Extended Experience of Lower Dose Sapropterin in Irish Adults with Mild Phenylketonuria.

Adherence to dietary and treatment recommendations is a long-standing concern for adults and adolescents with PKU and treating clinicians. In about 20-30% of PKU patients, Phe levels may be controlled by tetrahydrobiopterin (BH4) therapy. The European PKU 2017 Guidelines recommends treatment with BH4 for cases of proven long-term BH4 responsiveness, with a recommended dosage of Sapropterin 10-20 mg/kg/day.We report four young Irish patients with mild PKU, known to be BH4 responsive, who were treated with lower doses of Sapropterin for over 7 years.Case 1: Female, currently age 20. Genotype p. 165T/p/F39L, c.[194T>C]; [117C>G]. Newborn Phe: 851 µmol/L. Pre-Sapropterin Phe tolerance: 600 mg Phe/day to maintain Phe levels <400 µmol/L. Commenced on Sapropterin 400 mg (6.5 mg/kg/day) with increase in Phe tolerance to 800 mg/day.Case 2: Female, currently age 23. Genotype p. 165T/pF39L; c.[194T>C]; [117C>G]. Newborn Phe: 714 µmol/L. Pre-Sapropterin Phe tolerance: 700 mg Phe/day. Commenced on Sapropterin 400 mg (8 mg/kg/day) with increase in Phe tolerance to 800 mg/day.Case 3: Male, currently age 22. Genotype p. 165T/p.S349P; c.[194T>C][1045T>C]. Newborn Phe: 1,036 µmol/L. Pre-Sapropterin Phe tolerance: 600 mg Phe/day. Commenced on Sapropterin 400 mg (5.4 mg/kg/day). Increased to 1,600 mg Phe/day.Case 4: Female, currently age 29. Genotype p.R408W/p/p.Y414C; c.[1222C>T], [1241A>G]. Newborn Phe: 1,600 µmol/L. Pre-Sapropterin tolerance: 450 mg/day. Commenced on Sapropterin 400 mg (5.0 mg/kg/day). Increased to 900 mg Phe/day.Almost 7 years of surveillance for these four patients has shown that this dose of Sapropterin (range 5-8 mg/kg day) was well tolerated and effective with a significant response to treatment and a marked improvement in quality of life at these lower Sapropterin doses.

Lipoxin A4 antagonizes the mitogenic effects of leukotriene D4 in human renal mesangial cells. Differential activation of MAP kinases through distinct receptors.

The lipoxygenase-derived eicosanoids leukotrienes and lipoxins are well defined regulators of hemeodynamics and leukocyte recruitment in inflammatory conditions. Here, we describe a novel bioaction of lipoxin A(4) (LXA(4)), namely inhibition of leukotriene D(4) (LTD(4))-induced human renal mesangial cell proliferation, and investigate the signal transduction mechanisms involved. LXA(4) blocked LTD(4)-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity in parallel to inhibition of LTD(4)-induced mesangial cell proliferation. Screening of a human mesangial cell cDNA library revealed expression of the recently described cys-leukotriene(1)/LTD(4) receptor. LTD(4)-induced mesangial cell proliferation required both extracellular-related signal regulated kinase (erk) and PI 3-kinase activation and may involve platelet-derived growth factor receptor transactivation. LTD(4)-stimulated the MAP kinases erk and p38 via a pertussis toxin (PTX)-sensitive pathway dependent on PI 3-kinase and protein kinase C activation. On screening a cDNA library, mesangial cells were found to express the previously described LXA(4) receptor. In contrast to LTD(4), LXA(4) showed differential activation of erk and p38. LXA(4) activation of erk was insensitive to PTX and PI 3-kinase inhibition, whereas LXA(4) activation of p38 was sensitive to PTX and could be blocked by the LTD(4) receptor antagonist SKF 104353. These data suggest that LXA(4) stimulation of the MAP kinase superfamily involves two distinct receptors: one shared with LTD(4) and coupled to a PTX-sensitive G protein (G(i)) and a second coupled via an alternative G protein, such as G(q) or G(12), to erk activation. These data expand on the spectrum of LXA(4) bioactions within an inflammatory milieu.

Atlantic salmon HNF-3/forkhead: cDNA sequence, evolution, expression, and functional analysis.

We report the isolation and characterization of a cDNA encoding an HNF-3 family member (as HNF-3) from Atlantic salmon (Salmo salar L). The important functional domains of HNF-3 proteins that have been characterized previously are revealed by segments of high identity along the alignment of the asHNF-3 with winged helix/forkhead amino acid sequences isolated from other species. A comparison of asHNF-3 cDNA and genomic DNA indicated that there were no introns present in the asHNF-3 gene. Expression of asHNF-3 protein in adult salmon tissues was not exclusive to liver but was also present in the pancreas and intestine. An RT-PCR analysis performed on salmon development showed that asHNF3 expression is detectable before gastrulation at the mid blastula transition stage. Functional analysis of the asHNF-3 protein using a characterized HNF-3 consensus binding site demonstrated that the protein can recognize and bind to specific HNF-3 consensus sequences. We also report the identification of a novel HNF3 binding site in the promoter of the Atlantic salmon transferrin gene.