESULTS: The MMPI psychosis-prone and substance abuse factors identified significantly distressed and dysfunctional individuals with a relatively high degree of accuracy. CONCLUSIONS: It is becoming increasingly apparent that the cursory self-report screening of normal subjects may result in unacceptable levels of psychopathology in comparison groups. The current results also indicate that an adequate substance abuse evaluation is extremely important and that brief self-report information may be misleading. Empirically derived assessment tools, such as the MMPI, may prove useful in allowing researchers to more accurately define control parameters and group membership.

Learning and memory in rape victims with posttraumatic stress disorder.

OBJECTIVE: Studies have shown memory deficits among combat veterans with posttraumatic stress disorder (PTSD); however, high rates of comorbid conditions, including alcoholism, make it difficult to definitively associate these findings with the PTSD diagnosis. In this study the authors examined memory functioning among rape survivors without alcoholism or substance abuse but with PTSD. METHOD: Rape victims with (N = 15) and without (N = 16) PTSD were compared to age- and education-matched nontraumatized comparison subjects (N = 16) on measures of learning and memory. RESULTS: The subjects with PTSD performed significantly worse than the other groups on delayed free recall. The deficits were ameliorated by cueing and recognition testing. CONCLUSIONS: Recall deficits in noncombat PTSD patients strengthen the theory that memory deficits are associated with the PTSD diagnosis. The deficits were mild and were not attributable to comorbid depression, anxiety, or substance abuse.

Physiological evidence of exaggerated startle response in a subgroup of Vietnam veterans with combat-related PTSD.

One of the diagnostic criteria for posttraumatic stress disorder (PTSD) is an exaggerated startle response; however, this phenomenon has not been verified empirically. The authors compared 20 Vietnam combat veterans with PTSD and 18 combat veterans without PTSD on the eyeblink reflex electromyographic response of the startle reaction. Subjects in both groups who failed to show an eyeblink response to the startle stimuli were eliminated from further analyses. Among the remaining subjects, the 13 with PTSD had a significantly greater startle response amplitude than the 12 control subjects at intermediate intensities of acoustic stimuli. The relationship between startle responsivity and both negative and positive symptoms was also investigated.

Impairments of attention after cingulotomy.

BACKGROUND: Outcome studies have generally not indicated significant cognitive disturbances after cingulotomy. There is now considerable evidence that the cingulate may play an important role in emotional behavior and attention. OBJECTIVE: To characterize impairments of attention associated with bilateral lesions of the anterior cingulate cortex produced by cingulotomy. METHODS: Twelve patients who underwent cingulotomy for treatment of intractable pain were administered tests of attention, executive functions, response intention and production, and a broad range of other neurocognitive functions before surgery and again 3 and 12 months after surgery. Data from this within-subjects repeated-measures design were analyzed by multivariate analysis of variance procedures. RESULTS: After cingulotomy, patients initially had executive and attentional impairments. By 12 months, these had resolved into more circumscribed deficits, with greatest impairments on tasks requiring intention and spontaneous response production, and milder impairments of focused and sustained attention. Other aspects of attention and other cognitive functions were generally unaffected. CONCLUSION: The anterior cingulate cortex modulates response intention and focused attention.

Validation of questionnaire and bronchial hyperresponsiveness against respiratory physician assessment in the diagnosis of asthma.

BACKGROUND: The Tasmanian Asthma survey (TAS) and the International Study of Asthma and Allergies in Childhood (ISAAC) have used questionnaires to measure the prevalence of asthma in adults and children. We have investigated the validity of these questionnaires by comparing response to questionnaire with a physician assessment of asthma status in the past 12 months. METHODS: Ninety-three adults were given the TAS questionnaire to complete and 361 children were given the ISAAC questionnaire. Ninety-one adults and 168 children completed bronchial challenge with hypertonic saline. A consultation with a respiratory physician blinded to the results of the questionnaire and bronchial challenge was given to all subjects. RESULTS: In both adults and children, questionnaires showed high agreement with respiratory physician diagnosis with respect to asthma symptoms in the past 12 months. For the TAS questionnaire the positive and negative predictive values (95% confidence limits) for physician diagnosis for adults were 0.89 (0.68-0.98) and 0.94 (0. 86-0.98) respectively. The instrument was also sensitive 0.80 (0. 58-0.93) and highly specific 0.97 (0.90-0.99). For the ISAAC questionnaire the positive and negative predictive vales for physician diagnosis of asthma in children were 0.61 (0.50-0.71) and 0.94 (0.88-0.98) respectively. Sensitivity and specificity were 0.85 (0.73-0.93) and 0.81 (0.76-0.86) respectively. Compared to the physician diagnosis, the sensitivity of bronchial hyperresponsiveness (BHR) for asthma was low for adults 0.39 (0.21-0. 61) and children 0.54 (0.48-0.67) as were the positive predictive values: 0.55 (0.31-0.79) for adults and 0.64 (0.449-0.77) for children. A definition of asthma requiring both a positive questionnaire response and BHR was highly specific but not sensitive for adults 0.37 (0.20-0.59) or children 0.47 (0.35-0.60). CONCLUSIONS: Both the TAS and ISAAC questionnaires are valid instruments for the determination of asthma symptoms in the past 12 months.