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.

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.

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.

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.

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.

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.

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.

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.

Clinical outcome data for symptomatic breast cancer: the Breast Cancer Clinical Outcome Measures (BCCOM) Project.

BACKGROUND: Data collection for screen-detected breast cancer in the United Kingdom is fully funded, which has led to improvements in clinical practice. However, data on symptomatic cancer are deficient, and the aim of this project was to monitor the current practice. METHODS: A data set was designed together with surrogate outcome measures to reflect best practice. Data from cancer registries initially required the consent of clinicians, but in the third year anonymised data were available. RESULTS: The quality of data improved, but this varied by region and only a third of the cases were validated by clinicians. Regional variations in mastectomy rates were identified, and one-third of patients who underwent conservative surgery for the treatment invasive breast cancer were not recorded as receiving radiotherapy. CONCLUSION: National data are essential to ensure that all patients receive appropriate treatment for breast cancer, but variations still exist in the United Kingdom and further improvement in data capture is required.

Severe HDL deficiency due to novel defects in the ABCA1 transporter.

OBJECTIVES: The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency. SUBJECTS: Patients were referred to the clinic because of almost complete HDL deficiency. METHODS: The ABCA1 gene was sequenced directly. The analysis of the ABCA1 protein, ABCA1 mRNA and ABCA1-mediated cholesterol efflux was performed in cultured fibroblasts. Intracellular localization of ABCA1 mutants was investigated in transfected HEK293 cells. RESULTS: Two patients were homozygous for mutations in the coding region of the ABCA1 gene, resulting in an amino acid substitution (p.A1046D) and a truncated protein (p.I74YFsX76). The third patient was homozygous for a splice site mutation in intron 35 (c.4773 + 1g>a), resulting in an in-frame deletion of 25 amino acids (del p.D1567_K1591) in ABCA1. These patients had clinical manifestations of accumulation of cholesterol in the reticulo-endothelial system. The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). ABCA1-mediated cholesterol efflux was abolished in fibroblasts from patients with p.A1046D and del p.D1567_K1591 mutants and in fibroblasts homozygous for p.R587W. A reduced ABCA1 protein content was observed in these cells, suggesting an increased intracellular degradation. The mutant p.W1699C was largely retained in the endoplasmic reticulum, when expressed in HEK293 cells. CONCLUSIONS: The homozygotes for mutations which abolish ABCA1 function showed overt signs of involvement of the reticulo-endothelial system. This was not the case in the compound heterozygote for missense mutations, suggesting that this patient retains some residual ABCA1 function that reduces cholesterol accumulation in the reticulo-endothelial system.

Importance of routine cavity sampling in breast conservation surgery.

BACKGROUND: The role of cavity biopsy (CB) at the time of wide local excision (WLE) for primary breast cancer has not been evaluated fully. This study compared four groups of patients to determine the significance of margins and CB histology on tumour characteristics and outcome. METHODS: This was a retrospective study of patients undergoing WLE and CB in one institution over 21 years. Demographic data, tumour characteristics and survival information were obtained. Four subgroups of patients were compared according to their margin and cavity status (positive or negative). RESULTS: A total of 957 patients had WLE. The median 10-year survival was 85.6 per cent and breast cancer-specific survival was 92.4 per cent. Tumour size, grade, node and oestrogen receptor status were independent predictors of survival. There was poor concordance between positivity of resection margins and CB (32.0 per cent); a negative margin carried a 10.8 per cent risk of demonstrable residual disease. A positive CB, but not a positive margin, was associated with reduced overall survival and breast cancer-specific survival. CONCLUSION: Cavity status was more significant with regard to survival than margin status. CB is important in identifying residual and multifocal disease, as margin and cavity positivity are often not concordant.

The effects of antidepressants on cyclic AMP-response element-driven gene transcription in a model cell system.

The effects of the antidepressant drugs clomipramine (CLOM), desipramine (DMI), tianeptine (TIAN) and of norfluoxetine (NORF, the active metabolite of fluoxetine), were investigated in CHO cells expressing human beta2 adrenoceptors and a secreted placental alkaline phosphatase (SPAP) reporter gene to determine their actions on cyclic AMP-driven gene transcription. After 18 h of exposure, CLOM, DMI and NORF, but not TIAN, had biphasic effects on 1 microM isoprenaline-stimulated SPAP fsproduction with concentrations between 10 nM and 1 microM enhancing the maximal (E(max)) SPAP response, without changing EC50 values, but higher concentrations produced marked inhibitory effects. At nanomolar concentrations, CLOM and DMI increased expression of phospho-CREB (cyclic AMP response element binding protein). NORF was less effective but did significantly increase phospho-CREB at a concentration of 200 nM. TIAN had no effect. None of the antidepressants had any effect on CREB expression, nor on the accumulation of cyclic AMP. After prolonged exposure (7-21 days) to a low concentration (200 nM) of the antidepressants, the enhanced E(max) values for SPAP production evident after 18 h were not maintained but CLOM and DMI induced a significant leftward shift in the isoprenaline EC50 after a 7-day period of treatment and this was sustained at the 21 day time point. TIAN did not produce any significant changes. The results demonstrate that, in vitro, some but not all antidepressants can modify gene transcription via monoamine and cyclic AMP-independent mechanisms. The in vivo adaptive responses to TIAN probably involve alterations in different gene sets to those affected by other antidepressants.

The significance of the site of recurrence to subsequent breast cancer survival.

AIM: To investigate differences in the 3-year survival of patients with recurrent breast cancer dependent on recurrence site. METHODS: The study was a review of 294 patients from a breast cancer database, who were treated for operable breast cancer and subsequently developed a recurrence between 1989 and 2003. Patients were divided into four groups according to the site of first recurrence (local, lymph node, bone or visceral). Breast Cancer Specific Survival (BCSS) was compared using Kaplan-Meier life table analysis and the log rank test. RESULTS: Patient and tumour characteristics were comparable between the four groups. Survival rates between the recurrence site groups were significantly different. Patients in whom first recurrence was local had the best prognosis with a 3-year BCSS of 83% compared to 33% for patients with first node recurrence (p<0.001), 23% for patients with first bone recurrence (p=0.03) and 13% for patients with first visceral recurrence (p=0.004). CONCLUSION: Survival of patients with recurrent breast cancer is associated with the site of first recurrence. The prognosis from recurrence is progressively worse with local, regional, bone and visceral metastasis.

Metabolites in the developing rat liver--a proton nuclear magnetic resonance spectroscopic study.

We have used 1H-NMR spectroscopy in vitro to investigate metabolite changes in the rat liver in the first 21 days of life. The principle findings are firstly that betaine, a metabolite of choline, was relatively low (1-2 mumol/g) on days 1-7, then rose sharply to 5-6 mumol/g by day 19, whereas approximately reciprocal changes occurred in taurine levels. Secondly the lactate levels were remarkably low (0.1-0.8 mumol/g) on days 1-7. Changes in two other choline derivatives, phosphocholine (PC) and glycerophosphorylcholine (GPC) are also reported. The results are discussed in the context of the origin of these metabolites in the neonatal period, their levels in the adult (180 day-old) rat and the significance of the measured changes in metabolite levels during liver development.

Endoplasmic reticulum: the major contributor to the PDE peak in hepatic 31P-NMR spectra at low magnetic field strengths.

31P-NMR spectra of liver in vivo, subcellular fractions and model systems were acquired in order to characterise further the hepatic phosphodiester peak seen at low magnetic field strengths previously shown to be predominantly due to phospholipid bilayers. The data obtained in this study in vitro suggested that the phospholipid membranes of the endoplasmic reticulum provide the dominant contribution to this phosphodiester peak. Support for this hypothesis was provided by experiments on rats. Phenobarbitone, which is known to induce proliferation of the endoplasmic reticulum produced a considerable increase in intensity of the phosphodiester peak in liver spectra in vivo.