Danish children with ZZ-homozygous alpha-1 antitrypsin deficiency are more affected on liver parameters than children with heterozygosity.

AIM: The longitudinal health status of Danish children with alpha-1 antitrypsin deficiency had never previously been characterised. This study aimed to assess the changes in growth, lung and liver function through childhood in these children. METHODS: Danish children diagnosed between 2005 and 2020 with pathogenic variants in the Serpin family A member 1 gene were included. Retrospective data on growth, lung and liver parameters were obtained from local databases. Anthropometric Z-scores and composite liver scores were computed. Growth and blood results were analysed using robust linear mixed models. RESULTS: The study included 184 children (68 with ZZ-homozygosity, 116 with heterozygosity). The median follow-up time was 7 years [IQR 3.75-9.00] for children with ZZ-homozygosity and 0.5 years [IQR 0.0-2.0] for children with heterozygosity. Both groups had low weight-for-height Z-scores at diagnosis but experienced catch-up growth during the first year of life. In addition, children with ZZ-homozygosity had higher serum concentrations of γ-glutamyl transferase and alanine aminotransferase throughout childhood, when compared with children with heterozygosity. Data proved insufficient to assess lung function properly. CONCLUSION: Children with ZZ-homozygosity were more affected on serum liver parameters throughout childhood when compared with children with heterozygosity. Both groups experienced catch-up growth during the first year of life.

Disease Status at Diagnosis in Danish Children with α 1 -antitrypsin Deficiency.

OBJECTIVES: The aim of this cross-sectional study was to assess the state of disease at the time of diagnosis in Danish children with α 1 -antitrypsin deficiency as Denmark has a high prevalence of ZZ-homozygosity. METHODS: Children either heterozygous, compound heterozygous, or homozygous for Z- and S-variants in the SERPINA1 -gene were included. Clinical characteristics, SERPINA1 -genotype, and blood serum (S) concentrations were recorded concurrently with genetic testing. Serum liver marker concentrations were compared using T tests and Wilcoxon-Mann-Whitney tests. Generalized estimating equation (GEE) linear regression models, both univariable and multivariable adjusted for age and sex, were applied to identify correlations with serum α 1 -antitrypsin (S-AAT). The relationship between S-AAT concentration and genotype was assessed using logistic regression with GEE. RESULTS: The study included 183 of 225 children genetically tested for alpha-1-antitrypsin deficiency (AATD). Of these, 36.6% were homozygous for the Z-variant. Of the heterozygotes, 89.7% had a ZM genotype and the remaining had either an MS genotype or were compound heterozygous. At diagnosis, ZZ-homozygous children had higher serum concentrations of liver enzymes and conjugated bilirubin, but lower concentrations of S-AAT compared with heterozygotes. Serum concentrations of conjugated bilirubin and liver enzymes were negatively associated with S-AAT. Children under 6 months of age had higher total S-bilirubin concentrations than children over 6 months of age. CONCLUSIONS: A low S-AAT concentration is a strong indicator of homozygosity, and homozygous children have higher enzymatic and cholestatic parameters compared with heterozygous children at diagnosis. This underlines the importance of measuring the S-AAT concentration in children with prolonged neonatal jaundice.

Self-Testing of Vision in Age-Related Macula Degeneration: A Longitudinal Pilot Study Using a Smartphone-Based Rarebit Test.

Purpose. There is a need for efficient self-tests of vision in patients with neovascular age-related macula degeneration. A new tablet/smartphone application aiming to meet this need is described and its performance is assessed in a longitudinal pilot study. Materials and Methods. The new MultiBit Test (MBT) employs segmented digits defined by rarebits, that is, receptive field-size bright dots briefly presented against a dark background. The number of rarebits per digit segment was varied in a cyclic fashion, in preset steps. There were no fixation demands. Twenty-eight patients with neovascular AMD of varying severity were monitored for an average of 30 weeks. Test scores were evaluated on an individual basis, by contrasting observed trends with the clinical status recorded at independently scheduled clinical examinations. Results. Serial plots of MBT results revealed gradual improvement after successful antineovascular treatment. Recurrences were signalled by gradual deteriorations of results. Test results remained stable during clinically stable time intervals. MBT results agreed well with clinical assessments whereas an acuity test performed at chance level. The MBT was well accepted by all subjects. Conclusions. The MBT appears to have a good potential for effective self-testing of vision in AMD and merits large-scale studies. Exploration of MBT performance with other forms of macula conditions may be worthwhile.

New rarebit vision test captures macular deficits hidden to acuity tests.

PURPOSE: Evaluation of a new personal-computer-based vision test aimed for rapid and accurate assessment of macular conditions such as age-related macular degeneration (AMD). METHODS: The new test depends on segmented digits defined by rarebits, that is, receptive field-size bright dots briefly presented against a dark background. Digit size was fixed at 40 × 50 min of arc. Digit positions were varied at random within a 4.6 × 3.5-degree test field. There were no fixation demands. The number of rarebits per digit segment could be varied between 3 (the minimum needed for veridical perception) and 128, in 11 preset steps. The test task was to find the smallest rarebit number required to recognize the test digits. Thirty-seven patients with various stages of AMD and 25 control subjects participated in the evaluation, which also included a standard acuity test. RESULTS: Analysis of receiver operating characteristics indicated significantly better discrimination by the rarebit test. Rarebit numbers >16 appeared to reliably indicate the presence of oedema. CONCLUSION: The rarebit test appeared well suited for fine grading of vision in AMD. The simple set-up and the lack of fixation demands made for practicable examinations of short durations. The test is available for free on the Internet.

Corticosteroid production in H295R cells during exposure to 3 endocrine disrupters analyzed with LC-MS/MS.

The adrenocortical human cell line H295R is a valuable tool for screening endocrine disrupting compounds. In general, previous research focus has been on the production of the 2 sex steroids, 17ß-estradiol and testosterone, and less attention has been paid to other important steroid end points in the steroidogenesis with a wide range of physiological functions, such as the glucocorticoids (corticosterone and cortisol). A newly developed and validated solid phase extraction (SPE) liquid chromatography-mass spectroscopy (LC-MS/MS) method was used to measure the production of cortisol and corticosterone in the H295R cell line. The method was applied by studying the effects of 2 model endocrine disrupters, ketoconazole and prochloraz, the pharmaceutical budesonide, and the inducer forskolin on the steroid production in this cell line. Dose-response curves were obtained for the correlation between hormone concentrations and the concentration of the individual disruptors. Exposing cells to ketoconazole resulted in a decrease in cortisol and corticosterone concentrations in a dose-dependent manner with EC50 values of 0.24 and 0.40 µmol/L, respectively. The same applied for cells exposed to prochloraz with EC50 values of 0.06 and 0.09 µmol/L for cortisol and corticosterone, respectively. Budesonide also inhibited glucocorticoid secretion. The EC50 value for cortisol was 19.50 µmol/L, whereas the EC50 value for corticosterone was 71.42 µmol/L. Forskolin induced the secretion of both cortisol (EC50 = 4.09 µmol/L) and corticosterone (EC50 = 0.28 µmol/L). The results obtained demonstrated the validity of the method. Based on these findings, quality criteria for the production of these steroids in this cell line were suggested.

A compact rarebit test for macular diseases.

BACKGROUND: Rarebit testing implies probing for gaps in the neuro-retinal receptive field matrix, using bright microdots on a dark background. Previous reports have found rarebit testing useful for the detection of macular lesions. In its original implementation, the test requires darkroom facilities and a long test distance (2 m). METHODS: A self-contained rarebit test device was realised using a modified miniature data projector driven by a laptop computer. Its performance was assessed in normal subjects and in patients with advanced age-related macular degeneration. RESULTS: Normal subjects (N=49) produced test results very similar to those reported for the original rarebit fovea test. The patient group (N=12) performed significantly worse. The reproducibility was good, and the mean test time was 142 s. CONCLUSION: The new test allows portable rarebit testing for neuro-macular damage, without the need for a darkroom. It may prove useful for screening for early age-related macular degeneration.