Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb(3) concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant alpha-galactosidase A. The marked decline in urine Gb(3) on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment.

The growth of a pluripotent embryonic stem (ES) cell population is dependent on cell survival, proliferation and self-renewal. The nucleotide ATP represents an important extracellular signalling molecule that regulates the survival of differentiated cells, however, its role is largely undefined in embryonic stem cells. Here we report a role for ATP-gated P2X7 receptors in ES cell survival. The functional expression of P2X7 receptors in undifferentiated mouse ES cells is demonstrated using a selective P2X7 antagonist and small interfering RNA knockdown of these receptors. Our data illustrate a key role for the P2X7 receptor as an essential pro-survival signal required for optimal ES cell colony growth in the presence of leukemia inhibitor factor (LIF). However, chronic exposure to exogenous ATP leads to rapid P2X7-dependent cell death via necrosis. Together, these data demonstrate a novel role for P2X7 receptors in regulation of ES cell behaviour where they can mediate either a pro-survival or pro-death signal depending on the mode of activation.

<p style="margin-bottom: 0.46cm; line-height: 150%; widows: 0; orphans: 0;"><span style="font-family: Palatino Linotype,serif;"><span lang="en-GB"><span style="font-family: Palatino Linotype,serif;"><span lang="en-GB">A significant number of homeless people own dogs, with these animals contributing to the well-being of their owners by providing emotional support and in many cases, a reason for living as well as acting as what might be termed a social catalyst improving bonds between their owners. Yet many consider that homeless people should not be allowed, let alone encouraged to keep a dog. They consider that living with a homeless people must have a negative impact on the dog’s health and welfare compared to that of a dog owned by people with a home. Here we sought to determine the health and welfare of dogs owned by homeless people, comparing 50 dogs owned by homeless people with 50 owned by people living in a home. In contradistinction to the negative view noted above, we found that dogs owned by homeless people were healthy animals, less likely to be obese, had fewer behaviour issues such as aggression to strangers and separation anxiety  when compared to dogs owned by people living in a conventional home. We suggest that these findings should be taken into account when deciding whether a homeless person with a dog should be allowed into a hostel, and indeed the general attitude of the public to homeless people living with a dog by their side on the street</span></span></span></span></p>

Background: Creatine plays an important role in the storage and transmission of phosphate-bound energy. The cerebral creatine deficiency syndromes (CCDS) comprise three inherited defects in creatine biosynthesis and transport. They are characterized by mental retardation, speech and language delay and epilepsy. All three disorders cause low-creatine signal on brain magnetic resonance spectroscopy (MRS); however, MRS may not be readily available and even when it is, biochemical tests are required to determine the underlying disorder. Methods: Analysis was performed by liquid chromatography-tandem mass spectrometry in positive ionization mode. Samples were analysed underivatized using a rapid 'dilute and shoot' approach. Chromatographic separation of the three compounds was achieved. Stable isotope internal standards were used for quantification. Results: Creatine, creatinine and guanidinoacetate were measured with a 2.5 minute run time. For guanidinoacetate, the standard curve was linear to at least 5000 mmol/L and for creatine and creatinine it was linear to at least 25 mmol/L. The lower limit of quantitation was 0.4 mmol/L for creatine and guanidinoacetate and 0.8 mmol/L for creatinine. Recoveries ranged from 86% to 106% for the three analytes. Intra-and inter-assay variation for each analyte was ,10% in both urine and plasma. Conclusion: A tandem mass spectrometric method has been developed and validated for the underivatized determination of guanidinoacetate, creatine and creatinine in human urine and plasma. Minimal sample preparation coupled with a rapid run time make the method applicable to the routine screening of patients with suspected CCDS.

ObjectiveHepatitis C virus (HCV) infection is common. Although treatment is effective, with oral antivirals curing >95% of patients, most individuals have comorbidities that persist long term. Therefore, our aim was to determine the prevalence of potentially modifiable health problems in patients with HCV and develop an HCV care bundle to identify and target comorbidities.DesignCross-sectional, observational single-centre study that recruited consecutive patients with HCV from our viral hepatitis clinics. Data were collected on cardiovascular (CV) risk factors, lifestyle behaviours, anthropometry and health-related quality of life (HRQoL). QRISK 3 was used to predict 10-year CV event risk.Results100 patients were recruited (67% male, 93% white, median age 52 years (range 24–80); 71% were treated for HCV; 34% had cirrhosis; 14% had diabetes; 61% had hypertension; 31% had metabolic syndrome; and 54% were smokers). The median 10-year CV event risk was 8.3% (range 0.3%–63%). 45% had a predicted 10-year CV event risk of >10%. Only 10% of individuals were treated with statins and 27% with antihypertensives. 92% had a predicted ‘heart age’ greater than their chronological age (median difference +7 (−4 to +26) years). HRQoL was reduced in all SF36v2 domains in the cohort. Factors independently associated with HRQoL included cirrhosis, metabolic syndrome, history of mental health disorder, sedentary behaviour and HCV viraemia.ConclusionA large proportion of patients with HCV presented with increased risk of CV events, and rates of smoking and sedentary behaviour were high, while prescribing of primary prophylaxis was infrequent. HRQoL was also reduced in the cohort. A ‘care bundle’ was developed to provide a structured approach to treating potentially modifiable health problems.

Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare disorder of fatty acid metabolism which has recently been described in three adult cases. We have identified a further patient with clinical features of a relapsing encephalopathy, seizures and cognitive decline over a 40 year period. Biochemical studies revealed grossly elevated plasma pristanic acid levels, and a deficiency of AMACR in skin fibroblasts. Sequence analysis of AMACR cDNA identified a homozygous point mutation (c154T>C). This case adds to the phenotypic variation seen in this peroxisomal disorder and highlights the importance of screening for plasma pristanic acid levels in patients with unexplained relapsing encephalopathies.

We define 3-methylglutaconic aciduria type I as an inborn error of metabolism with slowly progressive leukoencephalopathy clinically presenting in adulthood. In contrast to the nonspecific findings in pediatric cases, the clinical and neuroradiologic pattern in adult patients is highly characteristic. White matter abnormalities may already develop in the first decades of life. The variable features found in affected children may be coincidental. Long-term follow-up in children is essential to learn more about the natural course of this presumably slowly progressive disease. Dietary treatment with leucine restriction may be considered.

α-Methylacyl-CoA racemase (AMACR) deficiency is a rare disorder of fatty acid metabolism which has recently been described in three adult cases. We have identified a further patient with clinical features of a relapsing encephalopathy, seizures and cognitive decline over a 40 year period. Biochemical studies revealed grossly elevated plasma pristanic acid levels, and a deficiency of AMACR in skin fibroblasts. Sequence analysis of AMACR cDNA identified a homozygous point mutation (c154T>C). This case adds to the phenotypic variation seen in this peroxisomal disorder and highlights the importance of screening for plasma pristanic acid levels in patients with unexplained relapsing encephalopathies.