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Vitamin B12 is one of the most complex cofactors known, and this chapter will discuss current understanding with regards to the cobalt insertion step of its syntheses. Two total syntheses of vitamin B12 were reported in the 1970s, which remain two of the most exceptional achievements of natural product synthesis. In subsequent years, two distinct biosynthetic pathways were identified in aerobic and anaerobic organisms. For these biosynthetic pathways, selectivity for Co(II) over other divalent metal ions with similar ionic radii and coordination chemistry remains an open question with three competing hypotheses proposed: metal affinity, tetrapyrrole distortion, and product inhibition. A 20 step biosynthetic route to convert 5-aminolevulinic acid (ALA) to vitamin B12 was elucidated in aerobic organisms in the 1990s, where cobalt is inserted relatively late in the pathway by the CobNST multi-protein complex. This chapter includes a mechanistic proposal for this reaction, but the majority of the proposal is based upon analogy to the ChlDHI magnesium chelatase complex as critical data for the cobalt chelatase is lacking. Later, in the 2010s, a distinct 21 step pathway from ALA to vitamin B12 was reported in anaerobic organisms, where cobalt is inserted early in the pathway by the enzyme CbiK. A recent study strongly suggests that the cobalt affinity of CbiK is the origin of cobalt selectivity for CbiK, but several important mechanistic questions remain unanswered. In general, it is expected that significant insight into the cobalt insertion mechanisms of CobNST and CbiK could be derived from additional structural, spectroscopic, and computational data.

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Alzheimer's disease is the commonest form of senile dementia. It is characterised by neuronal cell death and amyloid deposition. Amyloid precursor protein (APP), which is highly conserved in evolution, is expressed in neurones in response to a wide range of damaging agents. The hypothesis proposed is that APP has a protective function to counter damage but if it fails and the neurone dies then breakdown products of APP miss-fold and lead to amyloid deposition. This fits with the evidence that amyloid deposition is a consequence rather than a cause of cell death. Germ line mutations in APP impair the protective role and lead to increased neuronal loss in response to damage. This leads to early onset and severe Alzheimer's disease. Inflammation, infection, hypoxia, trauma and pollution are damaging agents which interact to cause the disease. The bacteria which cause chronic periodontitis appear to have a significant role. Prevention needs to focus on avoiding trauma, reducing pollution and improving dental hygiene. Furthermore we should attempt to optimise the oral microbial flora by suppressing the growth of pathogenic bacteria that cause gum disease and the bacterial pathogens in the oropharynx that cause life threatening infections following viral upper respiratory infections. This leads to a key research question: does the regular consumption of natural live yoghurt reduce the carriage of periodontal and oropharyngeal bacterial pathogens? Theoretical considerations indicate it should and if so regular natural live yoghurt consumption could be an important preventive agent.

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The cerebral ventricles have been studied since the fourth century BC and were originally thought to harbor the soul and higher executive functions. During the infancy of neuroradiology, alterations to the ventricular shape and position on pneumoencephalography and ventriculography were signs of mass effect or volume loss. However, in the current era of high-resolution cross-sectional imaging, variation in ventricular anatomy is more easily detectable and its clinical significance is still being investigated. Interpreting radiologists must be aware of anatomic variations of the ventricular system to prevent mistaking normal variants for pathology. We will review of the anatomy and development of the lateral ventricles and discuss several ventricular variations.

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BACKGROUND: The hierarchical model of stem cell genesis is based on the idea that the number of cell divisions between the zygote and fully differentiated epithelial cells is kept close to the minimum, which is log to the base 2 of the total number of cells produced in a human lifetime. The model assumes the orderly progression of stem cell divisions requires precise control at every stage in development. If the orderly progression is maintained then cancer will be rare. A prediction of the model is that if the orderly progression of the stem cell hierarchy is disturbed by trauma, ulceration or inflammation then cancer will occur. HYPOTHESIS: Bacterial induced inflammation in breast ducts disturbs the stem cell hierarchy and is a cause of breast cancer. EVIDENCE: Mammalian milk is not sterile. It contains a range of bacteria, derived endogenously by the entero-mammary circulation. The dominant flora consists of lactose fermenting bacteria. Pregnancy and breast feeding reduce the risk of subsequent breast cancer. The implication is that a lactose fermenting bacterial flora in breast ducts is protective. Malignant and benign breast tissue contains bacteria derived endogenously, but studies so far have not revealed a specific flora associated with malignancy. Periodontitis is associated with oral, oesophageal, colonic, pancreatic, prostatic and breast cancer. The pathogenic bacteria which cause periodontitis spread endogenously to cause inflammation at other epithelial sites. Meta-analysis of epidemiological studies shows that the consumption of yoghurt is associated with a reduction in the risk of breast cancer. CONCLUSION: The hypothesis, although not proven, is supported by the available evidence. Lactose fermenting bacteria protect but pathogenic bacteria which induce inflammation raise the risk of breast cancer. The consumption of yoghurt also appears to be protective.

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Through the analysis of acoustic recordings of captive Pterois spp., this study has confirmed anecdotal evidence that Pterois spp. are soniferous. This report of sound production in Pterois spp. provides the foundation for future research into their specific acoustic capabilities including sound production mechanisms, the role of social behaviour and applied techniques for controlling and monitoring invasive Pterois spp. in the tropical and temperate western Atlantic Ocean.

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Aphids are phloem-feeding insects that cause yield loss on a wide range of crops, including cereals such as barley. Whilst most aphid species are limited to one or few host species, some are able to reproduce on many plants belonging to different families. Interestingly, aphid probing behaviour can be observed on both host and non-host species, indicating that interactions take place at the molecular level that may impact host range. Here, we aimed to gain insight into the interaction of barley with aphid species differing in their ability to infest this crop by analysing transcriptional responses. Firstly, we determined colonization efficiency, settlement and probing behaviour for the aphid species Rhopalosiphum padi, Myzus persicae and Myzus cerasi, which defined host, poor-host and non-host interactions, respectively. Analyses of barley transcriptional responses revealed gene sets differentially regulated upon the different barley-aphid interactions and showed that the poor-host interaction with M. persicae resulted in the strongest regulation of genes. Interestingly, we identified several thionin genes strongly up-regulated upon interaction with M. persicae, and to a lesser extent upon R. padi interaction. Ectopic expression of two of these genes in Nicotiana benthamiana reduced host susceptibility to M. persicae, indicating that thionins contribute to defences against aphids.

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The hypothesis proposed is that functional disorders, such as irritable bowel syndrome, chronic fatigue syndrome and anorexia nervosa are caused by auto-antibodies to neuronal proteins induced by molecular mimicry with microbial antigens. The age incidence of these conditions, the marked female excess, increase with economic and technological advance, precipitation by infection, and the paucity of histological changes are all consistent with the hypothesis. It can be tested directly using human sera to search for cross reaction with brain proteins in model systems such as Drosophila melanogaster. The conditions might be amenable to treatment using pooled immunoglobulin. Identification and elimination from the microbial flora of the bacteria that express the cross reacting antigens should be possible.

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BACKGROUND: Hospitalised patients with inflammatory bowel disease are 1.5- to 3.5-fold more likely to develop venous thromboembolism compared to controls. Clinical guidelines recommend pharmacological prophylaxis. AIM: To determine the rate of pharmacological venous thromboembolism prophylaxis prescription and administration in a cohort of hospitalised patients with severe active ulcerative colitis and to assess predictors of failure to order pharmacological prophylaxis at 24 h. METHODS: This is a retrospective review of hospitalised patients with severe active ulcerative colitis, identified by ICD-9-CM discharge code 556.x, admitted to a single tertiary care hospital from 1 January 2005 to 31 August 2012. Adequate thromboembolism prophylaxis was defined as an order for low-dose unfractionated heparin two to three times daily, low-molecular weight heparin 40 mg daily or fondaparinux 2.5 mg daily ordered and administered for >80% of the admission. Patient related factors associated with failure to order prophylaxis at 24 h were accessed as secondary outcomes. RESULTS: Three hundred and thirty-six patients were hospitalised with severe active ulcerative colitis. Hospitalists had prescribed appropriate pharmacological prophylaxis by 48 h in only 37% of cases. Of these, nurses administered all prescribed doses in 18% of cases. Only 7% of patients (22/304, 95% CI: 5-11%) received adequate pharmacological prophylaxis for >80% of their hospitalisation. Hematochezia (P = 0.002), elevated platelets (P = 0.008), male gender coupled with younger age (P = 0.005) and admission on a biologic (P = 0.03) were associated with failure to order prophylaxis. CONCLUSION: Hospitalised patients admitted with severe active ulcerative colitis are not receiving appropriate pharmacological venous thromboembolism prophylaxis.

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MOTIVATION: Existing microarray genotype-calling algorithms adopt either SNP-by-SNP (SNP-wise) or sample-by-sample (sample-wise) approaches to calling. We have developed a novel genotype-calling algorithm for the Illumina platform, optiCall, that uses both SNP-wise and sample-wise calling to more accurately ascertain genotypes at rare, low-frequency and common variants. RESULTS: Using data from 4537 individuals from the 1958 British Birth Cohort genotyped on the Immunochip, we estimate the proportion of SNPs lost to downstream analysis due to false quality control failures, and rare variants misclassified as monomorphic, is only 1.38% with optiCall, in comparison to 3.87, 7.85 and 4.09% for Illuminus, GenoSNP and GenCall, respectively. We show that optiCall accurately captures rare variants and can correctly account for SNPs where probe intensity clouds are shifted from their expected positions. AVAILABILITY AND IMPLEMENTATION: optiCall is implemented in C++ for use on UNIX operating systems and is available for download at http://www.sanger.ac.uk/resources/software/opticall/.

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Adults of Lecithochirium floridense (Digenea: Hemiuridae) parasitized the stomach in each of 22 necropsied lionfish, Pterois cf. volitans (Scorpaeniformes: Scorpaenidae) (prevalence  =  100%, mean intensity  =  11), captured in the northwestern Atlantic Ocean off Beaufort, North Carolina (34°14.83'N, 76°35.25'W). This is the first report of a digenean from the invasive lionfish and that of L. floridense from a species of Pterois. The leech specimen previously identified as Myzobdella lugubris from P. volitans in the northwestern Atlantic Ocean is re-identified as Trachelobdella lubrica based on a study of the original voucher specimen.

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UNLABELLED: BACKGROUND/SETTING: Treatment for 3 months with rifampicin (R) and isoniazid (H) (3RH) for latent tuberculosis infection (LTBI), defined as an inappropriately positive tuberculin skin test with no clinical or x-ray evidence of disease, has been used locally since 1989. The efficacy of this regimen in children in the UK has only been studied indirectly. The long-term outcome of those children treated with 3RH, in the Chest Clinic of this high tuberculosis (TB) incidence district, has been studied to derive a more direct assessment of effectiveness. METHODS: All children treated with 3RH for LTBI from 1989 to 2004 inclusive were matched with the local patient administration system (PAS), GP registration and local TB notification databases. Only those persons still registered locally on PAS, or locally GP registered were then checked for subsequent TB notification. RESULTS: A total of 334 patients were identified, of whom 252 remained locally, with 82 lost to follow-up; 3 cases of clinical TB developed in the 252 (1.19%), with 3113 years observation (mean 12.35 years) giving 0.964/1000 person years (95% CI 0.199 to 2.816). Sensitivity analyses showed a 'best case' scenario of 0.727/1000 person years (95% CI 0.15 to 2.12), and if 10% of those lost to follow-up developed clinical TB of 2.66/1000 person years (95% CI 1.33 to 4.77). CONCLUSIONS: Follow-up of those cases treated with 3RH, for a mean of 12.35 years, and over 3100 patient years observation, shows a rate of active TB of under 1/1000 patient years. This suggests that 3RH has very high efficacy when used to treat LTBI in children in the UK and compares favourably with the expected untreated TB rate.

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The red lionfish Pterois volitans is important not only in the aquarium trade but also as an invasive species in the western Atlantic. Introduced to waters off the southeastern coast of the United States, red lionfish have rapidly spread along much of the East Coast and throughout Bermuda, the Bahamas, and much of the Caribbean. Hematology and plasma biochemistry were evaluated in red lionfish captured from the offshore waters of North Carolina to establish baseline parameters for individual and population health assessment. Blood smears were evaluated for total and differential white blood cell counts, and routine clinical biochemical profiles were performed on plasma samples. To improve the interpretive value of routine plasma biochemistry profiles, tissue enzyme activities (alkaline phosphatase [ALP], alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], lactate dehydrogenase [LD], and creatine kinase [CK]) were analyzed from liver, kidney, skeletal muscle, gastrointestinal tract, and heart tissues from five fish. The hematological and plasma biochemical values were similar to those of other marine teleosts except that the estimated white blood cell counts were much lower than those routinely found in many species. The tissue enzyme activity findings suggest that plasma LD, CK, and AST offer clinical relevance in the assessment of red lionfish.

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AIM: To screen infant urine for staphylococcal pyrogenic toxins as a possible marker for a toxigenic, transient bacteraemia. METHODS: Nasopharyngeal swabs, skin swabs, stool and urine samples were collected from 30 infants at 2 weeks, 10 weeks and 7 months of age when the infants were healthy, and from infants of 7 months of age when they had a cold. Samples were cultured and Staphylococcus aureus isolates identified. Isolates were tested for the production of staphylococcal enterotoxin B (SEB), staphylococcal enterotoxin C (SEC) and toxic shock syndrome toxin (TSST-1). Urine samples were analysed for the presence of these toxins by ELISA. RESULTS: Nasopharyngeal carriage of S aureus decreased with age from 50% at 2 weeks of age to 13% in healthy infants at 7 months of age. Carriage was increased in infants over 7 months of age with a cold (36%). Stool carriage remained constant (37-40%) in healthy infants but increased significantly in infants over 7 months of age with a cold (82%). 13.9% of the isolates produced SEB, 16.7% produced SEC and 18% produced TSST-1. Some isolates produced more than one toxin. 43% of infants were colonised at some time with a toxigenic S aureus strain. S aureus toxins were detected in 9/101 urine samples. The proportion of positive samples was increased with infection and at 10 weeks of age. CONCLUSIONS: Infants are exposed early in life to S aureus pyrogenic toxins, which can be detected in infant urine samples. Age and infection affect the proportion of positive samples. The pattern of results can be explained by episodes of transient bacteraemia.

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SETTING: There is little information regarding the prognosis of respiratory symptoms in early adulthood or the effects of potential risk factors. OBJECTIVE: To observe changing respiratory morbidity in a group of young adults over a period of 6-8 years. DESIGN: Subjects responding to three or more consecutive postal respiratory surveys carried out between 1993 and 2001 were included in the study. In addition to asthma (defined by a validated scoring system), two symptoms were examined: wheeze and being woken by cough. Five outcomes were defined: persistent, remission, new onset, never and intermittent. RESULTS: Of 2693 subjects who responded to at least one survey, about one third were eligible for inclusion: 10.2% reported wheeze at each survey (persistent) and 3.6% had persistent asthma. Persistent wheeze was seen in almost half (46.7%) of those reporting the symptom at their first survey. The corresponding figure for asthma was 32%. New onset wheeze was found in 16.2% of subjects without wheeze at baseline (asthma 9.7%). Smoking was significantly associated with new onset wheeze (OR 1.97, 95% CI 1.30-3.00) and asthma (OR 2.14, 95% CI 1.26-3.50), but not with persistent symptoms. CONCLUSION: These findings highlight the importance of policies to reduce smoking prevalence in young adults, and will help in the planning of future health care.

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AIM: To assess the value of postmortem bacteriology in necropsy practice, with specific emphasis on bacterial invasion of blood and cerebrospinal fluid (CSF). METHODS: A review of published articles on postmortem bacteriology. Studies were selected to cover the full range of necropsy practice including adults, the perinatal period, and infancy. The review covers over 5000 necropsies, mainly in adults, but including 1108 perinatal cases and 468 cases of sudden unexpected death in infancy. Data are available on 4992 blood cultures, 1168 specimens of CSF, and 743 cultures of spleen. RESULTS: Studies in which careful precautions have been taken to reduce contamination show that approximately two thirds of blood cultures are negative, two in nine yield a single isolate, and one in nine have a mixed growth. The postmortem interval has only a small effect on the isolation rate. A pure growth of a known pathogen has a more than 50% likelihood of being found in association with genuine infection in adults and in the perinatal period. CONCLUSIONS: The main postmortem artefact is contamination, but this can be considerably reduced by careful technique. Agonal spread is less common than is often assumed. Postmortem translocation is not a problem if the body is appropriately stored. A pure growth of a pathogen in blood or CSF should be regarded as a possible contributing factor to death at all ages.

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The present study investigated the safety of induction therapy with daclizumab (compared with no induction treatment), in adult renal transplant patients reported to the Scientific Registry of Transplant Recipients (SRTR) database between January 1, 1998 and July 27, 2003. Patients who were discharged from the hospital on mycophenolate mofetil, azathioprine, or sirolimus were divided into two groups: induction treatment with daclizumab (n = 8203) and no induction treatment (n = 25,368). Patient survival, death due to infection and death due to malignancy were evaluated at 1 and 3 yr post-transplantation. Rejection and graft survival were also examined. Kaplan-Meier and Cox regression models were used to evaluate outcomes. No significant differences were found between patients treated with daclizumab compared with patients who received no induction therapy for death due to infection or malignancy at 1 and 3 yr post-transplantation. Patients treated with daclizumab (compared with no induction treatment) had statistically significantly better survival rates at 1 (96.9% vs. 96.2%, p = 0.003) and 3 yr (92.4% vs. 91.4%, p = 0.004) although absolute differences were minimal. This was confirmed in the multivariable Cox regression analysis for patient death at 1 (HR = 0.77, p < 0.001) and 3 yr (HR = 0.83, p = 0.001) post-transplantation. Patients treated with daclizumab compared to no induction had lower rejection rates at 1 (13.1% vs. 17.3%, p < 0.001) and 3 yr post-transplantation (16.7% vs. 21.3%, p < 0.001). Cox regression confirmed a decreased risk for rejection at 1 (HR = 0.74, p < 0.001) and 3 yr (HR = 0.75, p < 0.001). Treatment with daclizumab was associated with reduced risk for graft loss at 1 (HR = 0.82, p < 0.001) and 3 years (HR = 0.86, p < 0.001). In conclusion, daclizumab was associated with a significantly reduced risk for rejection and graft loss compared with no induction treatment, and improved patient survival. In addition, daclizumab was not associated with an increase in risk of death due to infection or malignancy, when compared with no induction therapy. These findings demonstrate the short and long-term safety and efficacy of daclizumab in patients transplanted between January 1998 and July 2003.

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Six of eight cases of retinoblastoma previously identified as having a residential association with West Cumbria, England, in which the Sellafield nuclear installation is situated, were examined for the presence of a constitutional RB1 mutation. No mutations were detected, thus providing strong evidence against an environmental or occupational genotoxic effect causing germline mutations in the parents of these children.

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AIM: The aim of this study was to compare subjective (Ramsay sedation score, RSS) with objective electroencephalogram-based bispectral index (BIS) assessment, and to validate the appropriate BIS range for measurement of conscious sedation in interventional procedures. MATERIALS AND METHODS: One hundred patients undergoing sedo-analgesia (midazolam and fentanyl) for interventional gastrointestinal procedures were divided into two groups. In group A (n=30) sedation was guided by the RSS with the operator blinded to the BIS recording. In group B (n=70) the operator titrated intravenous sedation to maintain an optimal BIS, predetermined from the results in group A. Recovery time, procedure duration, physiological parameters and unplanned events were recorded in both groups. RESULTS: There was a significant correlation between the BIS and RSS (p<0.001). BIS values of 87.2 and 80.9 corresponded to an RSS of 3 and 4, respectively. The optimal BIS level was defined as 80-85. Fifty-seven point five percent of readings were within this range in group B compared with 26.5% in group A (p<0.001). Sedation approaching general anaesthesia (BIS<60) occurred in 5.5% of patients in group A but not in group B. Mean recovery time, duration of procedure, midazolam and fentanyl doses were significantly reduced in group B. Unplanned events were reduced from 27 to 17%, but this was not statistically significant (p=0.29). CONCLUSION: BIS monitoring enables more effective titration of sedatives to maintain a suitable level of consciousness, whilst reducing procedure time. The BIS offers an objective, safe and reliable measure of sedation, without disturbing either patient or operator. BIS monitoring raises the standard of patient care, and in our view, should be used to augment standard assessment.

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