A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

What is the optimum methodology for the clinical measurement of resting anal sphincter pressure?

UNLABELLED: There are conflicting recommendations from consensus groups with regard to the assessment of resting anal sphincter pressure. Our aims were to evaluate and compare the performance of three recognized techniques for the clinical measurement of resting anal sphincter pressure. METHODS: In each of 54 patients presenting for anorectal manometry, and suffering from constipation or fecal incontinence, three different techniques for assessment of resting anal pressure were undertaken, namely stationary, stationary pull-through and slow pull-through techniques. Resting anal sphincter pressures were compared between groups and between techniques. RESULTS: Mean resting anal sphincter pressure was lower with stationary, compared with stationary pull-through and slow pull-through, techniques (P < or = 0.002). Resting pressure was higher for constipation than incontinence regardless of technique used (P < 0.00001). The techniques were highly correlated with each other (P < 0.0001). The stationary pull-through technique conferred a minor advantage in the discrimination between constipation and incontinence. The stationary technique required significantly less time for completion (P < 0.0001). CONCLUSION: Resting anal sphincter pressure varies according to the specific technique employed, yet each technique is valid. The stationary pull-through technique confers a minor advantage in clinical discrimination of patients, but the stationary technique is more time-efficient. Standardized anal sphincter testing should be established to enable inter-laboratory comparisons.

Family and twin studies in systemic lupus erythematosus.

We have estimated how much of the total genetic predisposition to SLE may be attributable to genes outside the HLA region by comparing figures for concordance of SLE in monozygotic twins with those for concordance in HLA identical siblings in Australia. None of six dizygotic co-twins of white Australian SLE probands was concordant for SLE. One of four (25%) monozygotic co-twins of white Australian SLE probands was concordant for SLE which when added to previously published figures for Caucasoid populations gives an overall concordance rate for SLE in monozygotic twins of 25%. None of 18 HLA identical, same sex siblings of SLE probands, had definite SLE by the study criteria (i.e. less than 6%). The comparison of these figures shows that most of the genetic predisposition to SLE is attributable to genes outside the HLA region.

Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism.

We describe a new hypothesis for the development of autism, that it is driven by imbalances in brain development involving enhanced effects of paternally expressed imprinted genes, deficits of effects from maternally expressed genes, or both. This hypothesis is supported by: (1) the strong genomic-imprinting component to the genetic and developmental mechanisms of autism, Angelman syndrome, Rett syndrome and Turner syndrome; (2) the core behavioural features of autism, such as self-focused behaviour, altered social interactions and language, and enhanced spatial and mechanistic cognition and abilities, and (3) the degree to which relevant brain functions and structures are altered in autism and related disorders. The imprinted brain theory of autism has important implications for understanding the genetic, epigenetic, neurological and cognitive bases of autism, as ultimately due to imbalances in the outcomes of intragenomic conflict between effects of maternally vs. paternally expressed genes.

Level of chronic life stress predicts clinical outcome in irritable bowel syndrome.

BACKGROUND: Life stress contributes to symptom onset and exacerbation in the majority of patients with irritable bowel syndrome (IBS) and functional dyspepsia (FD); research evidence is conflicting, however, as to the strength of these effects. AIMS: To test prospectively the relation of chronic life stress threat to subsequent symptom intensity over time. PATIENTS: One hundred and seventeen consecutive outpatients satisfying the modified Rome criteria for IBS (66% with one or more concurrent FD syndromes) participated. METHODS: The life stress and symptom intensity measures were determined from interview data collected independently at entry, and at six and 16 months; these measures assessed the potency of chronic life stress threat during the prior six months or more, and the severity and frequency of IBS and FD symptoms during the following two weeks. RESULTS: Chronic life stress threat was a powerful predictor of subsequent symptom intensity, explaining 97% of the variance on this measure over 16 months. No patient exposed to even one chronic highly threatening stressor improved clinically (by 50%) over the 16 months; all patients who improved did so in the absence of such a stressor. CONCLUSION: The level of chronic life stress threat predicts the clinical outcome in most patients with IBS/FD.

Alterations in cerebral potentials evoked by rectal distension in irritable bowel syndrome.

OBJECTIVE: Central nervous system correlates of the visceral hyperalgesia documented in patients with irritable bowel syndrome are limited. Reproducible cerebral evoked potentials can be recorded in response to rhythmic balloon distension of the rectum in healthy adults. Irritable bowel syndrome patients and healthy subjects were studied to compare the characteristics of mechanically-evoked rectal cerebral potentials obtained during fasting and after the ingestion of a standard meal. METHODS: Twenty-two pairs of age-matched healthy female subjects and female irritable bowel syndrome patients were studied. Cerebral evoked potentials were recorded in response to rhythmic rectal distension (two distension series each of 100 repetitions at 0.8 hertz); cerebral evoked potential recordings were repeated after a 1000 kcal (46% fat) liquid meal. Trait and state anxiety questionnaires were also completed. RESULTS: Compared to healthy subjects, irritable bowel syndrome patients demonstrated higher prevalence of cerebral evoked potential early peaks (latency < 100 ms) postprandially, and uniformly shorter cerebral evoked potential latencies both before and after feeding. CONCLUSION: These findings provide further objective evidence for defective visceral afferent transmission in irritable bowel syndrome patients.

Discordance of pressure recordings from biliary and pancreatic duct segments in patients with suspected sphincter of Oddi dysfunction.

It remains controversial whether manometric parameters recorded from the pancreatic and biliary segment of the sphincter of Oddi (SO) differ. We therefore studied 48 consecutive patients (40 women, 43 +/- 11 years) with suspected SO dysfunction, in 33 of whom successful dual-duct SO manometry was obtained. Measures of concordance between the two duct segments were moderate for basal sphincter pressure (K = 0.31) and for contractile frequency (0.35), and were low for peak pressure (0.15) and for proportion of retrograde propagation (-0.19). There was also low concordance (-0.13) for the overall manometric diagnosis, and in 48% (CI 31-66%) of patients a conflicting diagnosis (normal/abnormal) was obtained from the two ducts. There was no evidence of a differential motor effect of CCK on either duct, nor were there significant differences in the rate of manometric abnormality according to the order of initial duct cannulation. These results indicate that, if technically feasible, dual-duct manometry of the sphincter of Oddi is required for diagnostic precision.

Effects of budesonide and fluticasone on 24-hour plasma cortisol. A dose-response study.

Comparison of the risk-benefit profiles of different inhaled glucocorticoids has been limited by inadequate information about the dose-response relationships for efficacy relative to side effects. Fluticasone propionate (FP) is twice as effective as budesonide (BUD), but the potency ratio of FP:BUD with respect to suppression of cortisol production is unknown. The effects of 5 d of treatment with BUD (800, 1,600, and 3,200 micrograms/d via pMDI) and FP (750, 1,500, and 2,000 micrograms/d via pMDI) on integrated area under the curve of 24-h plasma cortisol profiles (AUC24 h) were compared in a randomized, placebo-controlled, seven-period crossover study in normal male volunteers (n = 28). Plasma cortisol concentrations were measured during the last 24 h of each treatment period. Each treatment (except BUD 800 micrograms) produced significant dose-dependent reductions in AUC24 h compared with placebo; e.g., percent reductions in AUC24 h were 23, 41, and 69% for the three doses of BUD, and, correspondingly, 46, 85, and 93% for the three doses of FP. Model-derived measurements of dose potency ratios showed that FP was 2.9 times more potent than BUD in reducing AUC24 h (95% CI, 2.5 to 3.5) and 3.1 times more potent in reducing 8:00 A.M. plasma cortisol (95% CI, 2.4 to 4.0). Thus, on a microgram-for-microgram notional dose basis, the systemic effects of a given dose of FP on AUC24 h cortisol were equivalent to the effects of three times the dose of BUD.

Functional gastrointestinal disorders: psychological, social, and somatic features.

BACKGROUND: Psychological, social, and extraintestinal (somatic) disturbances are prominent features of functional gastrointestinal disorders (FGID); little attention, however, has been given to differences in the nature of these disturbances in the various FGID subgroups. AIMS: (1) To determine whether psychological, social, and extraintestinal factors are associated with specific FGID, and/or with the overall severity and extent of FGID disturbance (the number of coexistent FGID subgroups present in any individual); and (2) to determine whether chronic social stressors link gastrointestinal, extraintestinal, and emotional symptomatologies in FGID. PATIENTS: One hundred and eighty eight outpatients, fulfilling standard criteria for one or more functional gastroduodenal or functional bowel disorders. METHODS: Utilising detailed and objective interview and questionnaire methods, detailed gastrointestinal, extraintestinal, psychological, and social data were collected. RESULTS: Chronic stressors and extraintestinal and emotional symptomatologies were prominent features of functional dyspepsia (FD) and irritable bowel syndrome (IBS) alone. These particular features were, however, highly specific for particular FD and/or IBS subgroups. The chronic threat component of social stressors predicted the nature and extent of multisystem (gastrointestinal, extraintestinal, and emotional) symptomatology. CONCLUSIONS: Notable differences between the various FGID subgroups support the symptom based classification of FGID. Chronic stressor provoked psychological and extraintestinal disturbance is most specific for the FD-IBS group of syndromes.

Psychological and sex features of delayed gut transit in functional gastrointestinal disorders.

BACKGROUND: The relation of demographic and psychological factors to the presence and extent of gut transit impairment in the functional gastrointestinal disorders has received little attention. AIMS: To compare the psychosocial and demographic features of patients with functional gastrointestinal disorders and delayed transit in one region of the gastrointestinal tract with those displaying more widespread delayed transit (that is, delay in two or three regions), and those with normal transit in all three regions. PATIENTS: Of 110 outpatient participants who satisfied standardised criteria for functional gastrointestinal disorders, 46 had delayed transit in one region, 32 had delay in two or three regions, and 17 exhibited normal transit in all regions. METHODS: Transit in the stomach, the small intestine, and the large intestine was assessed concurrently using a wholly scintigraphic technique; psychological status was assessed using established psychometric measures. RESULTS: Patients with delayed transit displayed demographic and psychological features that contrasted with patients with normal transit in all regions. In particular, widespread delayed transit featured female sex, a highly depressed mood state, increased age, frequent control of anger, and more severe gastric stasis, while the features distinguishing normal transit were male sex and high levels of hypochondriasis. CONCLUSION: These data suggest the existence of a distinct psychophysiological subgroup, defined by the presence of delayed transit, in patients with functional gastrointestinal disorders.

Optimal asthma control, starting with high doses of inhaled budesonide.

The aim of this study was to determine whether outcomes in poorly controlled asthma can be further improved with a starting dose of inhaled budesonide higher than that recommended in international guidelines. The study had a parallel-group design and included 61 subjects with poorly controlled asthma, randomized to receive 3,200 microg or 1,600 microg budesonide daily by Turbuhaler for 8 weeks (double-blind), then 1,600 microg x day(-1) for 8 weeks (single-blind), followed by 14 months of open-label budesonide dose down-titration using a novel algorithm, with a written asthma crisis plan based on electronic peak expiratory flow monitoring. The primary outcome variable for weeks 1-16 was change in airway hyperresponsiveness (AHR), and, for the open-label phase, mean daily budesonide dose. By week 16, there were large changes from baseline in all outcomes, with no significant differences between the 3,200- and 1,600-microg x day(-1) starting dose groups (AHR increased by 3.2 versus 3.0 doubling doses, p=0.7; morning peak flow increased by 134 versus 127 L x min(-1), p=0.8). Subjects starting with 3,200 microg x day(-1) were 3.8 times more likely to achieve AHR within the normal range, as defined by a provocative dose of histamine causing a 20% fall in forced expiratory volume in one second (PD20) of > or = 3.92 micromol by week 16 (p=0.03) [corrected]. During dose titration, there was no significant difference in mean budesonide dose (1,327 versus 1,325 microg x day(-1), p>0.3). Optimal asthma control was achieved in the majority of subjects (at completion/withdrawal: median symptoms 0.0 days x week(-1), beta2-agonist use 0.2 occasions x day(-1), and PD20 2.4 micromol). In subjects with poorly controlled asthma, a starting dose of 1,600 microg x day(-1) budesonide was sufficient to lead to optimal control in most subjects. The high degree of control achieved, compared with previous studies, warrants further investigation.