BACKGROUND: During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0-4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin. RESULTS: All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only ('sapropterin extension' group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period ('sapropterin continuous' group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the 'sapropterin continuous' group (95% CI 28.9, 48.6; p < 0.0001). In the 'sapropterin extension' group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI - 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters. CONCLUSIONS: Long-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908 .

• Klíčová slova
• Hyperphenylalaninaemia, Infants, Phenylketonuria, Sapropterin dihydrochloride, Therapy recommendations,
• MeSH
• biopteriny analogy a deriváty   terapeutické užití   MeSH
• dítě MeSH
• fenylalanin MeSH
• fenylalaninhydroxylasa * MeSH
• fenylketonurie * farmakoterapie   MeSH
• lidé MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• biopteriny MeSH
• fenylalanin MeSH
• fenylalaninhydroxylasa * MeSH
• sapropterin MeSH Prohlížeč

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.

• Klíčová slova
• BH4, PAH deficiency, PKU, hyperphenylalaninemia, phenylalanine, tetrahydrobiopterin,
• MeSH
• alely MeSH
• biopteriny analogy a deriváty   genetika   MeSH
• fenotyp MeSH
• fenylalanin krev   MeSH
• fenylalaninhydroxylasa genetika   MeSH
• fenylketonurie krev   epidemiologie   genetika   MeSH
• frekvence genu genetika   MeSH
• genetická predispozice k nemoci genetika   MeSH
• genetické asociační studie metody   MeSH
• genotyp MeSH
• homozygot MeSH
• lidé MeSH
• mutace genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• biopteriny MeSH
• fenylalanin MeSH
• fenylalaninhydroxylasa MeSH
• sapropterin MeSH Prohlížeč

BACKGROUND: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies. CONCLUSION: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients.

• Klíčová slova
• 6-pyruvoyltetrahydropterin synthase deficiency, BH4, Consensus guidelines, Dihydropteridine reductase deficiency, Guanosine triphosphate cyclohydrolase deficiency, Hyperphenylalaninemia, Neurotransmitter, SIGN, Sepiapterin reductase deficiency, pterin-4-alpha-carbinolamine dehydratase deficiency, Tetrahydrobiopterin deficiency, iNTD,
• MeSH
• biopteriny analogy a deriváty   terapeutické užití   MeSH
• dystonie * MeSH
• fenylketonurie * diagnóza   farmakoterapie   genetika   MeSH
• lidé MeSH
• vrozené poruchy metabolismu * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biopteriny MeSH
• sapropterin MeSH Prohlížeč

The molecular genetics of well-characterized inherited diseases, such as phenylketonuria (PKU) and hyperphenylalaninemia (HPA) predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene, is often complicated by the identification of many novel variants, often with no obvious impact on the associated disorder. To date, more than 1100 PAH variants have been identified of which a substantial portion have unknown clinical significance. In this work, we study the functionality of seven yet uncharacterized PAH missense variants p.Asn167Tyr, p.Thr200Asn, p.Asp229Gly, p.Gly239Ala, p.Phe263Ser, p.Ala342Pro, and p.Ile406Met first identified in the Czech PKU/HPA patients. From all tested variants, three of them, namely p.Asn167Tyr, p.Thr200Asn, and p.Ile406Met, exerted residual enzymatic activity in vitro similar to wild type (WT) PAH, however, when expressed in HepG2 cells, their protein level reached a maximum of 72.1% ± 4.9%, 11.2% ± 4.2%, and 36.6% ± 7.3% compared to WT PAH, respectively. Remaining variants were null with no enzyme activity and decreased protein levels in HepG2 cells. The chaperone-like effect of applied BH4 precursor increased protein level significantly for p.Asn167Tyr, p.Asp229Gly, p.Ala342Pro, and p.Ile406Met. Taken together, our results of functional characterization in combination with in silico prediction suggest that while p.Asn167Tyr, p.Thr200Asn, and p.Ile406Met PAH variants have a mild impact on the protein, p.Asp229Gly, p.Gly239Ala, p.Phe263Ser, and p.Ala342Pro severely affect protein structure and function.

• Klíčová slova
• BH4, functional studies, missense variants, phenylalanine hydroxylase, phenylketonuria,
• MeSH
• biopteriny analogy a deriváty   chemie   genetika   MeSH
• buňky Hep G2 MeSH
• fenylalaninhydroxylasa chemie   genetika   MeSH
• fenylketonurie genetika   metabolismus   patologie   MeSH
• genotyp MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• počítačová simulace MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biopteriny MeSH
• fenylalaninhydroxylasa MeSH
• sapropterin MeSH Prohlížeč

BACKGROUND: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years. RESULTS: In total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. CONCLUSIONS: The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.

• Klíčová slova
• Hyperphenylalaninemia, Pharmacokinetics, Phenylalanine hydroxylase, Phenylketonuria, SPARK, Sapropterin,
• MeSH
• algoritmy MeSH
• biopteriny aplikace a dávkování   analogy a deriváty   metabolismus   terapeutické užití   MeSH
• dieta metody   MeSH
• fenylalanin aplikace a dávkování   krev   MeSH
• fenylalaninhydroxylasa metabolismus   MeSH
• fenylketonurie krev   dietoterapie   farmakoterapie   MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• biopteriny MeSH
• fenylalanin MeSH
• fenylalaninhydroxylasa MeSH
• sapropterin MeSH Prohlížeč

Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS). Oxidative stress oxidises BH4 to dihydrobioptein (BH2), resulting in the uncoupling of the two enzymatic domains of NOS and the production of superoxide rather than NO (NOS uncoupling). Oxidative stress is known to be increased in the early stage of chronic hypoxia. This study investigated the participation of NOS uncoupling in the early phase of hypoxia-induced pulmonary hypertension in rats. Rats were exposed to 10% O(2) for 4 days. We investigated the effect of BH4 in vitro on isolated rat lungs and isolated rat peripheral pulmonary blood vessels and in vivo on exhaled NO concentration in exhaled air. BH4 attenuated hypoxic pulmonary vasoconstriction in isolated lungs and its effect was reversed by l-NAME (NOS inhibitor). The main finding of the study is that the effect of BH4 was smaller in rats exposed to 4 days of hypoxia than in normoxic controls. The finding was similar in isolated pulmonary blood vessels. BH4 increased exhaled NO in both normoxic and hypoxic rats. This increase was blunted by l-NIL (specific iNOS inhibitor) and therefore attributable to iNOS. We conclude that BH4 increased NO production in both normoxic and hypoxic rats. The increase was, however, smaller in hypoxic lungs than in controls. We assume that the smaller increase in NO production in hypoxic lungs is due to the decreased BH4/BH2 ratio in chronic hypoxia and NOS uncoupling resulting from this condition.

• MeSH
• biopteriny analogy a deriváty   metabolismus   MeSH
• hypoxie metabolismus   patofyziologie   MeSH
• krysa rodu Rattus MeSH
• oxid dusnatý biosyntéza   MeSH
• plíce metabolismus   patofyziologie   MeSH
• plicní hypertenze metabolismus   patofyziologie   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biopteriny MeSH
• oxid dusnatý MeSH
• sapropterin MeSH Prohlížeč

Dietary supplementation with L-arginine was shown to improve immune responses in various inflammatory models. However, the molecular mechanisms underlying L-arginine effects on immune cells remain unrecognized. Herein, we tested the hypothesis that a limitation of L-arginine could lead to the uncoupled state of murine macrophage inducible nitric oxide synthase and, therefore, increase inducible nitric-oxide-synthase-derived superoxide anion formation. Importantly, we demonstrated that L-arginine dose- and time dependently potentiated superoxide anion production in bacterial endotoxin-stimulated macrophages, although it did not influence NADPH oxidase expression and activity. Detailed analysis of macrophage activation showed the time dependence between LPS-induced iNOS expression and increased O(2)(∙-) formation. Moreover, downregulation of macrophage iNOS expression, as well as the inhibition of iNOS activity by NOS inhibitors, unveiled an important role of this enzyme in controlling O(2)(∙-) and peroxynitrite formation during macrophage stimulation. In conclusion, our data demonstrated that simultaneous induction of NADPH oxidase, together with the iNOS enzyme, can result in the uncoupled state of iNOS resulting in the production of functionally important levels of O(2)(∙-) soon after macrophage activation with LPS. Moreover, we demonstrated, for the first time that increased concentrations of L-arginine further potentiate iNOS-dependent O(2) (∙-) formation in inflammatory macrophages.

• Klíčová slova
• L-arginine, Macrophages, NO., inducible nitric oxide synthase, superoxide anion,
• MeSH
• aktivace enzymů MeSH
• arginin imunologie   MeSH
• biopteriny analogy a deriváty   metabolismus   MeSH
• buněčné linie MeSH
• časové faktory MeSH
• Escherichia coli imunologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• lipopolysacharidy škodlivé účinky   MeSH
• makrofágy účinky léků   imunologie   metabolismus   MeSH
• myši MeSH
• NADPH-oxidasy metabolismus   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• oxid dusnatý metabolismus   MeSH
• respirační vzplanutí MeSH
• superoxidy metabolismus   MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   metabolismus   MeSH
• tyrosin analogy a deriváty   metabolismus   MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-nitrotyrosine MeSH Prohlížeč
• arginin MeSH
• biopteriny MeSH
• inhibitory enzymů MeSH
• lipopolysacharidy MeSH
• NADPH-oxidasy MeSH
• NG-nitroargininmethylester MeSH
• oxid dusnatý MeSH
• sapropterin MeSH Prohlížeč
• superoxidy MeSH
• synthasa oxidu dusnatého, typ II MeSH
• tyrosin MeSH

Nitric-oxide synthase (NOS) catalyzes both coupled and uncoupled reactions that generate nitric oxide and reactive oxygen species. Oxygen is often the overlooked substrate, and the oxygen metabolism catalyzed by NOS has been poorly defined. In this paper we focus on the oxygen stoichiometry and effects of substrate/cofactor binding on the endothelial NOS isoform (eNOS). In the presence of both L-arginine and tetrahydrobiopterin, eNOS is highly coupled (>90%), and the measured stoichiometry of O(2)/NADPH is very close to the theoretical value. We report for the first time that the presence of L-arginine stimulates oxygen uptake by eNOS. The fact that nonhydrolyzable L-arginine analogs are not stimulatory indicates that the occurrence of the coupled reaction, rather than the accelerated uncoupled reaction, is responsible for the L-arginine-dependent stimulation. The presence of 5,6,7,8-tetrahydrobiopterin quenched the uncoupled reactions and resulted in much less reactive oxygen species formation, whereas the presence of redox-incompetent 7,8-dihydrobiopterin demonstrates little quenching effect. These results reveal different mechanisms for oxygen metabolism for eNOS as opposed to nNOS and, perhaps, partially explain their functional differences.

• MeSH
• arginin chemie   metabolismus   MeSH
• biopteriny analogy a deriváty   chemie   metabolismus   MeSH
• katalýza MeSH
• kyslík chemie   metabolismus   MeSH
• lidé MeSH
• nitrosaminy chemie   metabolismus   MeSH
• oxid dusnatý chemie   metabolismus   MeSH
• reaktivní formy kyslíku chemie   metabolismus   MeSH
• rekombinantní proteiny chemie   metabolismus   MeSH
• synthasa oxidu dusnatého, typ I chemie   metabolismus   MeSH
• synthasa oxidu dusnatého, typ III chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• arginin MeSH
• biopteriny MeSH
• kyslík MeSH
• N-nitrosoallyl-2,3-dihydroxypropylamine MeSH Prohlížeč
• nitrosaminy MeSH
• NOS3 protein, human MeSH Prohlížeč
• oxid dusnatý MeSH
• reaktivní formy kyslíku MeSH
• rekombinantní proteiny MeSH
• sapropterin MeSH Prohlížeč
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého, typ III MeSH

Antibiotics, in addition to killing or inhibiting the growth of microorganisms, may also affect the mechanism of host defence in many ways. Such effects may be clinically relevant especially in the case where an impairment of immunological function can be seen. We, therefore, decided to study the influence of penicillin G, cefotaxim, ceftazidime, streptomycin, and lincomycin on the function of phagocytes by using the macrophage adherence assay and the macrophage spreading assay. We also followed the concentrations of neopterin and interferon gamma (IFN gamma) in the plasma of mice treated with the above mentioned antibiotics. Changes in adherence of peritoneal macrophages were seen in mice treated with therapeutic doses of penicillin G and cefotaxim, after 2 h of incubation. Cefotaxim and streptomycin in the usual therapeutic dose and ceftazidime in a fourfold higher dose influenced the capacity of peritoneal macrophages to spread on a glass surface. The same was seen with lincomycin when administered in the therapeutic dose and in a fourfold higher dose. In all the mice treated with antibiotics the concentration of IFN gamma was higher than in the control mice, while the reverse was seen concerning neopterin release, with an exception in mice treated with streptomycin.

• MeSH
• antibakteriální látky farmakologie   MeSH
• biopteriny analogy a deriváty   biosyntéza   MeSH
• buněčná adheze účinky léků   MeSH
• cefotaxim farmakologie   MeSH
• ceftazidim farmakologie   MeSH
• inbrední kmeny myší MeSH
• interferon gama biosyntéza   MeSH
• linkomycin farmakologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední CBA MeSH
• myši inbrední DBA MeSH
• myši MeSH
• neopterin MeSH
• penicilin G farmakologie   MeSH
• peritoneální makrofágy účinky léků   fyziologie   MeSH
• pohyb buněk účinky léků   MeSH
• streptomycin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• biopteriny MeSH
• cefotaxim MeSH
• ceftazidim MeSH
• interferon gama MeSH
• linkomycin MeSH
• neopterin MeSH
• penicilin G MeSH
• streptomycin MeSH

The importance of cytokines as mediators and immunomodulators is increasing in all disciplines. Acute pancreatitis is a disease where the trigger mechanisms of the inflammation and thus also the influence of cytokines are very closely associated and are therefore apparent. The authors investigated on that model the levels of IL-2, IL-6, IL-8, IL-2r and neopterin in relation to the stage of the disease and time. They provided evidence in a group of 33 patients that the cytokine level indicates very accurately the stage of the disease and thus also its prognosis. For the assessment proper of the diagnosis the cytokine level is less important as the rise of the level is quite unspecific.

• MeSH
• akutní nemoc MeSH
• biologické markery krev   MeSH
• biopteriny analogy a deriváty   krev   MeSH
• interleukiny krev   MeSH
• lidé MeSH
• neopterin MeSH
• pankreatitida krev   diagnóza   MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• biopteriny MeSH
• interleukiny MeSH
• neopterin MeSH