Concomitant composite adrenal pheochromocytoma, multiple gastric stromal tumours and pseudohermaphrodism in a patient with von Recklinghausen's disease

Although pheochromocytoma occurs in 1% of patients with von Recklinghausen's disease, composite tumors in this syndrome are much rarer, with isolated case reports in the literature. Most gastrointestinal stromal tumors (GISTs) are solitary and sporadic. Multiple GISTs however, are associated with clinical syndromes particularly von Recklinghausen's disease. We believe this is the first report of composite adrenal pheochromocytoma and multiple GISTs occurring in an 82 year old woman with neurofibromatosis type 1 (NF1), manifested by clitoral and subcutaneous neurofibromas, epilepsy and Lisch nodules. The extreme clitoromegaly raised concerns of pseudohermaphrodism at presentation

Low 25-Hydroxyvitamin D Concentration Is Not Associated With Refractive Error in Middle-Aged and Older Western Australian Adults

Purpose: To investigate the association between serum 25-hydroxyvitamin D (25[OH]D) concentration and refractive error in a community-based cohort of adults aged 46 to 69 years. Methods: Residents of the City of Busselton in Western Australia born between 1946 and 1964 were invited to participate. Participants underwent cycloplegic autorefraction and completed questionnaires on education, occupational sun exposure, and physical activity. Blood samples were collected and serum frozen at −80°C. Serum 25[OH]D concentration was measured by immunoassay. Data on 25[OH]D were deseasonalized and multivariate models built to analyze the association between 25[OH]D concentration and spherical equivalent and myopia, defined as spherical equivalent <−0.50 D. Results: After exclusions, data were available for 4112 participants. Serum 25[OH]D concentration was not associated with spherical equivalent or myopia after adjustment for confounding factors (β = −0.01, 95% confidence interval [CI]: −0.03 to −0.008, P = 0.25, and odds ratio = 1.02, 95% CI: 0.99 to 1.05, P = 0.12, respectively). When participants were classified into 25[OH]D groups of lower (<50 nmol/L), medium (≥50 to <75 nmol/L), and upper (≥75 nmol/L), the upper group had slightly greater myopic refractive error than the medium group (P = 0.02) but not the lower group, after adjustment for confounders. Conclusions: There was no substantial association between 25[OH]D levels and spherical equivalent or odds of myopia in this study. The association previously noted between low serum 25[OH]D level and myopia in younger Western Australians is not evident in later adulthood. Translational Relevance: This study provides further evidence suggesting that vitamin D levels are unrelated to myopia risk in adults and thus not a suitable target for myopia intervention

Single dose prednisolone alters endocrine and haematologic responses and exercise performance in men

The aim of this study was to investigate the effect of a single dose of prednisolone on (A) high-intensity interval cycling performance and (B) post-exercise metabolic, hormonal and haematological responses. Nine young men participated in this double-blind, randomised, cross-over study. The participants completed exercise sessions (4 × 4 min cycling bouts at 90–95% of peak heart rate), 12 h after ingesting prednisolone (20 mg) or placebo. Work load was adjusted to maintain the same relative heart rate between the sessions. Exercise performance was measured as total work performed. Blood samples were taken at rest, immediately post exercise and up to 3 h post exercise. Prednisolone ingestion decreased total work performed by 5% (P 0.05). Prednisolone suppressed the increase in blood lactate immediately post exercise (P < 0.05). Total white blood cell count was elevated at all time-points with prednisolone (P < 0.01). Androgens and sex hormone-binding globulin were elevated immediately after exercise, irrespective of prednisolone or placebo. In contrast, prednisolone significantly reduced the ratio of testosterone/luteinizing hormone (P < 0.01). Acute prednisolone treatment impairs high-intensity interval cycling performance and alters metabolic and haematological parameters in healthy young men. Exercise may be an effective tool to minimise the effect of prednisolone on blood glucose levels

Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases.

Funder: FP7 Ideas: European Research Council; Grant(s): 278535, 305280, 324400, 315997The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD

In silico-guided sequence modifications of K-ras epitopes improve immunological outcome against G12V and G13D mutant KRAS antigens

Background: Somatic point substitution mutations in the KRAS proto-oncogene primarily affect codons 12/13 where glycine is converted into other amino acids, and are highly prevalent in pancreatic, colorectal, and non-small cell lung cancers. These cohorts are non-responsive to anti-EGFR treatments, and are left with non-specific chemotherapy regimens as their sole treatment options. In the past, the development of peptide vaccines for cancer treatment was reported to have poor AT properties when inducing immune responses. Utilization of bioinformatics tools have since become an interesting approach in improving the design of peptide vaccines based on T- and B-cell epitope predictions. Methods: In this study, the region spanning exon 2 from the 4th to 18th codon within the peptide sequence of wtKRAS was chosen for sequence manipulation. Mutated G12V and G13D K-ras controls were generated in silico, along with additional single amino acid substitutions flanking the original codon 12/13 mutations. IEDB was used for assessing human and mouse MHC class I/II epitope predictions, as well as linear B-cell epitopes predictions, while RNA secondary structure prediction was performed via CENTROIDFOLD. A scoring and ranking system was established in order to shortlist top mimotopes whereby normalized and reducing weighted scores were assigned to peptide sequences based on seven immunological parameters. Among the top 20 ranked peptide sequences, peptides of three mimotopes were synthesized and subjected to in vitro and in vivo immunoassays. Mice PBMCs were treated in vitro and subjected to cytokine assessment using CBA assay. Thereafter, mice were immunized and sera were subjected to IgG-based ELISA. Results: In silico immunogenicity prediction using IEDB tools shortlisted one G12V mimotope (68-V) and two G13D mimotopes (164-D, 224-D) from a total of 1,680 candidates. Shortlisted mimotopes were predicted to promote high MHC-II and -I affinities with optimized B-cell epitopes. CBA assay indicated that: 224-D induced secretions of IL-4, IL-5, IL-10, IL-12p70, and IL-21; 164-D triggered IL-10 and TNF-α; while 68-V showed no immunological responses. Specific-IgG sera titers against mutated K-ras antigens from 164-D immunized Balb/c mice were also elevated post first and second boosters compared to wild-type and G12/G13 controls. Discussion: In silico-guided predictions of mutated K-ras T- and B-cell epitopes were successful in identifying two immunogens with high predictive scores, Th-bias cytokine induction and IgG-specific stimulation. Developments of such immunogens are potentially useful for future immunotherapeutic and diagnostic applications against KRAS(+) malignancies, monoclonal antibody production, and various other research and development initiatives

Performance of Detecting IgM Antibodies against Enterovirus 71 for Early Diagnosis

Enterovirus 71 (EV71) infection is more likely to induce severe complications and mortality than other enteroviruses. Methods for detection of IgM antibody against EV71 had been established for years, however, the performance of the methods in the very early diagnosis of EV71 infection had not been fully evaluated, which is especially meaningful because of the short incubation period of EV71 infection. In this report, the performance of an IgM anti-EV71 assay was evaluated using acute sera collected from 165 EV71 infected patients, 165 patients infected with other enteroviruses, and more than 2,000 sera from healthy children or children with other infected diseases. The results showed a 90% sensitivity in 20 patients who were in their first illness day, and similar sensitivity remained till 4 days after onset. After then the sensitivity increased to 95% to 100% for more than one month. The specificity of the assay in non-HFMD children is 99.1% (95% CI: 98.6–99.4), similar as the 99.9% specificity in healthy adults. The cross-reaction rate in patients infected with other non-EV71 enteroviruses was 11.4%. In conclusion, the data here presented show that the detection of IgM anti-EV71 by ELISA affords a reliable, convenient, and prompt diagnosis of EV71 infection

Study Protocol for a Randomized Controlled Trial of Choral Singing Intervention to Prevent Cognitive Decline in At-Risk Older Adults Living in the Community

Introduction: This study is a parallel-arm randomized controlled trial evaluating choral singing’s efficacy and underlying mechanisms in preventing cognitive decline in at-risk older participants.Methods: Three-hundred and sixty community-dwelling, non-demented older participants are recruited for a 2-year intervention. Inclusion criteria are self-reported cognitive complaints, early cognitive impairment based on neuropsychological test scores or multiple risk factors of dementia. Participants are randomized to either weekly choral singing sessions or general health education. The primary outcome is cognitive performance, measured by a composite cognitive test score (CCTS). Secondary outcomes include depression, anxiety and neuropsychiatric symptoms; perceived stress; sleep quality and severity of dementia symptoms. Underlying mechanisms are examined using blood- and urine-based biomarkers and neuroimaging.Results: Screening began in July 2016. The first group of participants (n = 93) have been recruited. Intervention and control treatments are ongoing and will end in December 2019.Discussion: An evidence-based singing intervention for dementia prevention holds potential for healthcare savings and societal welfare.Trial Registration: NCT02919748, IRB Approval Number: NUS 2508

Mediator Acts Upstream of the Transcriptional Activator Gal4

We show that Mediator, a protein originally isolated on the basis of its ability to respond to transcriptional activators, and thought to be regulated by an activator, can also be the master that controls the activator