Living with trimethylaminuria and body and breath malodour: personal perspectives.

Background: Many people suffer from body and breath malodour syndromes. One of these is trimethylaminuria, a condition characterized by excretion in breath and bodily fluids of trimethylamine, a volatile and odorous chemical that has the smell of rotting fish. Trimethylaminuria can be primary, due to mutations in the gene encoding flavin-containing monooxygenase 3, or secondary, due to various causes.

Metabolomic and transcriptomic analyses of Fmo5-/- mice reveal roles for flavin-containing monooxygenase 5 (FMO5) in NRF2-mediated oxidative stress response, unfolded protein response, lipid homeostasis, and carbohydrate and one-carbon metabolism.

Flavin-containing monooxygenase 5 (FMO5) is a member of the FMO family of proteins, best known for their roles in the detoxification of foreign chemicals and, more recently, in endogenous metabolism. We have previously shown that Fmo5-/- mice display an age-related lean phenotype, with much reduced weight gain from 20 weeks of age. The phenotype is characterized by decreased fat deposition, lower plasma concentrations of glucose, insulin and cholesterol, higher glucose tolerance and insulin sensitivity, and resistance to diet-induced obesity.

Treatment of wild-type mice with 2,3-butanediol, a urinary biomarker of mice, decreases plasma cholesterol and epididymal fat deposition.

We previously showed that mice exhibit a lean phenotype and slower metabolic ageing. Their characteristics include lower plasma glucose and cholesterol, greater glucose tolerance and insulin sensitivity, and a reduction in age-related weight gain and whole-body fat deposition. In this paper, nuclear magnetic resonance (NMR) spectroscopy-based metabolite analyses of the urine of and wild-type mice identified two isomers of 2,3-butanediol as discriminating urinary biomarkers of mice.

Diagnoses after newly recorded abdominal pain in primary care: observational cohort study.

Background: Non-acute abdominal pain in primary care is diagnostically challenging.

Aim: To quantify the 1-year cumulative incidence of 35 non-malignant diagnoses and nine cancers in adults after newly recorded abdominal pain in primary care.

Design And Setting: Observational cohort study of 125 793 Clinical Practice Research Datalink GOLD records.

Intra-abdominal cancer risk with abdominal pain: a prospective cohort primary care study.

Background: Quantifying cancer risk in primary care patients with abdominal pain informs diagnostic strategies.

Aim: To quantify oesophagogastric, colorectal, liver, pancreatic, ovarian, uterine, kidney, and bladder cancer risks associated with newly reported abdominal pain with or without other symptoms, signs, or abnormal blood tests (that is, features) indicative of possible cancer.

Design And Setting: This was an observational prospective cohort study using Clinical Practice Research Datalink records with English cancer registry linkage.

Recognizing sinonasal cancer in primary care: a matched case-control study using electronic records.

Background: Cancers of the nasopharynx, nasal cavity, and accessory sinuses ("sinonasal") are rare in England, with around 750 patients diagnosed annually. There are no specific National Institute for Health and Care Excellence (NICE) referral guidelines for these cancers and no primary care research published.

Objective: To identify and quantify clinical features of sinonasal cancer in UK primary care patients.

Quantifying the impact of pre-existing conditions on the stage of oesophagogastric cancer at diagnosis: a primary care cohort study using electronic medical records.

Background: Pre-existing conditions interfere with cancer diagnosis by offering diagnostic alternatives, competing for clinical attention or through patient surveillance.

Objective: To investigate associations between oesophagogastric cancer stage and pre-existing conditions.

Methods: Retrospective cohort study using Clinical Practice Research Datalink (CPRD) data, with English cancer registry linkage.

Microcytosis as a risk marker of cancer in primary care: a cohort study using electronic patient records.

Background: Microcytosis (smaller than normal red blood cells) has previously been identified as a possible early risk marker for some cancers. However, the role of microcytosis across all cancers has not been fully investigated.

Aim: To examine cancer incidence in a cohort of patients with microcytosis, with and without accompanying anaemia.

Flavin-Containing Monooxygenase 1 Catalyzes the Production of Taurine from Hypotaurine.

Taurine is one of the most abundant amino acids in mammalian tissues. It is obtained from the diet and by de novo synthesis from cysteic acid or hypotaurine. Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive.

Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease.

The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease.The majority of FMO-mediated metabolism in adult human liver is catalyzed by FMO3. Some drugs are metabolized in human liver predominantly by FMO3, but most drug substrates of FMO3 are metabolized also by other enzymes, particularly cytochromes P-450, and the FMO3-catalyzed reaction is not the major route of metabolism.

Recognising laryngeal cancer in primary care: a large case-control study using electronic records.

Background: Over 1700 people are diagnosed with laryngeal cancer annually in England. Current National Institute for Health and Care Excellence (NICE) guidelines on referral for suspected laryngeal cancer were based on clinical consensus, in the absence of primary care studies.

Aim: To identify and quantify the primary care features of laryngeal cancer.

Selection of men for investigation of possible testicular cancer in primary care: a large case-control study using electronic patient records.

Background: Testicular cancer incidence has risen over the last two decades and is expected to continue to rise. There are no primary care studies on the clinical features of testicular cancer, with recent National Institute for Health and Care Excellence (NICE) guidance based solely upon clinical consensus.

Aim: To identify clinical features of testicular cancer and to quantify their risk in primary care patients, with the aim of improving the selection of patients for investigation.

Metabolic Biomarkers of Ageing in C57BL/6J Wild-Type and Flavin-Containing Monooxygenase 5 (FMO5)-Knockout Mice.

It was recently demonstrated in mice that knockout of the flavin-containing monooxygenase 5 gene, , slows metabolic ageing via pleiotropic effects. We have now used an NMR-based metabonomics approach to study the effects of ageing directly on the metabolic profiles of urine and plasma from male, wild-type C57BL/6J and (FMO5 KO) mice back-crossed onto the C57BL/6J background. The aim of this study was to identify metabolic signatures that are associated with ageing in both these mouse lines and to characterize the age-related differences in the metabolite profiles between the FMO5 KO mice and their wild-type counterparts at equivalent time points.

Effect of Flavin-Containing Monooxygenase Genotype, Mouse Strain, and Gender on Trimethylamine -oxide Production, Plasma Cholesterol Concentration, and an Index of Atherosclerosis.

The objectives of the study were to determine the contribution, in mice, of members of the flavin-containing monooxygenase (FMO) family to the production of trimethylamine (TMA) -oxide (TMAO), a potential proatherogenic molecule, and whether under normal dietary conditions differences in TMAO production were associated with changes in plasma cholesterol concentration or with an index of atherosclerosis (Als). Concentrations of urinary TMA and TMAO and plasma cholesterol were measured in 10-week-old male and female C57BL/6J and CD-1 mice and in mouse lines deficient in various genes ( , , , and ). In female mice most TMA -oxygenation was catalyzed by FMO3, but in both genders 11%-12% of TMA was converted to TMAO by FMO1.

A highly sensitive liquid chromatography electrospray ionization mass spectrometry method for quantification of TMA, TMAO and creatinine in mouse urine.

Our method describes the quantification in mouse urine of trimethylamine (TMA), trimethylamine -oxide (TMAO) and creatinine. The method combines derivatization of TMA, with ethyl bromoacetate, and LC chromatographic separation on an ACE C column. The effluent was continuously electrosprayed into the linear ion trap mass spectrometer (LTQ), which operated in selective ion monitoring (SIM) modes set for targeted analytes and their internal standards (IS).

Identification of Flavin-Containing Monooxygenase 5 (FMO5) as a Regulator of Glucose Homeostasis and a Potential Sensor of Gut Bacteria.

We have previously identified flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic aging. The aim of the present study was to investigate the role of FMO5 in glucose homeostasis and the impact of diet and gut flora on the phenotype of mice in which the gene has been disrupted ( mice). In comparison with wild-type (WT) counterparts, mice are resistant to age-related changes in glucose homeostasis and maintain the higher glucose tolerance and insulin sensitivity characteristic of young animals.

Clinical relevance of thrombocytosis in primary care: a prospective cohort study of cancer incidence using English electronic medical records and cancer registry data.

Background: Thrombocytosis (raised platelet count) is an emerging risk marker of cancer, but the association has not been fully explored in a primary care context.

Aim: To examine the incidence of cancer in a cohort of patients with thrombocytosis, to determine how clinically useful this risk marker could be in predicting an underlying malignancy.

Design And Setting: A prospective cohort study using Clinical Practice Research Datalink data from 2000 to 2013.

Clinical features of bowel disease in patients aged <50 years in primary care: a large case-control study.

Background: Incidences of colorectal cancer (CRC) and inflammatory bowel disease (IBD) are increasing in those aged <50 years.

Aim: To identify and quantify clinical features in primary care of CRC/IBD in those aged <50 years. This study considered the two conditions together and aimed to determine which younger patients, presenting in primary care with symptoms, would benefit from investigation for potentially serious colorectal disease.

Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease.

Flavin-containing monooxygenase 3 (FMO3) is known primarily as an enzyme involved in the metabolism of therapeutic drugs. On a daily basis, however, we are exposed to one of the most abundant substrates of the enzyme trimethylamine (TMA), which is released from various dietary components by the action of gut bacteria. FMO3 converts the odorous TMA to nonodorous TMA N-oxide (TMAO), which is excreted in urine.

Drug metabolism by flavin-containing monooxygenases of human and mouse.

Flavin-containing monooxygenases (FMOs) play an important role in drug metabolism. Areas covered: We focus on the role of FMOs in the metabolism of drugs in human and mouse. We describe FMO genes and proteins of human and mouse; the catalytic mechanism of FMOs and their significance for drug metabolism; differences between FMOs and CYPs; factors contributing to potential underestimation of the contribution of FMOs to drug metabolism; the developmental and tissue-specific expression of FMO genes and differences between human and mouse; and factors that induce or inhibit FMOs.

The integration and interpretation of pharmacogenomics - a comparative study between the United States of America and Europe: towards better health care.

The study of pharmacogenomics has, by harnessing sequence information from human genomes, the potential to lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. For this potential to be realized results need to be interpreted to the prescriber into a format which dictates an action. This mini review briefly describes the history, the regulatory environment, opinions towards, and implementation, integration and interpretation of pharmacogenomics in the United States of America and Europe.

A guide to the identification of metabolites in NMR-based metabonomics/metabolomics experiments.

Metabonomics/metabolomics is an important science for the understanding of biological systems and the prediction of their behaviour, through the profiling of metabolites. Two technologies are routinely used in order to analyse metabolite profiles in biological fluids: nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), the latter typically with hyphenation to a chromatography system such as liquid chromatography (LC), in a configuration known as LC-MS. With both NMR and MS-based detection technologies, the identification of the metabolites in the biological sample remains a significant obstacle and bottleneck.

Symptoms of adult chronic and acute leukaemia before diagnosis: large primary care case-control studies using electronic records.

Background: Leukaemia is the eleventh commonest UK cancer. The four main subtypes have different clinical profiles, particularly between chronic and acute types.

Aim: To identify the symptom profiles of chronic and acute leukaemia in adults in primary care.