Prodromal dementia with Lewy bodies: a case series of the 3 prodromal types from clinical practice

Prodromal dementia with Lewy bodies (DLB) refers to a state prior to the onset of dementia with clinical signs or symptoms that may indicate the future development of DLB. Prodromal symptoms can include not only cognitive deficits but also a mix of clinical features including sleep disorders, autonomic dysfunction, and neuro-psychiatric disturbances. While diagnostic criteria for the subtypes of prodromal DLB were recently published, they are largely for use in the research setting. However, these diagnostic criteria have important implications for clinical practice. Helping clinicians to recognize prodromal stages of DLB can lead to identifying deficits sooner, improved patient and family counseling, and advance care planning. This case series presents examples of the 3 subtypes of prodromal DLB – mild cognitive impairment-onset, delirium-onset, and psychiatric-onset – to help clinicians identify individuals who may be on a trajectory to develop DLB

Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: associations with asthmatic phenotype, airway inflammation and β(2)-agonist use

BACKGROUND: Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo β(2)-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion. METHODS: Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β(2)-adrenergic receptor haplotype determination. RESULTS: Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β(2)-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP. CONCLUSION: Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist. The decreased phosphorylation does not appear to be associated with a particular β(2)-adrenergic receptor haplotype. The observed decrease in VASP phosphorylation suggests greater inhibition of actin reorganization which is necessary for altering attachment and migration required during epithelial repair

Drug-Induced Regulation of Target Expression

Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention

Parathyroid hormone regulates 25-hydroxyvitamin D(3)-24-hydroxylase mRNA by altering its stability

The up-regulation of the 25-hydroxyvitamin D(3)-24-hydroxylase by 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is well established and occurs at the transcriptional level through two vitamin D response elements in the promoter of the gene. However, the mechanism of down-regulation of the 24-hydroxylase by parathyroid hormone (PTH) has not yet been elucidated. To study the mechanism of PTH action, we used AOK-B50 cells, a porcine kidney-cell line with stably transfected opossum PTH receptor in which both the 24-hydroxylase mRNA and activity are down-regulated by PTH. Cells dosed with 1,25(OH)(2)D(3) at 0 h, and subsequently at 0, 1, 2, or 4 h with 100 nM of PTH, showed levels of 24-hydroxylase mRNA equivalent to 72.6, 65.3, 57.2, and 37.1%, respectively, of the levels found in cells dosed with 1,25(OH)(2)D(3) only. All cells were collected 7 h after the initial 1,25(OH)(2)D(3) dose. This pattern of expression indicated that PTH does not act by repressing transcription but rather by making the mRNA for 24-hydroxylase susceptible to degradation. At least 1 h is required for PTH to act. Further RNA and protein syntheses are required for PTH to act. However, the sites and mechanism whereby PTH causes 24-hydroxylase mRNA degradation are unknown. Because the untranslated regions of genes can determine the stability of its transcripts, we studied the 5′ untranslated region and the 3′ untranslated region of the rat 24-hydroxylase gene by using reporter-gene strategy to identify possible PTH sites of action. None was found, suggesting that the destabilization site is elsewhere in the coding region

Potential importance of glomerular citrate synthase activity in remnant nephropathy

Potential importance of glomerular citrate synthase activity in remnant nephropathy.BackgroundAldosterone fosters progressive renal injury, but the mechanism is unknown. Both Wistar-Furth rats, which are resistant to aldosterone actions, and adrenalectomized Sprague-Dawley rats, which lack aldosterone, are characterized by resistance to remnant nephropathy and by reduced whole kidney citrate synthase activity. Increase in citrate synthase activity is a well-characterized, specific renal response to aldosterone. Therefore, we performed experiments to test the hypothesis that enhanced citrate synthase activity contributes to remnant nephropathy.MethodsRat models included Wistar (control for Wistar-Furth), Wistar-Furth (resistant to aldosterone), Sprague-Dawley (normal), adrenalectomy (lacking aldosterone), and 5/6 nephrectomy (renal injury). Glomeruli were obtained by differential sieving. Citrate synthase activity was determined spectrophotometrically. Binding characteristics of cytosolic mineralocorticoid receptors were determined by equilibrium competition binding between tritiated and unlabeled aldosterone. Gene sequencing was performed with reverse transcription-polymerase chain reaction (RT-PCR) and fluorescent dye terminators.ResultsIn glomeruli isolated from adrenalectomized Wistar rats with intact renal mass, aldosterone stimulated a threefold increase in citrate synthase activity; this stimulation was not observed in glomeruli from Wistar-Furth rats. Similarly, citrate synthase activity in glomeruli isolated from adrenally intact Sprague-Dawley rats was 65% greater than that from adrenalectomized Sprague-Dawley rats. Compared to sham surgery, subtotal nephrectomy resulted in 100% greater glomerular citrate synthase activity in Sprague-Dawley rats. In Wistar-Furth rats, mineralocorticoid receptor binding was not reduced, and mutations in the mineralocorticoid receptor DNA binding segment were not found.ConclusionCitrate synthase activity is elevated in remnant glomeruli, and experimental models characterized by reduced glomerular citrate synthase activity (Wistar-Furth rats, adrenalectomized Sprague-Dawley rats) are protected from remnant nephropathy