BH4 Treatment Research Articles

Prenatal chronic intermittent nicotine aerosol exposure programming a sex dependent hypertensive phenotype via vascular eNOS uncoupling

ObjectiveMaternal cigarette smoking/nicotine use during pregnancy is associated with an increased risk of cardiovascular diseases and development of hypertensive phenotype in later life. However, the involved molecular pathway is remain unclear. The present study tested the hypothesis that cigarette smoking‐relevant nicotine inhalation during pregnancy causes a gender‐dependent change the balance of resistance vasculatures eNOS and prooxidant functions in adult offspring, leading to development of hypertensive phenotype in adult male offspring.MethodsThe time‐dated pregnant rats were exposed to chronic intermittent nicotine aerosol (CINA) via a novel lung alveolar region‐targeted aerosol method during pregnancy (E4 to E20). Experiments were performed in adult (~6 month‐old) offspring.ResultsCINA exposure enhanced vascular H2O2 production which was inhibited by eNOS inhibitor, L‐NAME in male offspring. CINA exposure selectively enhanced vascular NOX2 expression. CINA exposure enhanced angiotensin II (Ang II)‐induced BP response in male offspring, which was not affected by NOX2 inhibitor (gp91 ds‐tat) but significantly reversed by L‐NAME or BH4 treatment in vivo. In pressure myography experiments. CINA exposure had no effect on pressure‐induced myogenic tone but decreased the Acetylcholine (Ach)‐induced relaxation in adult male but not female offspring. In the presence of L‐NAME or H2O2 scavenger (PEG‐catalase), there were no differences of Ach‐induced relaxation between CINA and saline control offspring. Furthermore, pretreatment of eNOS cofactor BH4 enhanced Ach‐induced relaxation in CINA‐exposed male offspring, while no effect in saline control group. In addition, exogenous NO donor (SNP)‐induced mesenteric artery relaxations were similar between CINA exposed and saline control male offspring.ConclusionsThese findings provide novel evidence that maternal inhaled nicotine exposure could impair fetal vascular development and induce a gender‐dependent development of endothelial dysfunction phenotype in adult male offspring via enhancing vascular eNOS uncoupling. The uncoupled eNOS‐mediated ROS plays a predominant role in CINA‐induced hypertensive response in male offspringSupport or Funding InformationSupported in part by the NIH grants: R01HL135623, R03DA041492, and R01HD088039; TRDRP grants: 29IR0437 and T30FT0936

Proton pencil beam scanning treatment with feedback based voluntary moderate breath hold

Introduction The aim of this article is to introduce a novel protocol for proton pencil beam scanning treatment with moderate deep inspiration breath hold (mDIBH) and report on our clinical implementation results. Methods Three computed tomography (CT) scannings to build the patient's anatomy model were performed during the patient's voluntary mDIBH. All 3 CT scans were used in the optimization during the treatment planning process. Both orthogonal kV imaging and cone-beam computed tomography (CBCT) were implemented for patient alignment with BH prior to the treatment. The BH CBCT images were analyzed for BH reproducibility and the virtual total dose (VTD) retrospectively. To find the VTD, a series of deformable image registrations (DIR) were performed between CBCT and pCT. The effect of the variation of lung density on the dose distribution was also analyzed in the study. Results The values of the mean, standard deviation, maximum, and minimum of the tumor location difference between the CBCT and pCT were 1.9, 1.6, 4.7, and 0.0 mm, respectively. The percentage difference in D99% of CTVs between VTD and the nominal plan was within 1.5%. Conclusions The feedback-based voluntary moderate BH proton PBS treatment was successfully performed in our clinic. This study shows that there is a potential to implement the BH treatment widely in proton centers.

Groundbreaking Medicaid demo project to expand D.C.'s BH treatment access

The Centers for Medicare & Medicaid Services (CMS) has designated the District of Columbia to be the first recipient of a “first‐of‐its‐kind” Medicaid demonstration project to expand treatment services to individuals diagnosed with serious mental illness (SMI) and/or serious emotional disturbance (SED). Additionally, the district can now receive Medicaid reimbursement for care provided in settings that qualify as institutions for mental disease (IMD).

The effects of processing on Garcinia xanthochymus fruit beverage

To identify fruit processing treatments relevant for functional food applications, beverages prepared from processed Garcinia xanthochymus fruits were investigated. Treatments, including air drying (AD), sun drying (SD), freeze drying (FD), high and low temperature blanching (BH and BL), and high and low sulfating (SH and SL) were evaluated for their effects on sensory quality, pH, color, free-radical scavenging activity (DPPH), and anti-inflammatory activity. Sensory analysis concluded that the BH treatment had an elevated tropical-note as compared to the SD treatment, whereas the highest pH, b* value and DPPH scavenging activities were recorded for FD, BL, and BH treatments, respectively. Activity-guided fractionation of fruit extracts led to the identification of 2,4,6,3′,4′-pentahydroxybenzophenone-2-O-s-D-glucopyranoside (1), showing an 80% reduction in IL-6 and a 31% reduction in nitric oxide (NO) levels. Quantitation of (1) revealed that FD followed by BH had the highest levels, at 24.9 mg/g and 2.3 mg/g, respectively. The results from this study demonstrated the potential of processed G. xanthochymus fruit as a functional beverage ingredient, with good sensory characteristics along with antioxidant and anti-inflammatory activities. This study examined the potential of processed G. xanthochymus fruit as the basis of a functional beverage.

Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach.

In phenylketonuria (PKU) patients, early diagnosis by neonatal screening and immediate institution of a phenylalanine-restricted diet can prevent severe intellectual impairment. Nevertheless, outcome remains suboptimal in some patients asking for additional treatment strategies. Tetrahydrobiopterin (BH4 ) could be one of those treatment options, as it may not only increase residual phenylalanine hydroxylase activity in BH4 -responsive PKU patients, but possibly also directly improves neurocognitive functioning in both BH4 -responsive and BH4 -unresponsive PKU patients. In the present review, we aim to further define the theoretical working mechanisms by which BH4 might directly influence neurocognitive functioning in PKU having passed the blood-brain barrier. Further research should investigate which of these mechanisms are actually involved, and should contribute to the development of an optimal BH4 treatment regimen to directly improve neurocognitive functioning in PKU. Such possible repurposing approach of BH4 treatment in PKU may improve neuropsychological outcome and mental health in both BH4 -responsive and BH4 -unresponsive PKU patients.

Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease.

BackgroundReduced oxygen delivery in congenital heart disease causes delayed brain maturation and white matter abnormalities in utero. No treatment currently exists. Tetrahydrobiopterin (BH4) is a cofactor for neuronal nitric oxide synthase. BH4 availability is reduced upon NOS activation, such as during hypoxic conditions, and leads to toxin production. We hypothesize that BH4 levels are depleted in the hypoxic brain and that BH4 replacement therapy mitigates the toxic effects of hypoxia on white matter.Methods and ResultsTransgenic mice were used to visualize oligodendrocytes. Hypoxia was introduced during a period of white matter development equivalent to the human third trimester. BH4 was administered during hypoxia. BH4 levels were depleted in the hypoxic brain by direct quantification (n=7–12). The proliferation (n=3–6), apoptosis (n=3–6), and developmental stage (n=5–8) of oligodendrocytes were determined immunohistologically. Total oligodendrocytes increased after hypoxia, consistent with hypoxia‐induced proliferation seen previously; however, mature oligodendrocytes were less prevalent in hypoxia, and there was accumulation of immature oligodendrocytes. BH4 treatment improved the mature oligodendrocyte number such that it did not differ from normoxia, and accumulation of immature oligodendrocytes was not observed. These results persisted beyond the initial period of hypoxia (n=3–4). Apoptosis increased with hypoxia but decreased with BH4 treatment to normoxic levels. White matter myelin levels decreased following hypoxia by western blot. BH4 treatment normalized myelination (n=6–10). Hypoxia worsened sensory‐motor coordination on balance beam tasks, and BH4 therapy normalized performance (n=5–9).ConclusionsSuboptimal BH4 levels influence hypoxic white matter abnormalities. Repurposing BH4 for use during fetal brain development may limit white matter dysmaturation in congenital heart disease.

Reactive oxygen species modulate Na+-coupled neutral amino acid transporter 1 expression in piglet pulmonary arterial endothelial cells.

We have previously shown that Na+-coupled neutral amino acid transporter 1 (SNAT1) modulates nitric oxide (NO) production in pulmonary arterial endothelial cells (PAECs) from newborn piglets. Specifically, the ability to increase NO production in response to the l-arginine-NO precursor l-citrulline is dependent on SNAT1 expression. Elucidating factors that regulate SNAT1 expression in PAECs could provide new insights and therapeutic targets relevant to NO production. Our major goals were to determine if reactive oxygen species (ROS) modulate SNAT1 expression in PAECs from newborn piglets and to evaluate the role of NADPH oxidase 1 (NOX1) and uncoupled endothelial NO synthase, enzymatic sources of ROS, in hypoxia-induced increases in SNAT1 expression. Treatment with either H2O2 or xanthine plus xanthine oxidase increased SNAT1 expression in PAECs from newborn piglets cultured under normoxic conditions. Hypoxia-induced increases in SNAT1 expression were inhibited by treatments with the ROS-removing agents catalase and superoxide dismutase, NOX1 siRNA, and the NO synthase inhibitor NG-nitro-l-arginine methyl ester. Both tetrahydropbiopterin (BH4) and l-citrulline, two therapies that decrease ROS by recoupling endothelial NO synthase, reduced the hypoxia-induced increase in SNAT1 expression. BH4 and l-citrulline treatment improved NO production in hypoxic PAECs despite a reduction in SNAT1 expression. In conclusion, SNAT1 expression is modulated by ROS in PAECs from newborn piglets. However, ROS-mediated decreases in SNAT1 expression per se do not implicate a reduction in NO production. Although SNAT1 may be critical to l-citrulline-induced increases in NO production, therapies designed to alter SNAT1 expression may not lead to a concordant change in NO production. NEW & NOTEWORTHY Na+-coupled neutral amino acid transporter 1 (SNAT1) modulates nitric oxide (NO) production in piglet pulmonary arterial endothelial cells. Factors that regulate SNAT1 expression in pulmonary arterial endothelial cells are unclear. Here, we show that ROS-reducing strategies inhibit hypoxia-induced increases in SNAT1 expression. l-Citrulline and tetrahydropbiopterin decrease SNAT1 expression but increase NO production. Although SNAT1 is modulated by ROS, changes in SNAT1 expression may not cause a concordant change in NO production.

Оценка величины эффекта деформационного старения среднеуглеродистых трубных сталей после BH-обработки

Оценка величины эффекта деформационного старения среднеуглеродистых трубных сталей после BH-обработки

Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis.

Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. Twenty-nine patients with CF (18 ± 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH4 (BH4-5; n = 17) or a 20 mg/kg dose of oral BH4 (BH4-20; n = 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n = 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 ± 3.4 vs. 8.4 ± 3.5%, respectively, P = 0.005). No change in FMD was observed following PLC or BH4-5 (∆FMD: -0.8 ± 1.9% and -0.5 ± 2.5%; P = 0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in significant improvements in FMD (∆FMD: 1.1 ± 1.4%) compared with BH4-5 ( P = 0.023) and PLC ( P = 0.017). Moreover, BH4-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH4 at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF. NEW & NOTEWORTHY For the first time, the present study documents that a single dose of oral BH4 can improve vascular endothelial function in patients with cystic fibrosis (CF), and our in vitro data suggest this is via decreasing uncoupled nitric oxide. These data provide insight into the important role of BH4 bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH4 treatment in patients with CF.

Protective effect of tetrahydrobiopterin on hepatic and renal damage after acute cadmium exposure in male rats

ABSTRACTCadmium (Cd) has been recognized as one of the most important environmental and industrial pollutants. This study investigated the impact of acute exposure to Cd on oxidative stress and the inflammatory marker interleukin-6 (IL-6) in the plasma of rats and the histological picture of liver and kidney, as well as to examine the potential protective effect of tetrahydrobiopterin (BH4). Methods: Rats were divided into control group, Cd group that received a single intraperitoneal (i.p.) dose of 4 mg/kg b.w. of CdCl2 and BH4+ Cd group that received a single dose of BH4 (20 mg/kg, i.p.) and subsequently exposed to a single dose of Cd 24 h after the BH4 treatment. Results: Cd increased the plasma levels of hepatic enzymes (ALT and AST), urea, creatinine, malondialdehyde (MDA), and IL-6 and decreased the superoxide dismutase (SOD) activity. Also, it induced histopathological alterations in the liver with severe degeneration, especially in centrilobular zones. Renal tubular epithelium showed vacuolated cytoplasm and dense nuclei. VEGF expression was mild. Ultrastuctural changes were seen in some renal tubules. The nuclei appeared distorted with electron dense chromatin. Mitochondria with destructed cristae were observed. BH4 pretreatment had protective effects, since it significantly reduced the levels of IL-6 and ameliorated the alteration in oxidative status biomarkers induced by Cd. Improvement of histopathological alterations was observed in Cd-groups. The nuclei were vesicular euchromatic, intact mitochondria and normal appearance of the filtration membrane. Moderate expression of VEGF was noted. Conclusion: This study has provided clear evidence for the protective efficacy of BH4 against experimental Cd toxicity.

Anthropomorphic measurements and nutritional biomarkers after 5 years of BH4 treatment in phenylketonuria patients

ObjectiveThe objective of this study was to assess the long-term effects of BH4 treatment on anthropomorphic measurements and nutritional biomarkers in phenylketonuria patients. Study designA retrospective cohort study was conducted using data from 21 BH4-treated (mean age ± SD: 13.12 ± 9.18 years) and 21 birth date- and gender-matched phenylketonuria patients. Study parameters were age- and gender-adjusted SD scores of anthropomorphic measurements, various nutritional biomarkers, and prescribed vitamin/mineral supplements from baseline and after 5 years of BH4 treatment. Parametric and non-parametric statistical analyses were performed for continuous data, and McNemar's and Chi-squared tests were used for dichotomous outcomes. ResultsPrescribed natural protein intake increased following BH4 treatment (p < 0.001), while amino acid supplement intake decreased (p < 0.001). Weight SDS had increased significantly after 5 years of BH4 treatment. Serum concentration of cholesterol, hemoglobin, phosphate, and MMA had changed significantly after 5 years of BH4 treatment as well. These changes in nutritional biomarkers are however probably age-related, as no differences compared to the control group were seen. A tendency to an increase in calcium supplementation was observed in BH4-treated patients (p = 0.063). ConclusionsThe dietary changes following BH4 treatment had little effect on anthropomorphic measurements and nutritional biomarkers when compared to a control group, although dietary follow-up of BH4-treated patients is still warranted.

Functional Characterization of Novel Phenylalanine Hydroxylase p.Gln226Lys Mutation Revealed Its Non-responsiveness to Tetrahydrobiopterin Treatment in Hepatoma Cellular Model

Treatment with tetrahydrobiopterin (BH4) is the latest therapeutic option approved for patients with phenylketonuria (PKU)-one of the most frequent inborn metabolic diseases. PKU or phenylalanine hydroxylase (PAH) deficiency is caused by mutations in the PAH gene. Given that some PAH mutations are responsive to BH4 treatment while others are non-responsive, for every novel mutation that is discovered it is essential to confirm its pathogenic effect and to assess its responsiveness to a BH4 treatment in vitro, before the drug is administered to patients. We found a c.676C>A (p.Gln226Lys) mutation in the PAH gene in two unrelated patients with PKU. The corresponding aberrant protein has never been functionally characterized in vitro and its response to BH4 treatment is unknown. Computational analyses proposed that glutamine at position 226 is an important, evolutionary conserved amino acid while the substitution with lysine probably disturbs tertiary protein structure and impacts posttranslational PAH modifications. Using hepatoma cellular model, we demonstrated that the amount of mutant p.Gln226Lys PAH detected by Western blot was only 1.2% in comparison to wild-type PAH. The addition of sepiapterin, intracellular precursor of BH4, did not increase PAH protein yield thus marking p.Gln226Lys as BH4-non-responsive mutation. Therefore, computational, experimental, and clinical data were all in accordance showing that p.Gln226Lys is a severe pathogenic PAH mutation. Its non-responsiveness to BH4 treatment in hepatoma cellular model should be considered when deciding treatment options for PKU patients carrying this mutation. Consequently, our study will facilitate clinical genetic practice, particularly genotype-based stratification of PKU treatment.

Tetrahydrobiopterin Prevents Coronary Artery Malformations Induced by Pregestational Diabetes

The heart is the first functional organ to form during embryogenesis. Coronary artery development in the heart begins at embryonic day (E)9.5 and involves coordinated epithelial to mesenchymal transition (EMT) and cell differentiation, which form a complete coronary artery network by E15 in the mouse. Alterations in angiogenic gene expression, cell migration or proliferation can have implications on vasculature and heart function, as seen during diabetic embryopathy. Hyperglycemia‐induced oxidative stress can lead to the inactivation of endothelial nitric oxide synthase (eNOS), vital for heart development. Tetrahydrobiopterin (BH4), an antioxidant, is the co‐factor for eNOS, and when oxidized leads to eNOS deactivation, further increasing the oxidative environment. Treatment with BH4 has been shown to improve vascular endothelial function in diabetes. This study aims to investigate the effect of BH4 on embryonic coronary artery development during pregestational maternal diabetes.Diabetes was induced by streptozotocin (STZ, 50 mg/kg, IPx5) to adult female C57BL/6 mice. BH4 (10 mg/kg/day) was orally administered to pregnant mice. Fetal hearts were collected at E18.5 for coronary artery analysis and 3D reconstruction. Markers of EMT and oxidative stress were examined at E12.5 via immunostaining and qPCR. Immunoblotting was used to determine activity of Akt and eNOS.Marked decreases in coronary artery diameter of both the left and right main branches for the coronary tree were found in hearts from diabetic mothers, which were prevented with BH4 administration. Coronary artery abundance and volume were also decreased in diabetic hearts, and recovered to normal levels with BH4 treatment. A normal branching pattern of the vessels was abolished in hearts from diabetic mothers, and returned to normal with BH4. Notably, BH4 treatment to diabetic dams significantly decreased the incidence of CAMs in their offspring from 47.4 to 23.3%. The expression of molecular regulators of angiogenesis such as Snail1, β‐Catenin, bFGF, Aldh1a2 were decreased with maternal diabetes and reestablished with BH4 supplementation. Additionally, more cell to cell connections, measured through E‐cadherin expression, were found in diabetic hearts and returned to control levels with BH4. The epicardium of hearts from diabetic dams exhibited decreased proliferation and expression of WT1, which were both normalized with BH4 treatment. Furthermore, Akt and eNOS activity, assessed through phosphorylation of both enzymes, was reduced in embryonic hearts from diabetic dams, and was returned to basal levels with BH4 treatment. Finally, oxidative stress, in the form of lipid peroxidation was significantly increased in diabetic hearts and reduced with BH4.BH4 treatment prevents CAMs induced by pregestational diabetes. The importance of BH4‐mediated increase in Akt/eNOS activity and reduction in oxidative stress during cardiac angiogenesis provides insight into factors contributing to CAMs. The therapeutic potential of BH4 during gestation can be extrapolated through these studies.Support or Funding InformationThis study was funding in parts by grants from the Canadian Institutes of Health Research (CIHR) to Q.F.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Tetrahydrobiopterin treatment reduces brain L-Phe but only partially improves serotonin in hyperphenylalaninemic ENU1/2 mice.

Hyperphenylalaninemia (HPA) caused by hepatic phenylalanine hydroxylase (PAH) deficiency has severe consequences on brain monoamine neurotransmitter metabolism. We have studied monoamine neurotransmitter status and the effect of tetrahydrobiopterin (BH4) treatment in Pahenu1/enu2 (ENU1/2) mice, a model of partial PAH deficiency. These mice exhibit elevated blood L-phenylalanine (L-Phe) concentrations similar to that of mild hyperphenylalaninemia (HPA), but brain levels of L-Phe are still ~5-fold elevated compared to wild-type. We found that brain L-tyrosine, L-tryptophan, BH4 cofactor and catecholamine concentrations, and brain tyrosine hydroxylase (TH) activity were normal in these mice but that brain serotonin, 5-hydroxyindolacetic acid (5HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) content, and brain TH protein, as well as tryptophan hydroxylase type 2 (TPH2) protein levels and activity were reduced in comparison to wild-type mice. Parenteral L-Phe loading conditions did not lead to significant changes in brain neurometabolite concentrations. Remarkably, enteral BH4 treatment, which normalized brain L-Phe levels in ENU1/2 mice, lead to only partial recovery of brain serotonin and 5HIAA concentrations. Furthermore, indirect evidence indicated that the GTP cyclohydrolase I (GTPCH) feedback regulatory protein (GFRP) complex may be a sensor for brain L-Phe elevation to ameliorate the toxic effects of HPA. We conclude that BH4 treatment of HPA toward systemic L-Phe lowering reverses elevated brain L-Phe content but the recovery of TPH2 protein and activity as well as serotonin levels is suboptimal, indicating that patients with mild HPA and mood problems (depression or anxiety) treated with the current diet may benefit from supplementation with BH4 and 5-OH-tryptophan.

Beneficial Effect of BH4 Treatment in a 15-Year-Old Boy with Biallelic Mutations in DNAJC12.

Biallelic mutations in DNAJC12 were recently identified as a BH4-responsive cause of hyperphenylalaninemia (HPA). Outcome was only favorable when treatment was initiated early in life. We report on a 15-year-old boy with HPA due to a homozygous deletion in DNAJC12 in whom - despite his advanced age - treatment was initiated. A boy with developmental delay, an extrapyramidal movement disorder, and persistently elevated plasma phenylalanine levels was diagnosed with DNAJC12 deficiency at the age of 15years. Diagnosis was made upon exome reanalysis revealing a homozygous 6.9kb deletion in DNAJC12 which had not been detected by the standard exome analysis pipeline. Treatment with the BH4 analog sapropterin dihydrochloride (10mg/kg/day) was initiated and evoked a 50% reduction of the plasma phenylalanine levels. More strikingly, a marked improvement in daily functioning and improved exercise tolerance was noted. Additionally, gait analysis before and after treatment initiation revealed a partial normalization of his movement disorder. Patients with hyperphenylalaninemia due to DNAJC12 deficiency may benefit from treatment with a BH4 analog - even when introduced at a later age.

Genotyping of patients with phenylketonuria from different regions of Russia for determining BH4 responsiveness

To date, the efficacy of the phenylalanine hydroxylase (PAH) cofactor is proved for the treatment of both BH4-dependent hyperphenylalaninemia and phenylketonuria patients with mutations in the PAH gene. Since the patient’s response depends on the presence of residual PAH enzyme activity, it is advisable to search for mutations in the PAH gene to identify the potential responders and nonresponders to therapy. Four hundred thirty-five phenylketonuria patients from 13 regions of the Russian Federation were genotyped in order to identify responders and nonresponders to tetrahydrobiopterin (BH4) therapy. According to the results of this study, the number of probable nonresponders to the BH4 treatment exceeds 50% owing to a higher overall allelic frequency of “severe” PAH gene mutations. Responder patients with two “mild” mutations in the PAH gene were identified (1.6%).

Grant to provide BH treatment, careers for young adults

Mental Health WeeklyVolume 27, Issue 4 p. 6-7 Articles Grant to provide BH treatment, careers for young adults Valerie A. Canady, Valerie A. CanadySearch for more papers by this author Valerie A. Canady, Valerie A. CanadySearch for more papers by this author First published: 24 January 2017 https://doi.org/10.1002/mhw.30903Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume27, Issue423 January 2017Pages 6-7 RelatedInformation

Tetrahydrobiopterin Protects against Radiation-induced Growth Inhibition in H9c2 Cardiomyocytes

Background:Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOSs) for the synthesis of nitric oxide (NO). BH4 therapy can reverse the disease-related redox disequilibrium observed with BH4 deficiency. However, whether BH4 exerts a protective effect against radiation-induced damage to cardiomyocytes remains unknown.Methods:Clonogenic assays were performed to determine the effects of X-ray on H9c2 cells with or without BH4 treatment. The contents of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) in H9c2 cells were measured to investigate oxidative stress levels. The cell cycle undergoing radiation with or without BH4 treatment was detected using flow cytometry. The expression levels of proteins in the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/P53 signaling pathway, inducible NOS (iNOS), and endothelial NOS (eNOS) were examined using Western blotting.Results:X-ray radiation significantly inhibited the growth of H9c2 cells in a dose-dependent manner, whereas BH4 treatment significantly reduced the X-ray radiation-induced growth inhibition (control group vs. X-ray groups, respectively, P < 0.01). X-ray radiation induced LDH release, apoptosis, and G0/G1 peak accumulation, significantly increasing the level of MDA and the production of NO, and decreased the level of SOD (control group vs. X-ray groups, respectively, P < 0.05 or P < 0.01). By contrast, BH4 treatment can significantly reverse these processes (BH4 treatment groups vs. X-ray groups, P < 0.05 or P < 0.01). BH4 reversed the X-ray radiation-induced expression alterations of apoptosis-related molecules, including B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein, and caspase-3, and molecules of the PI3K/Akt/P53 signaling pathway. BH4 enhanced the production of NO in 2 Gy and 4 Gy radiated groups by upregulating eNOS protein expression and downregulating iNOS protein expression.Conclusions:BH4 treatment can protect against X-ray-induced cardiomyocyte injury, possibly by recoupling eNOS rather than iNOS. BH4 treatment also decreased oxidative stress in radiated H9c2 cells.

Behavioral Health Screening among Massachusetts Children Receiving Medicaid

To assess the impact of a Massachusetts Medicaid policy change (the Children's Behavioral Health Initiative; CBHI, which required and reimbursed behavioral health [BH] screening with standardized tools at well child visits and developed intensive home- and community-based BH services) on primary care practice examining the relationship of BH screening to subsequent BH service utilization. Using a repeated cross-sectional design, our 2010 and 2012 Medicaid study populations each included 2000 children/adolescents under the age of 21 years. For each year, the population was randomly selected and stratified into 4 age groups, with 500 members selected per group. Two data sources were used: medical records and Medicaid claims. The CBHI had a large impact on formal BH screening and treatment utilization among children/adolescents enrolled in Medicaid. Screening increased substantially (73%: 2010; 74%: 2012) since the baseline/premandate period (2007) when only 4% of well child visits included a formal screen. BH utilization increased among those formally screened but decreased among those with informal assessments. CBHI implementation transformed the relationship between primary care and BH services. Changes in regulation and payment resulted in widespread BH screening in Massachusetts primary care practices caring for children/adolescents on Medicaid.

Long-term BH4 (sapropterin) treatment of children with hyperphenylalaninemia - effect on median Phe/Tyr ratios.

Phenylalanine hydroxylase deficiency causes various degrees of hyperphenylalaninemia (HPA). Tetrahydrobiopterin (BH4; sapropterin) reduces phenylalanine (Phe) levels in responders, enabling relaxation of dietary therapy. We aimed to assess long-term effects of BH4 treatment in HPA patients. Nine pre-pubertal BH4 responsive children were treated with BH4 for at least 2 years. The median dietary tolerance to Phe and levels of blood Phe, tyrosine (Tyr), zinc, selenium and vitamin B12 and anthropometric measurements, in the 2 years periods before and after the introduction of BH4 treatment were analyzed and compared. Adverse effects of BH4 were assessed. The daily Phe tolerance had tripled, from pretreatment median value of 620 mg (IQR 400-700 mg) to 2000 (IQR 1000-2000 mg) after 2 years of follow up (p<0.001). The median blood Phe levels during the 2 years period before introducing BH4 did not change significantly during the 2 years on therapy (from 200 μmol/L; IQR 191-302 to 190 μmol/L; IQR 135-285 μmol/L), but the median blood Phe/Tyr ratio had lowered significantly from pre-treatment value 4.7 to 2.4 during the 2 years on therapy (p=0.01). Median zinc, selenium, vitamin B12 levels and anthropometric measurements did not change while on BH4 therapy (p=NS). No adverse effects were noticed. BH4 therapy enabled patients much higher dietary Phe intakes, with no noticeable adverse effects. Median blood Phe and Tyr levels, median zinc, selenium, vitamin B12 levels and anthropometric measurements did not change significantly on BH4 therapy, but median Phe/Tyr ratios had lowered.