Distinct smell and taste disorder phenotype of post-acute COVID-19 sequelae.

PURPOSE: Olfactory dysfunction (OD) commonly accompanies coronavirus disease 2019 (COVID-19). We investigated the kinetics of OD resolution following SARS-CoV-2 infection (wild-type and alpha variant) and its impact on quality of life, physical and mental health. METHODS: OD prevalence was assessed in an ambulatory COVID-19 survey (n = 906, ≥ 90 days follow-up) and an observational cohort of ambulatory and hospitalized individuals (n = 108, 360 days follow-up). Co-occurrence of OD with other symptoms and effects on quality of life, physical and mental health were analyzed by multi-dimensional scaling, association rule mining and semi-supervised clustering. RESULTS: Both in the ambulatory COVID-19 survey study (72%) and the observational ambulatory and hospitalized cohort (41%) self-reported OD was frequent during acute COVID-19. Recovery from self-reported OD was slow (survey: median 28 days, observational cohort: 90 days). By clustering of the survey data, we identified a predominantly young, female, comorbidity-free group of convalescents with persistent OD and taste disorders (median recovery: 90 days) but low frequency of post-acute fatigue, respiratory or neurocognitive symptoms. This smell and taste disorder cluster was characterized by a high rating of physical performance, mental health, and quality of life as compared with convalescents affected by prolonged fatigue or neurocognitive complaints. CONCLUSION: Our results underline the heterogeneity of post-acute COVID-19 sequelae calling for tailored management strategies. The persistent smell and taste disorder phenotype is characterized by good clinical, physical, and mental recovery and may pose a minor challenge for public health. STUDY REGISTRATION: ClinicalTrials.gov: NCT04661462 (survey study), NCT04416100 (observational cohort).

The Impact of Iron Dyshomeostasis and Anaemia on Long-Term Pulmonary Recovery and Persisting Symptom Burden after COVID-19: A Prospective Observational Cohort Study.

Coronavirus disease 2019 (COVID-19) is frequently associated with iron dyshomeostasis. The latter is related to acute disease severity and COVID-19 convalescence. We herein describe iron dyshomeostasis at COVID-19 follow-up and its association with long-term pulmonary and symptomatic recovery. The prospective, multicentre, observational cohort study "Development of Interstitial Lung Disease (ILD) in Patients With Severe SARS-CoV-2 Infection (CovILD)" encompasses serial extensive clinical, laboratory, functional and imaging evaluations at 60, 100, 180 and 360 days after COVID-19 onset. We included 108 individuals with mild-to-critical acute COVID-19, whereas 75% presented with severe acute disease. At 60 days post-COVID-19 follow-up, hyperferritinaemia (35% of patients), iron deficiency (24% of the cohort) and anaemia (9% of the patients) were frequently found. Anaemia of inflammation (AI) was the predominant feature at early post-acute follow-up, whereas the anaemia phenotype shifted towards iron deficiency anaemia (IDA) and combinations of IDA and AI until the 360 days follow-up. The prevalence of anaemia significantly decreased over time, but iron dyshomeostasis remained a frequent finding throughout the study. Neither iron dyshomeostasis nor anaemia were related to persisting structural lung impairment, but both were associated with impaired stress resilience at long-term COVID-19 follow-up. To conclude, iron dyshomeostasis and anaemia are frequent findings after COVID-19 and may contribute to its long-term symptomatic outcome.

Tryptophan Metabolism and Related Pathways in Psychoneuroimmunology: The Impact of Nutrition and Lifestyle.

In the past, accelerated tryptophan breakdown was considered to be a feature of clinical conditions, such as infection, inflammation, and malignant disease. More recently, however, the focus has changed to include the additional modulation of tryptophan metabolism by changes in nutrition and microbiota composition. The regulation of tryptophan concentration is critical for the maintenance of systemic homeostasis because it integrates essential pathways involved in nutrient sensing, metabolic stress response, and immunity. In addition to tryptophan being important as a precursor for the synthesis of the neurotransmitter serotonin, several catabolites along the kynurenine axis are neuroactive. This emphasizes the importance of the immunometabolic fate of this amino acid for processes relevant to neuropsychiatric symptoms. In humans, besides hepatic catabolism, there is usually a strong relationship between immune activation-associated tryptophan breakdown and increased levels of biomarkers, such as neopterin, which has particular relevance for both acute and chronic diseases. A shift towards neopterin synthesis during oxidative stress may indicate a corresponding decrease in tetrahydrobiopterin, a cofactor of several mono-oxygenases, providing a further link between tryptophan metabolism and serotonergic and catecholaminergic neurotransmission. The psychoneuroimmunological consequences of tryptophan metabolism and the susceptibility of this pathway to modulation by a variety of nutritional and lifestyle-related factors have important implications for the development of both diagnostic and treatment options.

How acute and chronic physical disease may influence mental health - An Analysis of neurotransmitter precursor amino acid levels.

Patients with somatic diseases are more likely to develop depression than physically healthy individuals, and comorbid depression has been shown to incrementally worsen patients´ health. Physical conditions are known to influence neurotransmitter precursor amino acids, changes in which are associated with depressive symptoms. In this prospective study we investigated neurotransmitter precursor amino acids levels in patients with acute and chronic physical disease and evaluated their association with depressive symptoms. 177 subjects with and without chronic medical comorbidity (factor: chronic physical disease) admitted to the trauma and orthopaedic surgery ward for a surgical intervention (factor: acute physical disease) were included in the analysis. Chronic medical comorbidity was scored using Charlson Index and depressive and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS, factor: mental health). The effect of covariates was also evaluated. C-reactive protein (CRP), neopterin, kynurenine/tryptophan (KYN/TRP) and phenylalanine/tyrosine (PHE/TYR) were analysed by HPLC or ELISA prior to surgery and at discharge. Mixed Model as well as correlation analyses were performed. CRP and neopterin levels were influenced by the factors "acute physical disease" (both p < 0.001) and "chronic physical disease" (p = 0.024, p = 0.001 respectively). PHE/TYR, an index of the catecholamine pathway) was related to the factors "acute physical disease" (p < 0.001) and "mental health-depression" (p = 0.012), while KYN/TRP (an index of the kynurenine pathway affecting also serotonin) was associated with "chronic physical disease" (p = 0.005). No significant effect of "mental health-anxiety" was found. The effect of "mental health-depression" on PHE/TYR was more pronounced in females (gender p = 0.003). Differences in HADS depression values correlated with changes in PHE/TYR and both correlated with CRP values. In conclusion, inflammatory reactions related to acute or chronic physical conditions can influence the availability of neurotransmitter precursor amino acids l and these changes are associated with mental health.

A validated liquid chromatography-high resolution-tandem mass spectrometry method for the simultaneous quantitation of tryptophan, kynurenine, kynurenic acid, and quinolinic acid in human plasma.

Tryptophan (TRP) catabolism via the kynurenine pathway is considered to represent a major link between inflammation and various diseases, including neurodegenerative disorders, depression, schizophrenia, multiple sclerosis, cardiovascular disease, and cancer. The kynurenine pathway and levels of TRP and its metabolites kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) are well regulated under physiological conditions but may be altered as part of the activated immune response. A simple, sensitive, and specific liquid chromatography-time of flight mass spectrometry method was developed for determining levels of the four compounds in human plasma samples. The workflow involves protein precipitation with acetonitrile, chromatographic separation on a Phenomenex Luna NH2 column by applying a linear 6 min gradient of 50-5% acetonitrile in aqueous ammonium acetate solution (5 mM, pH 9.5), and mass spectrometric detection with high-resolution tandem mass spectrometry. Charcoal-treated plasma served as surrogate matrix for external standard calibration. Stable-isotope-labeled analogues were used as internal standards. The calibration ranges were 0.5-50 µg/ml for TRP, 20-1000 ng/mL for KYN und QUIN, and 1-50 ng/mL for KYNA. Validation proved fitness of the developed workflow for the intended purpose. The established method was applied to the quantification of the four targets in 100 authentic plasma samples.

Health Behavior and Quality of Life Outcome in Breast Cancer Survivors: Prevalence Rates and Predictors.

PURPOSE: Health behavior (HB) has been identified as contributing to breast cancer (BC) disease outcome. The present study was subjected to gain more in-depth insight into breast cancer survivors' (BCS) HB and its associations with patient quality of life (QOL) outcome. We investigated HB focusing on eating disturbances comparing the latter with a reference population sample (PS). MATERIALS AND METHODS: The research cohort included 303 BCS completing a comprehensive patient-reported-outcome assessment on HB (eating disturbances, exercise, substance use) and QOL. Data from an age- and education-matched reference PS (n = 303) on eating disturbances were included. RESULTS: Overall, 30% of BCS were overweight; 11.7% of BCS (2-11 years after diagnosis, mean = 5.2 years) reported eating disturbances compared with 5% of PS (P < .05). Approximately three-fourths of BCS indicated they exercise regularly, one-fourth smoke regularly, and 30% consume alcohol. Lower consumption of analgesics and tranquilizers, higher frequency of exercise, lower eating concern (EDE-Q), younger age, and lower body mass index were significant predictors for better physical QOL. Lower eating and shape concern were next to age-identified predictive for better psychological QOL. DISCUSSION: Obesity and eating disturbances are a considerable HB problem in women with a history of BC. Considering that HB is predictive for long-term QOL in BCS, routine counseling on HB should be integrated into survivorship care to increase patient education and contribute to behavioral changes.

Self-reported sexual health: Breast cancer survivors compared to women from the general population - an observational study.

BACKGROUND: Cancer survivorship is of increasing importance in post-treatment care. Sexual health (SH) and femininity can be crucial issues for women surviving cancer. We aimed to determine a more complete understanding of the contribution that a breast cancer (BC) diagnosis and its treatment exert on patients' follow-up SH. For this purpose, self-reported levels and predictors of SH in breast cancer survivors (BCS) were compared with those of women with no previous or current BC (WNBC). METHODS: BCS and WNBC underwent a comprehensive, cross-sectional patient-reported outcome (PRO) assessment. Validated PRO instruments were used to measure SH, body image, anxiety and depression and menopausal symptoms. Assessments were performed within the routine clinical setting. Instruments used were the Sexual Interest and Desire Inventory - Female, Sexual Activity Questionnaire, Body Image Scale, Hospital Anxiety and Depression Scale and the Menopause-Specific Quality of Life Questionnaire. RESULTS: One hundred five BCS (average time since diagnosis of 3 years) and 97 WNBC with a mean age of 49 years completed the assessment. SH was significantly worse in BCS compared to WNBC (p = 0.005; BCS SIDI-F mean = 24.9 vs. WNBC mean = 29.8). 68.8% of BCS and 58.8% of WNBC met criteria of a hypo-active sexual desire disorder. Higher depressive symptoms, higher age and lower partnership satisfaction were predictive for poorer SH in BCS. CONCLUSION: SH problems are apparent in BCS and differ significantly from those seen in the general population. Consequently, BC survivorship care should include interventions to ameliorate sexual dysfunction and provide help with depressive symptoms and partnership problems, which are associated with poor BCS SH.

Indications for liver transplantation in adults : Recommendations of the Austrian Society for Gastroenterology and Hepatology (ÖGGH) in cooperation with the Austrian Society for Transplantation, Transfusion and Genetics (ATX).

Liver transplantation has emerged as an established and well-accepted therapeutic option for patients with acute and chronic liver failure and hepatocellular carcinoma. The disproportion between recipients and donors is still an ongoing problem that has only been solved partially over the last centuries. For several patients no life-saving organs can be distributed. Therefore, objective and internationally established recommendations regarding indication and organ allocation are imperative. The aim of this article is to establish evidence-based recommendations regarding the evaluation and assessment of adult candidates for liver transplantation. This publication is the first Austrian consensus paper issued and approved by the Austrian Society of Gastroenterology and Hepatology in cooperation with the Austrian Society of Transplantation, Infusion and Genetics.

Psychosocial outcomes and counselee satisfaction following genetic counseling for hereditary breast and ovarian cancer: A patient-reported outcome study.

OBJECTIVE: We investigated the psychosocial consequences of genetic counseling and testing (GCT) for hereditary breast and ovarian cancer (HBOC) at follow-up in a "real-life" sample of counselees at an Austrian tertiary care center. METHODS: The study cohort included counselees who had undergone genetic counseling for HBOC and completed a follow-up self-report questionnaire battery on psychosocial outcomes (quality of life, psychological distress, satisfaction with counseling and decisions). For comparison of distress, we recruited a reference sample of breast cancer survivors (BCS; n=665) who had not requested GCT in the same setting. RESULTS: Overall, counselees did not exhibit increased levels of anxiety and depression when compared to BCS. No specific follow-up deleterious psychosocial consequences were detected among the former group. Of the 137 counselees, 22.6% and 9.8% experienced clinically relevant levels of anxiety and depression, respectively, at an average follow-up time of 1.8years. However, both anxiety and depression significantly decreased with time and were alike between counselees with and without cancer diagnosis. Follow-up cancer worry seems to be significantly higher among counselees who had not undergone genetic testing or were undecided about it than among counselees who had been tested. CONCLUSION: Our results strongly support GCT as part of routine care for patients with HBOC. The risk factors of increased distress in specific subgroups of counselees, such as recent cancer diagnosis or uncertainty about testing, warrant further exploration and specific attention in clinical routines. Particularly, the psychological needs of undecided counselees warrant ongoing attention and potential follow-ups.

Systematic review reveals lack of quality in reporting health-related quality of life in patients with gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NET) are often slow-growing and patients may live for years with metastasised disease. Hence, along with increasing overall and progression-free survival, treatments aim at preserving patients' well-being and health-related quality of life (HRQoL). However, studies on systematic HRQoL assessment in patients with GEP-NET are scarce. Therefore, the purpose of the current review is to systematically evaluate the methodological quality of the identified studies. METHODS: A targeted database search was performed in PubMed, EMBASE, and CENTRAL. Data extraction was conducted by two independent researchers according to predefined criteria. For study evaluation, the Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials and the CONSORT Patient-Reported Outcome extension were adapted. RESULTS: The database search yielded 48 eligible studies. We found the awareness for the need of HRQoL measurement to be growing and application of cancer-specific instruments gaining acceptance. Overall, studies were too heterogeneous in terms of patient characteristics and treatment interventions to draw clear conclusions for clinical practice. More importantly, a range of methodological shortcomings has been identified which were mainly related to the assessment and statistical analysis, as well as the reporting and interpretation of HRQoL data. CONCLUSION: Despite an increasing interest in HRQoL in GEP-NET patients, there is still a lack of knowledge on this issue. A transfer of HRQoL results into clinical practice is hindered not only by the scarceness of studies, but also by the often limited quality of HRQoL processing and reporting.

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing.

Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost-effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c.4183C>T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C>T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region-specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region.

[Depression in cancer patients]. / Depression bei onkologischen PatientInnen.

Cancer patients often suffer from major depression or depressive syndromes. Although it is well known that depressive symptoms can appear at any time during the course of an oncological disease, certain periods for instance time after diagnosis carry a higher risk. Reported prevalence rates differ widely (up to 60%), reflecting also diagnostic difficulties. Oncologists recognize depression in their patients only in 15 to 50% and the percentage of patients who receive adequate therapy is even lower. Consequently, this leads to a reduced quality of life. Furthermore, impaired compliance/adherence and consequently a poorer prognosis of the oncological disease are discussed in this context. It should be also emphasized, that concomitant depression increases the risk of suicide in cancer patients. Although the number of clinical trials using either psychotherapy or antidepressant medication for the therapy of depression in cancer patients is limited, good therapeutic options are available.

Bioprofiling of platelets in medicated patients with depression.

BACKGROUND: Changes in platelet bioactivity and aggregation are of interest when studying patients with depression as this could help to explain the statistically observed association of depression and chronic somatic, especially cardiovascular disease. This link could potentially be mediated through serotonergic signaling or immunological changes. METHODS: 38 medicated patients with major depressive disorder (MDD) and 30 mentally healthy controls, both without a diagnosis of cardiovascular disease, were included in this naturalistic study. Demographic and psychometric data were obtained. Platelet aggregability was measured by PFA-100 and bioactive compounds and serotonin levels were quantified in platelet sonicate. RESULTS: The comparison of patients with controls revealed no changes in platelet aggregability, but significant differences in platelet content of several bioactive compounds. In a second analysis, patients were grouped according to the receptors and transporters influenced by their medication and again compared to controls. A significant effect of MDD was found for platelet content of serotonin, CD40L, interleukin-1ß, and platelet factor-4, independent of medication. These markers can thus be classified as sensitive to MDD. The effect of medication on platelet parameters was also evaluated. Platelet content of matrix metalloproteinase-2 and ß-thromboglobulin was normalized in MDD patients by medication acting on the serotonin transporter. LIMITATIONS: Owing to the naturalistic study design, patients were on a variety of different medications and combination therapies. This was accounted for by a novel analysis method. CONCLUSION: Platelet serotonin levels and content of immunomodulatory compounds are significantly altered in patients with MDD, even if treatment effects are taken into account.

Increased suicide risk in cancer patients in Tyrol/Austria.

OBJECTIVES: To investigate whether suicide risk in Tyrol/Austria was increased for cancer patients as compared to the general population and whether subgroups at excess risk could be defined. STUDY DESIGN AND SETTING: Cohort design based on all malignant cancer cases diagnosed in Tyrol between 1991 and 2010 and excluding nonmelanoma skin cancer. Entry date was date of diagnosis of the index cancer; exit date was either date of suicide or date of death for reasons other than suicide or end of follow-up (Dec 31, 2011). Standardized mortality ratios (SMRs) were computed in the classical way after adjustment for sex, age and year of follow-up. RESULTS: For all cancer sites except nonmelanoma skin cancer, we observed a SMR of 1.86 [95% confidence interval (CI), 1.57-2.19]. Suicide risk was greatest during the first 6 months after diagnosis with an SMR of 4.74 (95% CI, 3.27-6.66) and was more than fivefold in cases with advanced Stage IV. We observed the greatest excess risk for suicide in patients with head and neck cancers (13 suicides; SMR, 4.73; 95% CI, 2.52-8.09) and lung cancer (14 suicides; SMR, 4.16; 95% CI, 2.27-6.98). CONCLUSION: In our study population in Tyrol/Austria, we observed a twofold suicide risk in cancer patients as compared with the general population, with the excess risk concentrated in the period shortly after diagnosis and in patients with poor prognosis. Therefore, psychooncological care should be intensified in this group of patients.

Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism.

Immune activation not only accompanies inflammation in various disorders including infections, autoimmune syndromes and cancer, but it also represents a characteristic feature of ageing. Immune deviations which are most widely expressed in the elderly include increased neopterin production and tryptophan breakdown. These biochemical events result from the activation of the immune system and are preferentially triggered by pro-inflammatory stimuli, such as the Th1-type cytokine interferon-γ. They seem to play a role in the development of several age-related disorders and might be involved in the pathogenesis of common symptoms, including neurobehavioral disorders (e.g., cognitive and mood disturbances), anemia, cachexia, weight-loss but also immunodeficiency. Concentrations of the biomarkers neopterin and Kyn/Trp were found to be predictive of overall disease specific mortality in coronary artery disease, infections and various types of cancer. Immune activation and inflammation are also accompanied by high output of reactive oxygen species and thereby may lead to the development of oxidative stress and contribute to the vitamin deficiency which is often observed in the elderly. Accordingly, increases in neopterin were found to correlate with a substantial decline in key vitamins, including folate and vitamin-B6, - B12, -C, -D and -E.

Does obesity interfere with anastrozole treatment? Positive association between body mass index and anastrozole plasma levels.

INTRODUCTION: The efficacy of adjuvant endocrine treatment with aromatase inhibitors (AIs), inhibiting the conversion of androgens to estrogen in adipose tissue, might depend on the overall volume of adipose tissue. However, little evidence is available regarding the pharmacokinetic behavior of AIs in women with obesity. The aim of this study was to investigate the interaction between body mass index (BMI) and anastrozole treatment as well as estrogenic activity. PATIENTS AND METHODS: A total of 216 postmenopausal patients with early-stage breast cancer who were receiving AI treatment with anastrozole constituted the final sample included in the analysis. During a regular 3-month after-care check-up, sociodemographic and clinical data and BMI were assessed. Blood samples were collected during routine blood testing. Measurement of AI plasma levels was performed by liquid chromatography-tandem mass spectrometry. Follicle stimulating hormone (FSH) and estradiol were measured within the routine blood examination. RESULTS: A median anastrozole plasma concentration of 34.7 ng/mL (mean, 37.4), with a large interindividual variability, was observed (SD, 15.1; range, 5.4-86.5). After age adjustment, it was found that anastrozole plasma concentrations significantly increased with BMI (r = 0.241; P = .001). Anastrozole serum concentrations in women with obesity (BMI ≥ 30) exceeded those of women with normal weight (BMI ≤ 25) by 25%. Women with excess weight had lower mean FSH levels, indicating higher estrogenic activity, compared with women with normal weight. CONCLUSION: This study indicates that BMI is a vital factor in anastrozole metabolism, as measured by anastrozole plasma concentration and FSH levels. Further research is mandatory to clarify results on the association of obesity and AI treatment efficacy to allow adapting AI treatment accordingly.

Distress in primary caregivers and patients listed for liver transplantation.

Orthotopic liver transplantation (LTx) has become a routine procedure in the treatment of end-stage liver disease. During the waiting period for transplantation, the patient's family members are also highly affected. We examined the course of distress and quality of life (QOL) in 47 patients awaiting LTx and distress in 24 caregivers at baseline and in intervals of 4-6 weeks, using The Hospital Anxiety and Depression Scale (HADS) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). All subscales of the EORTC QLQ-C30, except emotional functioning, were lower than normal at baseline. Little change in patients' QOL was observed during the waiting period. In the HADS, there were significantly higher anxiety scores in caregivers than in patients both at baseline and after 1-2 months and the third assessment, with the difference after 3-5 months reaching almost significance. Caregivers' anxiety levels increased significantly. Relatives showed more depression than patients only at month 1-2 and a significant increase in depression from baseline to month 1-2. In patients, depression scores remained relatively stable throughout all visits. Our results emphasize the importance of evaluation of psychic stress especially in relatives during the waiting period for LTx.

Immune changes and neurotransmitters: possible interactions in depression?

A disturbed metabolism of catecholamines and other neurotransmitters appears to play a major role in the pathogenesis of neurospychiatric symptoms, such as changes in mood and depression. This symptomatology is common in patients with chronic inflammatory disorders such as infections, autoimmune diseases, or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic system but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-γ stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is a co-factor for several aromatic amino acid mono-oxygenases and is rate-limiting for the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). Interferon-γ triggers the high output of reactive oxygen species in macrophages, which can destroy the oxidation-labile BH4. Recent data suggests that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.