Transfer of (15)N from oral lactose-ureide to lysine in normal adults

The metabolic fate of salvaged urea-nitrogen was explored in normal adults who had consumed a diet that provided 36 g protein/day for 7 days. We hypothesised that the colonic microflora utilise nitrogen derived from urea salvage to synthesise lysine in functionally significant amounts for the host. Oral lactose-[15N15N]ureide is resistant to digestion but is fermented by the colonic microflora to release 15NH3, which can be used for amino acid synthesis. Prime and intermittent oral doses of lactose-[15N15N]ureide were ingested for 18 h, urine was collected every 3 h and stools were collected for a further 2 days. Amino acids were isolated from urine and from faecal bacterial protein and the enrichment measured. Compared with baseline values, there was significant enrichment (atoms per cent excess) in faecal bacterial glycine (0.0526), alanine (0.117), lysine (0.0875) and histidine (0.0487), and in urinary glycine (0.016), alanine (0.0144) and lysine (0.0098), but not hisitidine. These data show that the gastrointestinal bacteria can utilise urea-nitrogen in the formation of essential and non-essential amino acids that are available to the host. We estimate that on this low protein diet the amount of lysine from bacterial synthesis and available to the host may be 30 mg/kg/day. These data have important implications for our current perceptions for the dietary requirements for essential amino acids

Efficacy and Safety of Pitavastatin in Children and Adolescents at High Future Cardiovascular Risk

Abstract: Objectives: Elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for coronary heart disease (CHD) in adults, but the underlying atherogenesis begins in childhood. Therefore guidelines recommend consideration of statin therapy in children at high future CVD risk. The aim of the study was to assess the safety and efficacy of pitavastatin in children and adolescents with hyperlipidemia. Study design: A total of 106 hyperlipidemic children and adolescents, ages 6 to 17 years, were enrolled in a 12 week randomized, double blind, placebo controlled study and randomly assigned to pitavastatin 1 mg, 2 mg, 4 mg or placebo. During a 52 week extension period, subjects were up-titrated from 1 mg pitavastatin to a maximum dose of 4 mg in an effort to achieve an optimum LDL-C treatment target of 110mg/dL (2.8 mmol/L). Safety was assessed in terms of adverse event rates, including abnormal clinical laboratory variables, vital signs and physical examination.Results: Compared with placebo, pitavastatin 1, 2 and 4 mg significantly reduced LDL-C from baseline by 23.5%, 30.1% and 39.3%, respectively and in the open label study 20.5% of the subjects reached the LDL-C goal < 110 mg/dL (2.8 mmol/L). No safety issues became evident.Conclusion: Pitavastatin at doses up to 4 mg is well tolerated and efficacious in children and adolescents aged 6-17 years

Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy

OBJECTIVE: High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator-activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS: A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non-HDL-C level lowering at week 12. RESULTS: Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non-HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations. CONCLUSIONS: Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment

Sediment provenance in a tropical fluvial and marine context by magnetic ‘fingerprinting’ of transportable sand fractions.

The sources and fluxes of sediment to the Great Barrier Reef lagoon from northeastern Australian rivers have been the subject of much concern and study, with the large catchments of the Burdekin and Fitzroy Rivers thought to be the key sources at present. Here, the utility of newly developed magnetic ‘fingerprinting’ methods for identifying sediment provenance, both onshore and offshore, and in association with individual large flood events, is investigated. Within the Burdekin catchment, sediments are mobilized from different subcatchments by runoff generated by intense, localized rainfall events. Magnetic measurements were made on untreated and acid-treated samples of river channel sediments within the Burdekin River subcatchments and from the estuarine and inner shelf depocentres of Burdekin River sediments. The acid treatment removes all discrete magnetic particles and coatings, and leaves magnetic inclusions (protected within host silicate grains) as the basis of the measured magnetic signature of a sample. The magnetic properties of the acid-treated samples display statistically distinct sediment provenance groupings. Sand samples from the Upper Burdekin River appear magnetically distinct from samples from tributaries of the Burdekin (e.g. Hann Creek, Fanning River) and also from nearby coastal rivers, including the Haughton. Suspended sand samples from a Burdekin flood event in 2000 appear to have a different source compared with those from floods in 1998 and 1999. Comparisons of the terrestrial, acid-treated sand fractions with the same, acid-treated, sand-size fractions from transects taken offshore suggest that the surface sediments in Upstart Bay and Bowling Green Bay have different sources. Some of these sources are as yet unidentified but may represent the unsampled, lower-discharge south-western Burdekin subcatchments, and/or along-shore drift of sand from the south, perhaps even from the Fitzroy River, over millennial timescales of cyclone pumping. The magnetic inclusion method precludes any obfuscation or confounding of sediment source, which might arise from hydraulic sorting and/or post-depositional magnetic diagenesis or authigenesis