Anticholinergic medication use and cognitive impairment in the older population:the Medical Research Council cognitive function and ageing study

OBJECTIVES: To determine whether the use of medications with possible and definite anticholinergic activity increases the risk of cognitive impairment and mortality in older people and whether risk is cumulative. DESIGN: A 2-year longitudinal study of participants enrolled in the Medical Research Council Cognitive Function and Ageing Study between 1991 and 1993. SETTING: Community-dwelling and institutionalized participants. PARTICIPANTS: Thirteen thousand four participants aged 65 and older. MEASUREMENTS: Baseline use of possible or definite anticholinergics determined according to the Anticholinergic Cognitive Burden Scale and cognition determined using the Mini-Mental State Examination (MMSE). The main outcome measure was decline in the MMSE score at 2 years. RESULTS: At baseline, 47% of the population used a medication with possible anticholinergic properties, and 4% used a drug with definite anticholinergic properties. After adjusting for age, sex, educational level, social class, number of nonanticholinergic medications, number of comorbid health conditions, and cognitive performance at baseline, use of medication with definite anticholinergic effects was associated with a 0.33-point greater decline in MMSE score (95% confidence interval (CI)=0.03–0.64, P=.03) than not taking anticholinergics, whereas the use of possible anticholinergics at baseline was not associated with further decline (0.02, 95% CI=-0.14–0.11, P=.79). Two-year mortality was greater for those taking definite (OR=1.68; 95% CI=1.30–2.16; P<.001) and possible (OR=1.56; 95% CI=1.36–1.79; P<.001) anticholinergics. CONCLUSION: The use of medications with anticholinergic activity increases the cumulative risk of cognitive impairment and mortality.

Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies

Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A-class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg(2.39), His(2.43) and Glu(3.46), which makes a polar lock with T(6.37). These alignments and models provide useful tools for understanding class B GPCR function.

On some Generalizations of a Class of Discrete Functions

In this paper we examine discrete functions that depend on their variables in a particular way, namely the H-functions. The results obtained in this work make the “construction” of these functions possible. H-functions are generalized, as well as their matrix representation by Latin hypercubes.

A Recession Notion for a Class of Monotone Bivariate Functions

Using monotone bifunctions, we introduce a recession concept for general equilibrium problems relying on a variational convergence notion. The interesting purpose is to extend some results of P. L. Lions on variational problems. In the process we generalize some results by H. Brezis and H. Attouch relative to the convergence of the resolvents associated with maximal monotone operators.

Compactness in the First Baire Class and Baire-1 Operators

For a polish space M and a Banach space E let B1 (M, E) be the space of first Baire class functions from M to E, endowed with the pointwise weak topology. We study the compact subsets of B1 (M, E) and show that the fundamental results proved by Rosenthal, Bourgain, Fremlin, Talagrand and Godefroy, in case E = R, also hold true in the general case. For instance: a subset of B1 (M, E) is compact iff it is sequentially (resp. countably) compact, the convex hull of a compact bounded subset of B1 (M, E) is relatively compact, etc. We also show that our class includes Gulko compact. In the second part of the paper we examine under which conditions a bounded linear operator T : X ∗ → Y so that T |BX ∗ : (BX ∗ , w∗ ) → Y is a Baire-1 function, is a pointwise limit of a sequence (Tn ) of operators with T |BX ∗ : (BX ∗ , w∗ ) → (Y, · ) continuous for all n ∈ N. Our results in this case are connected with classical results of Choquet, Odell and Rosenthal.

Partial Quasi-Bilateral Generating Function Involving some Special Functions

A group-theoretic method of obtaining more general class of generating functions from a given class of partial quasi-bilateral generating functions involving Hermite, Laguerre and Gegenbaur polynomials are discussed.

Isomorphism Problems for the Baire Function Spaces of Topological Spaces

Let a compact Hausdorff space X contain a non-empty perfect subset. If α < β and β is a countable ordinal, then the Banach space Bα (X) of all bounded real-valued functions of Baire class α on X is a proper subspace of the Banach space Bβ (X). In this paper it is shown that: 1. Bα (X) has a representation as C(bα X), where bα X is a compactification of the space P X – the underlying set of X in the Baire topology generated by the Gδ -sets in X. 2. If 1 ≤ α < β ≤ Ω, where Ω is the first uncountable ordinal number, then Bα (X) is uncomplemented as a closed subspace of Bβ (X). These assertions for X = [0, 1] were proved by W. G. Bade [4] and in the case when X contains an uncountable compact metrizable space – by F.K.Dashiell [9]. Our argumentation is one non-metrizable modification of both Bade’s and Dashiell’s methods.

On Two Saigo’s Fractional Integral Operators in the Class of Univalent Functions

2000 Mathematics Subject Classification: Primary 26A33, 30C45; Secondary 33A35

Applications of the Owa-Srivastava Operator to the Class of K-Uniformly Convex Functions

2000 Mathematics Subject Classification: Primary 30C45, 26A33; Secondary 33C15

Note on Radius Problems for Certain Class of Analytic Functions

MSC 2010: 30C45

Singular Solutions of Protter’s Problem for a Class of 3-D Hyperbolic Equations

Недю Иванов Попиванов, Алексей Йорданов Николов - През 1952 г. М. Протър формулира нови гранични задачи за вълновото уравнение, които са тримерни аналози на задачите на Дарбу в равнината. Задачите са разгледани в тримерна област, ограничена от две характеристични конуса и равнина. Сега, след като са минали повече от 50 години, е добре известно, че за безброй гладки функции в дясната страна на уравнението тези задачи нямат класически решения, а обобщеното решение има силна степенна особеност във върха на характеристичния конус, която е изолирана и не се разпространява по конуса. Тук ние разглеждаме трета гранична задача за вълновото уравнение с младши членове и дясна страна във формата на тригонометричен полином. Дадена е по-нова от досега известната априорна оценка за максимално възможната особеност на решенията на тази задача. Оказва се, че при по-общото уравнение с младши членове възможната сингулярност е от същия ред като при чисто вълновото уравнение.

Optimization Problem in a Class of Linear System. Application to Multiple Drug Administration

2000 Mathematics Subject Classification: 62H15, 62P10.

MicroRNA expression and function in neonatal hypoxic ischaemic encephalopathy

Hypoxic ischaemic encephalopathy (HIE) is a devastating neonatal condition which affects 2-3 per 1000 infants annually. The current gold standard of treatment - induced hypothermia, has the ability to reduce neonatal mortality and improve neonatal morbidity. However, to be effective it needs to be initiated within the therapeutic window which exists following initial insult until approximately 6 hours after birth. Current methods of assessment which are relied upon to identify infants with HIE are subjective and unreliable. To overcome this issue, an early and reliable biomarker of HIE severity must be identified. MicroRNA (miRNA) are a class of small non-coding RNA molecules which have potential as biomarkers of disease state and potential therapeutic targets. These tiny molecules can modulate gene expression by inhibiting translation of messenger RNA (mRNA) and as a result, can regulate protein synthesis. These miRNA are understood to be released into the circulation during cellular stress, where they are highly stable and relatively easy to quantify. Therefore, these miRNAs may be ideal candidates for biomarkers of HIE severity and may aid in directing the clinical management of these infants. By using both transcriptomic and proteomic approaches to analyse the expression of miRNAs and their potential targets in the umbilical cord blood, I have confirmed that infants with perinatal asphyxia and HIE have a significantly different UCB miRNA signature compared to UCB samples from healthy controls. Finally, I have identified and investigated 2 individual miRNAs; both of which show some potential as classifiers of HIE severity and predictors of long term outcome, particularly when coupled with their downstream targets. While this work will need to be validated and expanded in a new and larger cohort of infants, it suggests the potential of miRNA as biomarkers of neonatal pathological conditions such as HIE.

Unraveling the function of bacterial-type phosphoenolpyruvate carboxylase in vascular plants

Two distinct phosphoenolpyruvate carboxylase (PEPC) isozymes occur in vascular plants and green algae: plant-type PEPC (PTPC) and bacterial-type PEPC (BTPC). PTPC polypeptides typically form a tightly regulated cytosolic Class-1 PEPC homotetramer. BTPCs, however, appear to be less widely expressed and to exist only as catalytic and regulatory subunits that physically interact with co-expressed PTPC subunits to form hetero-octameric Class-2 PEPC complexes that are highly desensitized to Class-1 PEPC allosteric effectors. Yeast two-hybrid studies indicated that castor plant BTPC (RcPPC4) interacts with all three Arabidopsis thaliana PTPC isozymes, and that it forms stronger interactions with AtPPC2 and AtPPC3, suggesting that specific PTPCs are preferred for Class-2 PEPC formation. In contrast, Arabidopsis BTPC (AtPPC4) appeared to interact very weakly with AtPPC2 and AtPPC3, suggesting that BTPCs from different species may have different physical properties, hypothesized to be due to sequence dissimilarities within their ~10 kDa intrinsically disordered region. Recent RNA-seq and microarray data were analyzed to obtain a better understanding of BTPC expression patterns in different tissues of various monocot and dicot species. High levels of BTPC transcripts, polypeptides and Class-2 PEPC complexes were originally discovered in developing castor seeds, but the analysis revealed a broad range of diverse tissues where abundant BTPC transcripts are also expressed, such as the developing fruits of cucumber, grape, and tomato. Marked BTPC expression correlated well with the presence of ~116 kDa immunoreactive BTPC polypeptides, as well as Class-2 PEPC complexes in the immature fruit of cucumbers and tomatoes. It is therefore hypothesized that in vascular plants BTPC and thus Class-2 PEPC complexes maintain anaplerotic PEP flux in tissues with elevated malate levels that would potently inhibit ‘housekeeping’ Class-1 PEPCs. Elevated levels of malate can be used by biosynthetically active sink tissues such as immature tomatoes and cucumbers for rapid cell expansion, drought or salt stressed roots for osmoregulation, and developing seeds and pollen as a precursor for storage lipid and protein biosynthesis.

Effects of advanced glycation end-products (AGEs) on retinal pigment epithelial (RPE) cells lysosomal function:implications for age-related macular degeneration (AMD)

Purpose: RPE lysosomal dysfunction is a major contributor to AMD pathogenesis. Controlled activity of a major class of RPE proteinases, the cathepsins, is crucial in maintaining correct lysosomal function. Advanced glycation end-products (AGEs) accumulate in the Bruch’s membrane (BM) with age, impacting critical RPE functions and in turn, contributing to the development of AMD. The aim of this study was to assess the effect of AGEs on lysosomal function by analysing the expression, processing and activity of the cysteine proteinases cathepsins B, L and S, and the aspartic proteinase cathepsin D. Methods: ARPE-19 cells were cultured on AGE-containing BM mimics (matrigel) for 14 days and compared to untreated substrate. Expression levels and intracellular processing of cathepsins B, D, L and S, were assessed by qPCR and immunoblotting of cell lysates. Lysosomal activity was investigated using multiple activity assays specific to each of the analysed cathepsins. Statistical analysis was performed using the Student’s independent T-test. Results: AGE exposure produced a 36% decrease in cathepsin L activity when compared to non-treated controls (p=0.02, n= 3) although no significant changes were observed in protein expression/processing under these conditions. Both the pro and active forms of cathepsin S decreased by 40% (p=0.04) and 74% (p=0.004), respectively (n=3). In contrast, the active form of the cathepsin D increased by 125% (p=0.005, n= 4). However, no changes were observed in the activity levels of both cathepsins S and D. In addition, cathepsin B expression, processing and activity also remained unaltered following AGE exposure. Conclusions: AGEs accumulation in the extracellular matrix, a phenomenon associated with the natural aging process of the BM, attenuates the expression, intracellular processing and activity of specific lysosomal effectors. Altered enzymatic function may impair important lysosomal processes such as endocytosis, autophagy and phagocytosis of photoreceptor outer segments, each of which may influence the age-related dysfunction of the RPE and subsequently, AMD pathogenesis.