When is an SNP not an SNP?

Genomic duplications are important sources of structural change and gene innovation. In humans, the most recent and highly identical sequences (>90% homology, >1 kb long) are known as segmental duplications (SDs). Single-nucleotide variants or single-nucleotide polymorphisms within SDs have not been systematically assessed due to limitations around mapping short-read sequencing data.

The Intricacies of Renal Phosphate Reabsorption-An Overview.

To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions.

Biochemistry and pathophysiology of the Transient Potential Receptor Vanilloid 6 (TRPV6) calcium channel.

TRPV6 is a Transient Receptor Potential Vanilloid (TRPV) cation channel with high selectivity for Ca ions. First identified in 1999 in a search for the gene which mediates intestinal Ca absorption, its far more extensive repertoire as a guardian of intracellular Ca has since become apparent. Studies on TRPV6-deficient mice demonstrated additional important roles in placental Ca transport, fetal bone development and male fertility.

Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones.

Background: Calcium kidney stones are common and recurrences are often not preventable by available empiric remedies. Their etiology is multifactorial and polygenic, and an increasing number of genes are implicated. Their identification will enable improved management.

Evaluation of the economic burden of kidney stone disease in the UK: a retrospective cohort study with a mean follow-up of 19 years.

Objective: To estimate the cost of kidney stone disease (KSD) in England.

Patients And Methods: We conducted a retrospective cohort study of patients with KSD, referred to a metabolic stone clinic between 1990 and 2007 using electronic records of patients with KSD in a tertiary referral centre, to determine cost using UK National Health Service (NHS) tariff, with subsequent extrapolation to the entire England population. Those with no documentation and <5 years follow-up were excluded.

Phosphaturia in kidney stone formers: Still an enigma.

Calcium kidney stones are common worldwide. Most are idiopathic and composed of calcium oxalate. Calcium phosphate is present in around 80% and may initiate stone formation.

The acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) inhibits glutathione synthetase in vitro; a clue to the mechanism of 5-oxoprolinuric acidosis?

1. Metabolic acidosis due to accumulation of l-5-oxoproline is a rare, poorly understood, disorder associated with acetaminophen treatment in malnourished patients with chronic morbidity. l-5-Oxoprolinuria signals abnormal functioning of the γ-glutamyl cycle, which recycles and synthesises glutathione.

Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency.

Background: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients.

Methods: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire.

Monocarboxylate transporter 1 deficiency and ketone utilization.

Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in a patient with recurrent, severe ketoacidosis and identified a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 (SLC16A1, also called MCT1). Genetic analysis in 96 patients suspected of having ketolytic defects yielded seven additional inactivating mutations in MCT1, both homozygous and heterozygous.

2-Pentanone production from hexanoic acid by Penicillium roqueforti from blue cheese: is this the pathway used in humans?

Production of 2-pentanone, a methylketone, is increased in fasting ketotic humans. Its origin is unknown. We hypothesised that it is formed via β -oxidation of hexanoic acid by the peroxisomal pathway proposed for methylketone-producing fungi and yeasts.

Characterisation of risk factors for stones in hyperuricosuric men attending a stone clinic.

Hyperuricosuria is common among stone formers, but its significance is uncertain. To progress our understanding and target treatment, we need to identify and characterise patients with uniform underlying pathology. We aimed to identify hyperuricosuric patients with a primary defect in renal urate reabsorption (renal hyperuricosuria) and to look for associated risk factors for stones.

Ammonia metabolism and hyperammonemic disorders.

Human adults produce around 1000 mmol of ammonia daily. Some is reutilized in biosynthesis. The remainder is waste and neurotoxic.

Male hypercalciuric stone formers with low renal calcium reabsorption.

Aims: Hypercalciuria is a common poorly understood abnormality among stone formers. We aimed to identify hypercalciuric male stone formers with a primary defect in renal calcium reabsorption and to look for associated risk factors.

Methods: A retrospective cross-sectional database study of 623 male idiopathic calcium stone formers with normal plasma ultrafilterable calcium levels attending the Southampton stone clinic.

Who makes uric acid stones and why--observations from a renal stones clinic.

Aims: Excessively acidic urine is the dominant factor in uric acid stone formation. Recent evidence implicating insulin resistance has revived interest in its causation. We reviewed data on uric acid stone formers attending a general stones clinic to find out whether this supports and adds to current concepts.

Demography and biochemistry of 2800 patients from a renal stones clinic.

Background: Because the causes of stones are uncertain, interventions to prevent recurrence have an insecure foundation. Progress depends on careful evaluation of stone formers.

Methods: A descriptive retrospective database study of 1983 men and 816 women from the Southampton stones clinic from 1990 to March 2007.

Twenty-four-hour urinary trace element excretion: reference intervals and interpretive issues.

Background: Introduction of inductively coupled plasma mass spectrometry (ICP-MS) into clinical laboratories has led to an increasing application of analyses to risk assessment for toxicity from environmental exposure to trace elements, and in occupational monitoring. Interpretation of results from random urine samples may be problematic and measurement of excretion over 24 h is sometimes preferable. Recent reference data are sparse.

Severe hyperammonaemia in adults not explained by liver disease.

Ammonia is produced continuously in the body. It crosses the blood-brain barrier readily and at increased concentration it is toxic to the brain. A highly integrated system protects against this: ammonia produced during metabolism is detoxified temporarily by incorporation into the non-toxic amino acid glutamine.

Hsp40 chaperones promote degradation of the HERG potassium channel.

Loss of function mutations in the hERG (human ether-a-go-go related gene or KCNH2) potassium channel underlie the proarrhythmic cardiac long QT syndrome type 2. Most often this is a consequence of defective trafficking of hERG mutants to the cell surface, with channel retention and degradation at the endoplasmic reticulum. Here, we identify the Hsp40 type 1 chaperones DJA1 (DNAJA1/Hdj2) and DJA2 (DNAJA2) as key modulators of hERG degradation.

Potential in vitro effects of carbon nanotubes on human aortic endothelial cells.

Respiratory exposure of mice to carbon nanotubes induces pulmonary toxicity and adverse cardiovascular effects associated with atherosclerosis. We hypothesize that the direct contact of carbon nanotubes with endothelial cells will result in dose-dependent effects related to altered cell function and cytotoxicity which may play a role in potential adverse pulmonary and cardiovascular outcomes. To test this hypothesis, we examined the effects of purified single- and multi-walled carbon nanotubes (SWCNT and MWCNT) on human aortic endothelial cells by evaluating actin filament integrity and VE-cadherin distribution by fluorescence microscopy, membrane permeability by measuring the lactate dehydrogenase (LDH) release, proliferation/viability by WST-1 assay, and overall functionality by tubule formation assay.

3-Penten-2-one, a novel aldehyde adduct, is a biomarker for increased acetaldehyde in urine.

Diagnostic profiling of urine for volatile compounds of around 400 patients using headspace solid-phase microextraction (HS-SPME) in alkaline conditions identified 3-penten-2-one (approximately 1 to >6.3 micromol/L) in 26 patients. Five were in barbiturate coma.

Regulation of cell surface expression of functional pacemaker channels by a motif in the B-helix of the cyclic nucleotide-binding domain.

Previous studies have suggested that a portion of the cyclic nucleotide-binding domain (CNBD) of the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) "pacemaker" channel, composed of the A- and B-helices and the interceding beta-barrel, confers two functions: inhibition of channel opening in response to hyperpolarization and promotion of cell surface expression. The sequence determinants required for each of these functions are unknown. In addition, the mechanism underlying plasma membrane targeting by this subdomain has been limitedly explored.

Co-chaperone FKBP38 promotes HERG trafficking.

The Long QT Syndrome is a cardiac disorder associated with ventricular arrhythmias that can lead to syncope and sudden death. One prominent form of the Long QT syndrome has been linked to mutations in the HERG gene (KCNH2) that encodes the voltage-dependent delayed rectifier potassium channel (I(Kr)). In order to search for HERG-interacting proteins important for HERG maturation and trafficking, we conducted a proteomics screen using myc-tagged HERG transfected into cardiac (HL-1) and non-cardiac (human embryonic kidney 293) cell lines.

PI3K activation is required for PMA-directed activation of cSrc by AFAP-110.

Activation of PKCalpha will induce the cSrc binding partner AFAP-110 to colocalize with and activate cSrc. The ability of AFAP-110 to colocalize with cSrc is contingent on the integrity of the amino-terminal pleckstrin homology (PH1) domain, while the ability to activate cSrc is dependent on the integrity of its SH3 binding motif, which engages the cSrc SH3 domain. The outcome of AFAP-110-directed cSrc activation is a change in actin filament integrity and the formation of podosomes.

Solid-phase microextraction: investigation of the metabolism of substances that may be abused by inhalation.

Purified liquefied petroleum gas (LPG), a mixture of butane, isobutane, and propane, is commonly abused by inhalation. Little is known about the mammalian metabolism of these substances. Metabolism of other hydrocarbons, including n-hexane and cyclohexane, has been studied in vitro using a range of liver preparations, with metabolites analyzed by static headspace techniques.