Storiform collagenoma (sclerotic fibroma) of the oral mucosa.

Storiform collagenoma (also called sclerotic fibroma) is uncommon, occurs as a cutaneous fibrous neoplasm, and is particularly rare in mucosal tissue in the head and neck. We describe an unexpected diagnosis in the oral cavity. Histopathological examination showed a proliferation of fibrous tissue, which was well circumscribed but unencapsulated, with thick laminated bundles of eosinophilic collagen that exhibited a storiform or "whorled" pattern. First described by Weary et al in 1972, storiform collagenoma is a marker for Cowden's disease or PTEN hamartoma tumour syndrome. Identification of other synchronous lesions should prompt chromosomal analysis for a mutation in the PTEN gene on chromosome 10q23.

Laparoscopic colectomy in a district hospital: the single surgeon can be safe.

BACKGROUND: Several outcome measures have been identified for colorectal surgery and published in the literature. This study sought to compare outcomes of high volume laparoscopic colectomy by a single surgeon in a district hospital with outcomes from tertiary referral centres. METHODS: This was a retrospective review of elective laparoscopic colectomy by a single laparoscopic general surgeon in a district hospital over a 51-month period using a prospectively maintained database. The key outcome measures studied were length of hospital stay, conversion to open, anastomotic leak, wound infection, re-admission and 30-day mortality. RESULTS: 187 elective laparoscopic colectomies were performed at the Kent and Canterbury Hospital between July 2008 and October 2012. The median patient age was 69 years (range 22-90 years). Median length of hospital stay was 4 days (range 1-48 days). Anastomotic leak occurred in 4 (2.1%) patients. Seven (3.7%) patients underwent conversion to open surgery. Re-admission occurred in 4 (2.1%) patients for small bowel obstruction (1), wound infection (1), anastomotic leak (1) and colo-vaginal fistula (1). There was one post-operative death from severe chest infection (0.5%). These results are similar to those published by tertiary referral centres. CONCLUSIONS: This study of outcomes at a district hospital shows that the outcome reported from laparoscopic colorectal surgery in tertiary referral centres is reproducible at the district hospital level by a single surgeon with a high operative volume.

Examining non-syndromic autosomal recessive intellectual disability (NS-ARID) genes for an enriched association with intelligence differences.

Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.

Glycogenic hepatopathy is an under-recognised cause of hepatomegaly and elevated liver transaminases in type 1 diabetes mellitus.

Glycogenic hepatopathy (GH) is an under-recognised complication of type 1 diabetes mellitus (T1DM) not controlled to target resulting in hepatomegaly and elevated liver transaminases. We report the case of a 19-year-old man with T1DM not controlled to target who presented with abdominal pain, hepatomegaly and deranged liver transaminases. He was subsequently diagnosed with GH on liver biopsy, with the mainstay of treatment being reduction in caloric intake and insulin.

A population based study of variations in operation rates for breast cancer, of comorbidity and prognosis at diagnosis: failure to operate for early breast cancer in older women.

BACKGROUND: Older women are less likely to have surgery for operable breast cancer. This population-based study examines operation rates by age and identifies groups which present with early or late disease. METHODS: 37 000 cancer registrations for 2007 were combined with Hospital Episode Statistics comorbidity data for England. Operation rates were examined by age, ethnicity, deprivation, comorbidity, screen-detection, tumour size, grade and nodal status. Early and late presentation were correlated with Nottingham Prognostic Index (NPI) groups and tumour size. RESULTS: The proportion of women not having surgery increased from 7-10% at ages 35-69 to 82% from age 90. From age 70, the proportion not having surgery rose by an average of 3.1% per year of age. Women with a Charlson Comorbidity Index score of ≥1 (which increased with age), with tumours >50 mm or who were node positive, were less likely to have surgery. Although women aged 70-79 were more likely to have larger tumours, their tumours were also more likely to have an excellent or good NPI (p < 0.001). Good prognosis tumours were more likely to be screen-detected, and less likely in women aged 0-39, the deprived and certain ethnic groups (p < 0.02). CONCLUSIONS: From age 70 there is an increasing failure to operate for breast cancer. Younger women and certain ethnic groups presented with more advanced tumours. Older women had larger tumours which were otherwise of good prognosis, and this would not account for the failure to operate which may in part be related to comorbidity in this age group.

Genome-wide screening for DNA variants associated with reading and language traits.

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome-wide association scan (GWAS) meta-analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading- and language-related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10(-7) for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on-going international efforts to identify genes contributing to reading and language skills.

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins.

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

Personality and facial morphology: Links to assertiveness and neuroticism in capuchins (Sapajus [Cebus] apella).

Personality has important links to health, social status, and life history outcomes (e.g. longevity and reproductive success). Human facial morphology appears to signal aspects of one's personality to others, raising questions about the evolutionary origins of such associations (e.g. signals of mate quality). Studies in non-human primates may help to achieve this goal: for instance, facial width-to-height ratio (fWHR) in the male face has been associated with dominance not only in humans but also in capuchin monkeys. Here we test the association of personality (assertiveness, openness, attentiveness, neuroticism, and sociability) with fWHR, face width/lower-face height, and lower face/face height ratio in 64 capuchins (Sapajus apella). In a structural model of personality and facial metrics, fWHR was associated with assertiveness, while lower face/face height ratio was associated with neuroticism (erratic vs. stable behaviour) and attentiveness (helpfulness vs. distractibility). Facial morphology thus appears to associate with three personality domains, which may act as a signal of status in capuchins.

A genome-wide association study for reading and language abilities in two population cohorts.

Candidate genes have been identified for both reading and language, but most of the heritable variance in these traits remains unexplained. Here, we report a genome-wide association meta-analysis of two large cohorts: population samples of Australian twins and siblings aged 12-25 years (n = 1177 from 538 families), and a younger cohort of children of the UK Avon Longitudinal Study of Parents and their Children (aged 8 and 9 years; maximum n = 5472). Suggestive association was indicated for reading measures and non-word repetition (NWR), with the greatest support found for single nucleotide polymorphisms (SNPs) in the pseudogene, ABCC13 (P = 7.34 × 10(-8)), and the gene, DAZAP1 (P = 1.32 × 10(-6)). Gene-based analyses showed significant association (P < 2.8 × 10(-6)) for reading and spelling with genes CD2L1, CDC2L2 and RCAN3 in two loci on chromosome 1. Some support was found for the same SNPs having effects on both reading skill and NWR, which is compatible with behavior genetic evidence for influences of reading acquisition on phonological-task performance. The results implicate novel candidates for study in additional cohorts for reading and language abilities.

Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial.

BACKGROUND: The incidence of local recurrence (LR) after conservative surgery for early breast cancer without adjuvant therapy is unacceptably high even with favourable tumours. The aim of this study was to examine the effect of adjuvant therapies in tumours with excellent prognostic features. METHODS: Patients with primary invasive breast cancer <2 cm diameter, grade 1 or good prognosis special type, and node negative, treated by wide local excision (WLE) with clear margins were randomised into a 2 × 2 clinical trial of factorial design with or without radiotherapy and with or without tamoxifen. Trial entry was allowed to either comparison or both. FINDINGS: The actuarial breast cancer specific survival in 1135 randomised patients at 10 years was 96%. Analysis by intention to treat showed that LR after WLE was reduced in patients randomised to radiotherapy (RT) (HR 0.37, CI 0.22-0.61 p<0.001) and to tamoxifen (HR 0.33, CI 0.15 - 0.70 p<0.004). Actuarial analysis of patients entered into the four-way randomisation showed that LR after WLE alone was 1.9% per annum (PA) versus 0.7% with RT alone and 0.8% with tamoxifen alone. No patient randomised to both adjuvant treatments developed LR. Analysis by treatment received showed LR at 2.2%PA for surgery alone versus 0.8% for either adjuvant radiotherapy or tamoxifen and 0.2% for both treatments. CONCLUSIONS: Even in these patients with tumours of excellent prognosis, LR after conservative surgery without adjuvant therapy was still very high. This was reduced to a similar extent by either radiotherapy or tamoxifen but to a greater extent by the receipt of both treatments.

Correlation of age at oral contraceptive pill start with age at breast cancer diagnosis.

Breast cancer is progressively diagnosed with increasing age. This study aimed to determine whether women who started using the oral contraceptive pill (OCP) at an early age developed breast cancer earlier than women who started using the OCP later in life. A database review of 1,010 breast cancer patients, who had used the OCP at some point in their life, was carried out. Associations of age at OCP start with age at breast cancer diagnosis were determined by multiple linear regression analysis, considering year of birth, year of diagnosis, age at first pregnancy, number of live births, age at menarche, and length of OCP use. There was evidence of a linear trend between age at OCP start and age at breast cancer diagnosis. Women who started using the OCP aged 18 years or younger were, on average, 4 years younger at breast cancer diagnosis than women who started using the OCP over the age of 30 years, and women who started using the OCP aged 22-25 years were, on average, 3 years younger (p-value for trend <0.001). The age when the OCP was started was positively associated with the age when breast cancer was first diagnosed.

The case against climate regulation via oceanic phytoplankton sulphur emissions.

More than twenty years ago, a biological regulation of climate was proposed whereby emissions of dimethyl sulphide from oceanic phytoplankton resulted in the formation of aerosol particles that acted as cloud condensation nuclei in the marine boundary layer. In this hypothesis--referred to as CLAW--the increase in cloud condensation nuclei led to an increase in cloud albedo with the resulting changes in temperature and radiation initiating a climate feedback altering dimethyl sulphide emissions from phytoplankton. Over the past two decades, observations in the marine boundary layer, laboratory studies and modelling efforts have been conducted seeking evidence for the CLAW hypothesis. The results indicate that a dimethyl sulphide biological control over cloud condensation nuclei probably does not exist and that sources of these nuclei to the marine boundary layer and the response of clouds to changes in aerosol are much more complex than was recognized twenty years ago. These results indicate that it is time to retire the CLAW hypothesis.

Surgical vs general practitioner assessment: diagnostic accuracy in 2-week-wait colorectal cancer referrals.

AIM: It has been recommended that patients with suspected colorectal cancer should proceed straight to an endoscopic test to increase speed of diagnosis, using only the information in the general practitioner's referral letter. This study aims to establish whether the diagnostic accuracy of the first surgical outpatient assessment is significantly greater than the general practitioner's assessment and if so by what means. METHOD: Demographic variables, symptoms and signs were collected from the first surgical outpatient assessment letters and the general practitioners' referral letters in 2-week-wait colorectal cancer referrals made between 2002 and 2005. Multiple logistic regression models derived from both the surgeons' and the general practitioners' letters were compared with receiver operator characteristic curves. RESULTS: Variables were collected from 978 2-week-wait colorectal cancer referrals. The median age was 69 years (range 19-98) and the male to female ratio was 1:2. Seventy-eight referrals were diagnosed with colorectal cancer. Surgeons' models demonstrated significantly greater diagnostic accuracy than general practitioners' models (area under the curve, 0.84 vs 0.73; P < 0.003). General practitioners' letters contained significantly less information than surgeons' letters (P < 0.001), but correcting for this did not account for the difference in diagnostic accuracy. The single variable that accounted for the difference in diagnostic accuracy was examination of the rectum by rigid sigmoidoscopy. CONCLUSION: Rigid sigmoidoscopy significantly improves the diagnostic accuracy of clinical assessment in patients with suspected colorectal cancer. If rigid sigmoidoscopy were omitted in a straight-to-test pathway, some patients would be denied the opportunity for immediate diagnosis.

The effects of antidepressants on mitochondrial function in a model cell system and isolated mitochondria.

The in vitro effects of antidepressant drugs on mitochondrial function were investigated in a CHOß(2)SPAP cell line used previously to determine the effects of antidepressants on gene transcription (Abdel-Razaq et al., Biochem Pharmacol 73:1995-2003, 2007) and in rat heart isolated mitochondria. Apoptotic effects of clomipramine (CLOM), desipramine (DMI) and of norfluoxetine (NORF, the active metabolite of fluoxetine), on cellular viability were indicated by morphological changes and concentration-dependent increases in caspase-3 activity in CHO cells after 18 h exposure to CLOM, DMI and NORF. However, tianeptine (TIAN) was without effect. CLOM and NORF both reduced integrated mitochondrial function as shown by marked reductions in membrane potential (MMP) in mitochondria isolated from rat hearts. DMI also showed a similar but smaller effect, whereas, TIAN did not elicit any significant change in MMP. Moreover, micromolar concentrations of CLOM, DMI and NORF caused significant inhibitions of the activities of mitochondrial complexes (I, II/III and IV). The inhibitory effects on complex IV activity were most marked. TIAN inhibited only complex I activity at concentrations in excess of 20 µM. The observed inhibitory effects of antidepressants on the mitochondrial complexes were accompanied by a significant decrease in the mitochondrial state-3 respiration at concentrations above 10 µM. The results demonstrate that the apoptotic cell death observed in antidepressant-treated cells could be due to disruption of mitochondrial function resulting from multiple inhibition of mitochondrial enzyme complexes. The possibility that antimitochondrial actions of antidepressants could provide a potentially protective pre-conditioning effect is discussed.

Tricyclic antidepressants and the incidence of certain cancers: a study using the GPRD.

BACKGROUND: Several studies suggest links between cancer and tricyclic antidepressant use. METHODS: A case-control study using the General Practice Research Database examined whether previous tricyclic usage was associated with reduced incidence of brain (with glioma as a sub-category), breast, colorectal, lung and prostate cancers. Conditional logistic regression adjusted for age, gender, general practice, depression, smoking, body mass index, alcohol use and non-steroidal anti-inflammatory drug use. RESULTS: A total of 31 953 cancers were identified, each matched with up to two controls. We found a statistically significant reduction in tricyclic prescriptions compared with controls in glioma (odds ratio (OR) =0.59, 95% confidence interval (CI)=0.42-0.81) and colorectal cancer patients (OR=0.84, CI=0.75-0.94). These effects were dose-dependent (P-values for trend, glioma=0.0005, colorectal=0.001) and time-dependant (P-values for trend glioma=0.0005, colorectal=0.0086). The effects were cancer-type specific, with lung, breast and prostate cancers largely unaffected by antidepressant use. CONCLUSION: The biologically plausible, specific and dose- and time-dependant inverse association that we have found suggests that tricyclics may have potential for prevention of both colorectal cancer and glioma.

Dyslexia and DYX1C1: deficits in reading and spelling associated with a missense mutation.

The status of DYX1C1 (C15q21.3) as a susceptibility gene for dyslexia is unclear. We report the association of this gene with reading and spelling ability in a sample of adolescent twins and their siblings. Family-based association analyses were carried out on 13 single-nucleotide polymorphisms (SNPs) in DYX1C1, typed in 790 families with up to 5 offspring and tested on 6 validated measures of lexical processing (irregular word) and grapheme-phoneme decoding (pseudo-word) reading- and spelling-based measures of dyslexia, as well as a short-term memory measure. Significant association was observed at the misssense mutation rs17819126 for all reading measures and for spelling of lexical processing words, and at rs3743204 for both irregular and nonword reading. Verbal short-term memory was associated with rs685935. Support for association was not found at rs3743205 and rs61761345 as previously reported by Taipale et al., but these SNPs had very low (0.002 for rs3743205) minor allele frequencies in this sample. These results suggest that DYX1C1 influences reading and spelling ability with additional effects on short-term information storage or rehearsal. Missense mutation rs17819126 is a potential functional basis for the association of DYX1C1 with dyslexia.