Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's syndrome: Report of two cases and review of the literature

Cushing's syndrome due to nodular adrenal hyperplasia comprises a clinically and biochemically heterogeneous group of disorders whose pathogenesis is unclear. We describe two patients with atypical steroid dynamics and large unilateral adrenal nodules who had pituitary ACTH-dependent disease. In the differential diagnosis of Cushing's syndrome, we recommend repeated ACTH measurement and selective venous sampling—particularly in those patients with impaired dexamethasone suppressibility and abnormal findings on computerized tomography.     

Oral contraceptive use and hormone replacement therapy are associated with microalbuminuria

BACKGROUND: Controversy exists regarding the adverse and beneficial effects of oral contraceptive use and hormone replacement therapy. Microalbuminuria is associated with increased risk of renal and cardiovascular disease. OBJECTIVE: To examine the association between oral contraceptive use or hormone replacement therapy and microalbuminuria. METHODS: We performed a case-control study of the baseline data and historical pharmacy data of 4301 female subjects of the Prevention of Renal and Vascular End Stage Disease study cohort, aged 28 to 75 years, excluding women who were pregnant or had type 1 diabetes mellitus. The main outcome measure was microalbuminuria, defined as a urinary albumin excretion of 30 to 300 mg per 24 hours (recorded as the mean of two 24-hour urine collections). RESULTS: After adjusting for age, hypertension, diabetes, obesity, hyperlipidemia, and smoking, the odds ratio (OR) for having microalbuminuria was 1.90 (95% confidence interval [CI], 1.23-2.93) for premenopausal oral contraceptive users and 2.05 (95% CI, 1.12-3.77) for postmenopausal hormone replacement therapy users. The point estimate increased in a dose-dependent fashion, albeit insignificantly, according to the estrogen content of the oral contraceptives (<30 microg ethinyl estradiol: OR, 1.11; 95% CI, 0.14-8.56; 30 to <50 microg: OR, 1.83; 95% CI, 1.17-2.87; and 50 microg: OR, 2.72; 95% CI, 0.81-9.08). The OR was greater in oral contraceptives with a second-generation (OR, 2.04; 95% CI, 1.28-3.25) vs a third-generation progestin (OR, 1.39; 95% CI, 0.63-3.06). The OR increased with the duration of hormone replacement therapy (< or =5 years, OR, 1.28; 95% CI, 0.37-4.50; >5 years, OR, 2.56; 95% CI, 1.32-4.97). CONCLUSION: Regular and long-term oral contraceptive use and hormone replacement therapy are associated with an increased risk for microalbuminuria and cardiovascular disease.     

Cellular,synaptic, and biochemical features of resilient cognition in Alzheimer's disease

Although neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect, as some people exhibit normal cognition despite high levels of Alzheimer's disease (AD) pathology. We compared the cellular, synaptic, and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: (1) pathological AD with normal cognition (“AD-Resilient”), (2) pathological AD with AD-typical dementia (“AD-Dementia”), and (3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared with the AD-Dementia group, and increased densities of glial fibrillary acidic protein astrocytes compared with both the AD-Dementia and Normal Comparison groups. Further, in a discovery-type antibody microarray protein analysis, we identified a number of candidate protein abnormalities that were associated with a particular diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.     

Dendritic cells process synthetic long peptides better than whole protein,improving antigen presentation and T‐cell activation

The efficiency of antigen (Ag) processing by dendritic cells (DCs) is vital for the strength of the ensuing T‐cell responses. Previously, we and others have shown that in comparison to protein vaccines, vaccination with synthetic long peptides (SLPs) has shown more promising (pre‐)clinical results. Here, we studied the unknown mechanisms underlying the observed vaccine efficacy of SLPs. We report an in vitro processing analysis of SLPs for MHC class I and class II presentation by murine DCs and human monocyte‐derived DCs. Compared to protein, SLPs were rapidly and much more efficiently processed by DCs, resulting in an increased presentation to CD4⁺ and CD8⁺ T cells. The mechanism of access to MHC class I loading appeared to differ between the two forms of Ag. Whereas whole soluble protein Ag ended up largely in endolysosomes, SLPs were detected very rapidly outside the endolysosomes after internalization by DCs, followed by proteasome‐ and transporter associated with Ag processing‐dependent MHC class I presentation. Compared to the slower processing route taken by whole protein Ags, our results indicate that the efficient internalization of SLPs, accomplished by DCs but not by B or T cells and characterized by a different and faster intracellular routing, leads to enhanced CD8⁺ T‐cell activation.     

Effect of BH4 on blood phenylalanine and tyrosine variations in patients with phenylketonuria

BackgroundIn patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.MethodsBlood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).ResultsBH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.ConclusionBH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.     

Breakpoint characterization of the der(19)t(11;19)(q13;p13) in the ovarian cancer cell line SKOV‐3

About 20% of ovarian carcinomas show alterations of 19p13 and/or 19q13 in the form of added extra material whose origin often is from chromosome 11. Based on earlier spectral karyotype analysis of the ovarian cancer cell line SKOV‐3, which shows an unbalanced translocation der(19)t(11;19), the aim of this study was to determine the precise breakpoints of that derivative chromosome. After rough delimitation of the breakpoints of microdissected derivative chromosomes by array analysis, we designed a matrix of primers spanning 11q13.2 and 19p13.2 detecting multiple amplicons on genomic and cDNA. Sequencing the amplicons, accurate localization of both breakpoints on both chromosomes was possible and we found that exon 14 of HOOK2 from chromosome 19 and exon 2 of ACTN3 from chromosome 11 were fused in the derivative chromosome. The breakpoint in the HOOK2 gene was in an intrinsic triplet of nucleic acids leading to a shift in the ACTN3 reading frame in the derivative chromosome. This frameshift alteration should give rise to an early stop codon causing a loss of function of ACTN3. Signals in two‐dimensional Western blotting exactly match to calculated molecular mass and the isoelectric point of the fusion protein. © 2013 Wiley Periodicals, Inc.