Clinical and biochemical assessment of depressive symptoms in patients with Alkaptonuria before and after two years of treatment with nitisinone.

OBJECTIVE: Concerns exist over hypertyrosinaemia that is observed following treatment with nitisinone. It has been suggested that tyrosine may compete with tryptophan for uptake into the central nervous system, and or inhibit tryptophan hydroxylase activity reducing serotonin production. At the National Alkaptonuria (AKU) Centre nitisinone is being used off-licence to treat AKU, and there is uncertainty over whether hypertyrosinaemia may alter mood. Herein results from clinical and biochemical assessments of depression in patients with AKU before and after treatment with nitisinone are presented. PATIENTS AND METHODS: 63 patients were included pre-nitisinone treatment, of these 39 and 32 patients were followed up 12 and 24 months after treatment. All patients had Becks Depression Inventory-II (BDI-II) assessments (scores can range from 0 to 63, the higher the score the more severe the category of depression), and where possible urinary monoamine neurotransmitter metabolites and serum aromatic amino acids were measured as biochemical markers of depression. RESULTS: Mean (±standard deviation) BDI-II scores pre-nitisinone, and after 12 and 24 months were 10.1(9.6); 9.8(10.0) and 10.5(9.9) (p ≥ 0.05, all visits). Paired scores (n = 32), showed a significant increase at 24 months compared to baseline 10.5(9.9) vs. 8.6 (7.8) (p = 0.03). Serum tyrosine increased at least 6-fold following nitisinone (p ≤ 0.0001, all visits), and urinary 3-methoxytyramine (3-MT) increased at 12 and 24 months (p ≤ 0.0001), and 5-hydroxyindole acetic acid (5-HIAA) decreased at 12 months (p = 0.03). CONCLUSIONS: BDI-II scores were significantly higher following 24 months of nitisinone therapy in patients that were followed up, however the majority of these patients remained in the minimal category of depression. Serum tyrosine and urinary 3-MT increased significantly following treatment with nitisinone. In contrast urinary 5-HIAA did not decrease consistently over the same period studied. Together these findings suggest nitisinone does not cause depression despite some observed effects on monoamine neurotransmitter metabolism.

Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: Evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre.

QUESTION: Does Nitisinone prevent the clinical progression of the Alkaptonuria? FINDINGS: In this observational study on 39 patients, 2 mg of daily nitisinone inhibited ochronosis and significantly slowed the progression of AKU over a three-year period. MEANING: Nitisinone is a beneficial therapy in Alkaptonuria. BACKGROUND: Nitisinone decreases homogentisic acid (HGA), but has not been shown to modify progression of Alkaptonuria (AKU). METHODS: Thirty-nine AKU patients attended the National AKU Centre (NAC) in Liverpool for assessments and treatment. Nitisinone was commenced at V1 or baseline. Thirty nine, 34 and 22 AKU patients completed 1, 2 and 3 years of monitoring respectively (V2, V3 and V4) in the VAR group. Seventeen patients also attended a pre-baseline visit (V0) in the VAR group. Within the 39 patients, a subgroup of the same ten patients attended V0, V1, V2, V3 and V4 visits constituting the SAME Group. Severity of AKU was assessed by calculation of the AKU Severity Score Index (AKUSSI) allowing comparison between the pre-nitisinone and the nitisinone treatment phases. RESULTS: The ALL (sum of clinical, joint and spine AKUSSI features) AKUSSI rate of change of scores/patient/month, in the SAME group, was significantly lower at two (0.32 ±â€¯0.19) and three (0.15 ±â€¯0.13) years post-nitisinone when compared to pre-nitisinone (0.65 ±â€¯0.15) (p < .01 for both comparisons). Similarly, the ALL AKUSSI rate of change of scores/patient/month, in the VAR group, was significantly lower at one (0.16 ±â€¯0.08) and three (0.19 ±â€¯0.06) years post-nitisinone when compared to pre-nitisinone (0.59 ±â€¯0.13) (p < .01 for both comparisons). Combined ear and ocular ochronosis rate of change of scores/patient/month was significantly lower at one, two and three year's post-nitisinone in both VAR and SAME groups compared with pre-nitisinone (p < .05). CONCLUSION: This is the first indication that a 2 mg dose of nitisinone slows down the clinical progression of AKU. Combined ocular and ear ochronosis progression was arrested by nitisinone.

Correction to: Translation and cross-cultural adaptation of eight pediatric PROMIS® item banks into Spanish and German.

In the original publication of the article, two of the author names "L. A. Schröder, F. Metzner" and email address of the authors "J. Devine, J. Moon, A. C. Haller" were missed out. The correct author group with affiliations are provided in this correction.

Translation and cross-cultural adaptation of eight pediatric PROMIS® item banks into Spanish and German.

PURPOSE: The Patient-Reported Outcome Measurement Information System (PROMIS®) is a National Institutes of Health (NIH)-funded initiative to develop reliable, valid, and normed item banks to measure health. We describe the first large-scale translation and cross-cultural adaptation effort to German and Spanish of eight pediatric PROMIS item banks: Physical activity (PAC), subjective well-being (SWB), experiences of stress (EOS), and family relations (FAM). METHODS: We utilized methods outlined in the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) PRO Translation Task Force recommendations. Ten professional translators performed a translatability assessment and generated forward translations. Forward Translations were compared within a country and cross-culturally to identify problems and to produce a consensus-derived version, which was then back translated, evaluated, and revised where necessary. Reconciled versions were evaluated in cognitive interviews with 126 children before finalization. RESULTS: Eight resulting pediatric PROMIS® item banks were translated: Two PAC banks (22 total items), three SWB banks (125 total items), two EOS banks (45 total items), and one FAM bank (47 total items). Up to 92% of all items raised no or only minor translation difficulties, 0-5.6% were difficult to translate. Up to 20% item revisions were necessary to ensure conceptual equivalence and comprehensibility. Cognitive interviews indicated that 91-94% of the final items were appropriate for children (8-17 years). CONCLUSIONS: German and Spanish translations of eight PROMIS Pediatric item banks were created for clinical trials and routine pediatric health care. Initial translatability assessment and rigorous translation methodology helped to ensure conceptual equivalence and comprehensibility. Next steps include cross-cultural validation and adaptation studies.

The validation of a computer-adaptive test (CAT) for assessing health-related quality of life in children and adolescents in a clinical sample: study design, methods and first results of the Kids-CAT study.

PURPOSE: Recently, we developed a computer-adaptive test (CAT) for assessing health-related quality of life (HRQoL) in children and adolescents: the Kids-CAT. It measures five generic HRQoL dimensions. The aims of this article were (1) to present the study design and (2) to investigate its psychometric properties in a clinical setting. METHODS: The Kids-CAT study is a longitudinal prospective study with eight measurements over one year at two University Medical Centers in Germany. For validating the Kids-CAT, 270 consecutive 7- to 17-year-old patients with asthma (n = 52), diabetes (n = 182) or juvenile arthritis (n = 36) answered well-established HRQoL instruments (Pediatric Quality of Life Inventory™ (PedsQL), KIDSCREEN-27) and scales measuring related constructs (e.g., social support, self-efficacy). Measurement precision, test-retest reliability, convergent and discriminant validity were investigated. RESULTS: The mean standard error of measurement ranged between .38 and .49 for the five dimensions, which equals a reliability between .86 and .76, respectively. The Kids-CAT measured most reliably in the lower HRQoL range. Convergent validity was supported by moderate to high correlations of the Kids-CAT dimensions with corresponding PedsQL dimensions ranging between .52 and .72. A lower correlation was found between the social dimensions of both instruments. Discriminant validity was confirmed by lower correlations with non-corresponding subscales of the PedsQL. CONCLUSIONS: The Kids-CAT measures pediatric HRQoL reliably, particularly in lower areas of HRQoL. Its test-retest reliability should be re-investigated in future studies. The validity of the instrument was demonstrated. Overall, results suggest that the Kids-CAT is a promising candidate for detecting psychosocial needs in chronically ill children.

Timecourse of oocyte development in saithe Pollachius virens.

Wild caught North Sea saithe Pollachius virens were monitored for growth, sex steroid profiles and oocyte development pre-spawning and measured for egg size and group fecundity during the spawning season in the laboratory. Vitellogenesis commenced in late October-early November, at a leading cohort size (CL ) of c. 250 µm, after which oocytes grew rapidly in size until spawning started in February. Notably, a distinct cortical alveoli stage was virtually absent with yolk granules observed in developing oocytes at the very beginning of vitellogenesis. Little atresia was observed pre-spawning, but atretic re-absorption of remnant oocytes containing yolk granules was found in all females immediately post-spawning. As expected, concentrations of sex steroids, oestradiol-17ß (females), testosterone (both sexes) and 11-ketotestosterone (both sexes), increased pre-spawning before dropping post-spawning. The present experiment provides the first validation of sex steroid levels in P. virens. Post-ovulatory follicles were visible in histological sections from female gonads 9-11 months post-spawning, but then disappeared. Spawning commenced around a CL of c. 750 µm (700-800 µm). Hydrated oocytes (eggs) measured between 1·04 and 1·31 mm (mean = 1·18 mm) with decreasing sizes towards the end of spawning. The average estimated realized fecundity was c. 0·84 million eggs (median female total length, LT = 60 cm). Spawning lasted from 13 February to 29 March.

A new computerized adaptive test advancing the measurement of health-related quality of life (HRQoL) in children: the Kids-CAT.

PURPOSE: Assessing health-related quality of life (HRQoL) via Computerized Adaptive Tests (CAT) provides greater measurement precision coupled with a lower test burden compared to conventional tests. Currently, there are no European pediatric HRQoL CATs available. This manuscript aims at describing the development of a HRQoL CAT for children and adolescents: the Kids-CAT, which was developed based on the established KIDSCREEN-27 HRQoL domain structure. METHODS: The Kids-CAT was developed combining classical test theory and item response theory methods and using large archival data of European KIDSCREEN norm studies (n = 10,577-19,580). Methods were applied in line with the US PROMIS project. Item bank development included the investigation of unidimensionality, local independence, exploration of Differential Item Functioning (DIF), evaluation of Item Response Curves (IRCs), estimation and norming of item parameters as well as first CAT simulations. RESULTS: The Kids-CAT was successfully built covering five item banks (with 26-46 items each) to measure physical well-being, psychological well-being, parent relations, social support and peers, and school well-being. The Kids-CAT item banks proved excellent psychometric properties: high content validity, unidimensionality, local independence, low DIF, and model conform IRCs. In CAT simulations, seven items were needed to achieve a measurement precision between .8 and .9 (reliability). It has a child-friendly design, is easy accessible online and gives immediate feedback reports of scores. CONCLUSIONS: The Kids-CAT has the potential to advance pediatric HRQoL measurement by making it less burdensome and enhancing the patient-doctor communication.

German translation of the PROMIS® pediatric anxiety, anger, depressive symptoms, fatigue, pain interference and peer relationships item banks.

BACKGROUND: The present study aimed at the translation and cross-cultural adaptation of six PROMIS® pediatric self- and proxy- item banks and short forms to universal German: anxiety (ANX), anger (ANG), depressive symptoms (DEP), Fatigue (FAT), pain interference (P) and peer relationships (PR). METHODS: Using standardized methodology approved by the PROMIS Statistical Center and in line with recommendations of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) PRO Translation Task Force, two translators for each German-speaking country (Germany, Austria, and Switzerland) commented on and rated the translation difficulty and provided forward translations, followed by a review and reconciliation phase. An independent translator performed back translations, which were reviewed and harmonized. The items were tested in cognitive interviews with 58 children and adolescents from Germany (16), Austria (22), and Switzerland (20) for the self-report and 42 parents and other caregivers (Germany (12), Austria (17), and Switzerland (13)) for the proxy-report. RESULTS: Translators rated the translation difficulty of most items (95%) as easy or feasible. Pretesting showed that items of the universal German version were understood as they were intended, as only 14 out of 82 items of the self-report and 15 out of 82 items of the proxy-report versions required minor rewording. However, on average German translators rated the items more difficult to translate (M = 1.5, SD = 0.20) than the Austrian (M = 1.3, SD = 0.16) and the Swiss translators (M = 1.2, SD = 0.14) on a three-point Likert scale. CONCLUSIONS: The translated German short forms are ready for use by researchers and clinicians ( https://www.healthmeasures.net/search-view-measures ).

A multitude of questionnaires exist, which are not comparable due to different questions or no available translations. PROMIS is an initiative, which was funded by the National Institute of Health in the US, to build better, i.e., more precise and efficient questionnaires, which can be used and compared worldwide. The PROMIS questionnaires include paper-and-pencil short forms and computerized adaptive tests. So far numerous PROMIS surveys have been created using advanced methodologies. They can be used by health care professionals to assess different aspects of health and compare the results internationally. To allow for international comparability of studies using those questionnaires, they need to be translated. This study reports the thorough translation process of the US-American PROMIS^® questionnaires measuring anxiety, anger, depressive symptoms, fatigue, pain interference, and peer relationships in children and adolescents into German. The translation included researchers, children, and parents from Germany, Austria, and Switzerland to ensure that the final German version is fully and equally well understood in all of those German-speaking countries. The article describes the translation process, so that the user can understand the translations and use them in an informed way. The translated German questionnaires are ready for use by researchers and clinicians. ( https://www.healthmeasures.net/search-view-measures ).

BASE-STEP: A transportable antiproton reservoir for fundamental interaction studies.

Currently, the world's only source of low-energy antiprotons is the AD/ELENA facility located at CERN. To date, all precision measurements on single antiprotons have been conducted at this facility and provide stringent tests of fundamental interactions and their symmetries. However, magnetic field fluctuations from the facility operation limit the precision of upcoming measurements. To overcome this limitation, we have designed the transportable antiproton trap system BASE-STEP to relocate antiprotons to laboratories with a calm magnetic environment. We anticipate that the transportable antiproton trap will facilitate enhanced tests of charge, parity, and time-reversal invariance with antiprotons and provide new experimental possibilities of using transported antiprotons and other accelerator-produced exotic ions. We present here the technical design of the transportable trap system. This includes the transportable superconducting magnet, the cryogenic inlay consisting of the trap stack and detection systems, and the differential pumping section to suppress the residual gas flow into the cryogenic trap chamber.

A retrospective analysis of extended-interval dosing and the impact on bisphosphonate compliance in the US Military Health System.

UNLABELLED: This study evaluated whether patients treated with bisphosphonates in the US Military Health System were more compliant with treatment given monthly versus weekly. While medication compliance did improve with treatment given monthly, overall compliance with bisphosphonates was still suboptimal suggesting the need for further strategies to improve compliance with treatment for osteoporosis. INTRODUCTION: The study objective was to evaluate the relationship between bisphosphonate dosing interval and medication compliance among new users initiating oral bisphosphonates. METHODS: We conducted a retrospective observational cohort study of administrative claims data in the US Military Health System to examine medication compliance among 22,363 new users of oral bisphosphonates starting weekly (68%) or monthly (32%) therapy. Medication compliance during the first year of treatment was measured using two methods: (1) medication possession ratio (MPR) with compliance defined as ≥80% of days covered and (2) time to first gap of more than 30 days following initiation. Logistic regression and a proportional hazards model were used to detect differences in medication compliance between cohorts. RESULTS: After the first year of therapy, 57% of subjects were not compliant with bisphosphonates (MPR <80%), while 84% experienced a gap in treatment of more than 30 days. After adjustment for study covariates, the odds of a patient being compliant with treatment was 21% higher among monthly users compared to weekly users (OR 1.207, 95% confidence interval (CI) 1.119-1.257). Similarly, the risk of experiencing a 30-day gap in treatment was 6% lower among monthly users compared to weekly users (HR 0.934, 95% CI 0.905-0.964). CONCLUSIONS: Patients receiving oral bisphosphonates on a monthly basis showed higher rates of medication compliance compared to weekly dosing in our study. However, compliance with bisphosphonates among all new users was suboptimal, suggesting the need for improved strategies to enhance compliance with oral bisphosphonates in the US Military Health System.

Operative tactics in floor of mouth and tongue cancer resection - the importance of imaging and planning.

Complete tumour resection (R0 margin) is an axiom of surgical oncology. Oral cancer ablation is challenging, due to anatomical, functional, and aesthetic considerations. R0 margin is strongly linked to better survival outcomes with great variation in the R0 % across units. This is commonly attributed to disease biology. Without disputing the importance of biological characteristics, we contend that image-based anatomical surgical planning has an important role to play in achieving complete resection. Here, we present our approach utilising cross-sectional imaging, anatomical characteristics and spatial awareness in planning resections for floor of mouth (FOM) and oral tongue cancers. We highlight the challenge of controlling the deep tumour margin lingual to mandible due to anterior vector constraints and emphasise the importance of resecting the genial muscles in a planned fashion and that any rim resection should be obliquely sagittal. In resecting lateral FOM tumours, assessing extension to the parapharyngeal fat is crucial; and mandibular rim resection at a sagittal plane below the mylohyoid line is often required. Assessing the proximity of the contralateral neurovascular pedicle, pre-epiglottic space and hyoid bone are crucial parameters to determine the extent of tongue tumour resection. Our cohort included 173 patients with FOM SCC and 299 patients with tongue SCC. Six patients (3.5%) from the FOM group and eight patients (3%) from the tongue group had involved (R1) margins following surgery. This was associated with local relapse (p<0.05). In conclusion, we demonstrate that image-based planning can aid achieving R0 resections and reduce disease relapse.

Postoperative delirium in patients with head and neck oral cancer in the West of Scotland.

Our aims were to determine the prevalence and association of postoperative delirium (POD) in head and neck (H&N) cancer patients undergoing free flap reconstruction at the oral and maxillofacial surgery (OMFS) unit, Queen Elizabeth University Hospital (QEUH) Glasgow, and to assess whether these determinants can be modified to optimise patient care and reduce the occurrence of POD. Delirium remains an important problem in the postoperative care of patients undergoing major H&N surgery, and early detection and management improve overall outcomes. The patient database containing details of the preoperative physical status (including alcohol misuse, chronic comorbidity, and physiological status) of 1006 patients who underwent major H&N surgery with free-flap repair at the QEUH from 2009-2019, was analysed. Factors associated with delirium were studied, identifying univariate associations as well as multivariate models to determine independent risk factors. The incidence of POD was 7.5% (75/1006; 53 male:22 female; mean (SD) age 65.41 (13.16) years). POD was strongly associated with pre-existing medical comorbidities, excess alcohol, smoking, a prolonged surgical operating time (more than 700 minutes), tracheostomy, blood transfusion, and bony free flaps. Those with POD were at an increased risk of postoperative wound and lung complications, and were more likely to require a hospital stay of more than 21 days. Presurgical assessment should identify risk factors to optimise the diagnosis and treatment of POD, and will enhance patient care by reducing further medical and surgical complications, and overall hospital stay.

Postoperative risk stratification in oral squamous cell carcinoma.

Postoperative prognostic stratification using the Union for International Cancer Control (UICC) TNM 8th edition staging rules (UICC 8) may identify additional groups of patients who could benefit from adjuvant radiotherapy. Currently, selection for such treatment is not based on all known prognostic factors, and their relative importance may vary depending on the overall risk category. The objective of this study therefore was to evaluate these possibilities. We retrospectively studied 644 patients who had surgery with curative intent for oral squamous cell carcinoma (OSCC) between March 2006 and February 2017. The outcomes of interest were disease-specific survival (DSS) and locoregional recurrence (LRR). Patients were re-staged according to the UICC 8 staging rules. Putative clinical and pathological prognostic variables were evaluated and hazard ratios estimated. Regression analysis was done to identify independent prognostic factors, and iterative analyses identified clinically-relevant risk categories with a minimum of residual prognostic variables. The significance of recognised pathological prognostic factors differed according to the overall risk category. An intermediate risk group comprising patients with pN1 disease as well those with pT3 disease solely on the basis of a depth of invasion (DOI) of more than 10 mm, was identified. A trial to evaluate the benefit or otherwise of adjuvant radiotherapy in this group is now required. Individual prognostic risk factors should be considered within the context of the overall risk category in patients with OSCC.

Nucleotide sequence of a human Blym transforming gene activated in a Burkitt's lymphoma.

The nucleotide sequence of a human Blym-1 transforming gene activated in a Burkitt's lymphoma cell line was determined. This sequence predicts a small protein of 58 amino acids that is 33 percent identical to the predicted product of chicken Blym-1, the activated transforming gene of chicken B cell lymphomas. Both the human and chicken Blym-1 genes exhibit significant identity to an amino-terminal region of transferrins.

The 1986 lake nyos gas disaster in cameroon, west Africa.

The sudden, catastrophic release of gas from Lake Nyos on 21 August 1986 caused the deaths of at least 1700 people in the northwest area of Cameroon, West Africa. Chemical, isotopic, geologic, and medical evidence support the hypotheses that (i) the bulk of gas released was carbon dioxide that had been stored in the lake's hypolimnion, (ii) the victims exposed to the gas cloud died of carbon dioxide asphyxiation, (iii) the carbon dioxide was derived from magmatic sources, and (iv) there was no significant, direct volcanic activity involved. The limnological nature of the gas release suggests that hazardous lakes may be identified and monitored and that the danger of future incidents can be reduced.

Glucocorticoid and inflammatory reactivity to a repeated physiological stressor in insomnia disorder.

Despite known associations of insomnia disorder with alterations in cytokine and glucocorticoid (GC) production, neither the sensitivity of immune cells to a GC signal nor the reactivity of the hypothalamus-pituitary-adrenal (HPA) axis and inflammatory system to stress, or adaptation of these systems to repeated stress have been assessed in patients with insomnia. To investigate potential dysregulation in stress reactivity and adaptation to repeated exposure, a physiological stressor (the cold pressor test; CPT) was repeatedly administered to N = 20 participants with insomnia disorder (based on DSM-V, 18 females, age 30 ±â€¯2.5 years) and N = 20 sex-matched healthy controls following an at-home actigraphy and in-laboratory PSG. HPA and inflammatory markers (serum cortisol, plasma interleukin [IL]-6) were measured at baseline/resting levels and following each of the three CPTs. In addition, sensitivity of monocytes to the synthetic GC dexamethasone was assessed in-vitro at baseline levels in order to examine the cortisol-IL-6 interplay at the cell level. Compared to healthy controls, individuals with insomnia disorder exhibited shorter sleep duration as assessed by actigraphy and PSG (p ≤ 0.05). HPA, but not inflammatory reactivity to the repeated CPT challenge was greater in insomnia disorder (p ≤ 0.05 for group effect), due to greater cortisol responses to the initial CPT (p ≤ 0.05). There were no between-group differences in the ability of the HPA to adapt to stress repetition nor in basal/resting levels of cortisol, IL-6, and GC sensitivity. These findings suggest that insomnia disorder potentiates HPA axis reactivity to initial/novel stressors, which may constitute a pathway underlying adverse health consequences in the long term.

Serum Amino Acid Profiling in Patients with Alkaptonuria Before and After Treatment with Nitisinone.

BACKGROUND: Alkaptonuria (AKU) is a rare inherited disorder of the tyrosine metabolic pathway. Our group is evaluating the use of the homogentisic acid-lowering agent nitisinone in patients with AKU. A major biochemical consequence of this treatment is hypertyrosinaemia. Herein we report the concentration of 20 serum amino acids over a 36-month period pre- and post-treatment with nitisinone. METHODS: Fasting serum samples were collected at baseline (pre-nitisinone), 3 (2 mg nitisinone every other day), 6, 12, 24 and 36 (2 mg nitisinone daily) months. Amino acids were measured using the Biochrom 30 high-performance liquid chromatography cation exchange system with ninhydrin detection. RESULTS: Fifty patients [21 female, mean age (±standard deviation) 54.1 (15.6) years (range 25-75); 29 male, mean age 49.3 (11.6) years (range 22-70 years)] were included. Following treatment mean tyrosine concentrations increased seven- to eight-fold (baseline, 69.8 µmol/L; 3 months, 670.7 µmol/L; 6 months, 666.4 µmol/L; 12 months, 692.9 µmol/L; 24 months, 649.4 µmol/L; 36 months, 724.8 µmol/L, p = <0.001 for all visits compared to baseline).At baseline mean phenylalanine, aspartic acid and arginine were outside the normal reference range. Following treatment the ratios of phenylalanine/tyrosine, phenylalanine/large neutral amino acids, arginine/branched chain amino acids and branched chain/aromatic amino acids decreased (p = <0.05), and the tyrosine/large neutral amino acid ratio increased (p = <0.0001). CONCLUSIONS: Marked hypertyrosinaemia was observed following treatment with nitisinone. Noteworthy changes were also observed in the ratio of several amino acids following treatment with nitisinone suggesting that the availability of amino acids for neurotransmitter biosynthesis and liver function may be altered following treatment with nitisinone.

Data on items of AKUSSI in Alkaptonuria collected over three years from the United Kingdom National Alkaptonuria Centre and the impact of nitisinone.

Alkaptonuria is a rare genetic disorder characterized by a high level of circulating (and urine) homogentisic acid (HGA), which contributes to ochronosis when it is deposited in connective tissue as a pigmented polymer. In an observational study carried out by National AKU Centre (NAC) in Liverpool, a total of thirty-nine AKU patients attended yearly visits in varying numbers. At each visit a mixture of clinical, joint and spinal assessments were carried out and the results calculated to yield an AKUSSI (Alkaptonuria Severity Score Index), see "Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre" (Ranganath at el., 2018). The aim of this data article is to produce visual representation of the change in the components of AKUSSI over 3 years, through radar charts. The metabolic effect of nitisinone is shown through box plots.

PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene.

Phosphoenolpyruvate carboxykinase (PEPCK) is expressed at high levels in liver, kidney, and adipose tissue. This enzyme catalyzes the rate-limiting step in hepatic and renal gluconeogenesis and adipose glyceroneogenesis. The regulatory factors important for adipose expression of the PEPCK gene are not well defined. Previous studies with transgenic mice established that the region between bp -2086 and -888 is required for expression in adipose tissue but not for expression in liver or kidney tissue. We show here that a DNA fragment containing this region can function as an enhancer and direct differentiation-dependent expression of a chloramphenicol acetyltransferase gene from a heterologous promoter in cultured 3T3-F442A preadipocytes and adipocytes. We further demonstrate that the adipocyte-specific transcription factor PPAR gamma 2, previously identified as a regulator of the adipocyte P2 enhancer, binds in a heterodimeric complex with RXR alpha to the PEPCK 5'-flanking region at two sites, termed PCK1 (bp -451 to -439) and PCK2 (bp -999 to -987). Forced expression of PPAR gamma 2 and RXR alpha activates the PEPCK enhancer in non-adipose cells. This activation is potentiated by peroxisome proliferators and fatty acids but not by 9-cis retinoic acid. Mutation of the PPAR gamma 2 binding site (PCK2) abolishes both the activity of the enhancer in adipocytes and its ability to be activated by PPAR gamma 2 and RXR alpha. These results establish a role for PPAR gamma 2 in the adipose expression of the PEPCK gene and suggest that this factor functions as a coordinate regulator of multiple adipocyte-specific genes.