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Background: The communication skills of older adults living in care homes is an underexplored topic. Aging can lead to reduced communication ability and activity; and in the care home environment, there may also be fewer communication opportunities. This situation is likely to negatively impact wellbeing. Previous reviews have found evidence of the effectiveness of behavioural interventions in increasing wellbeing, but no systematic review to date has focused specifically on the evidence base for group language and communication interventions in this population. \ud Aims: To identify and evaluate the evidence for behavioural interventions with older adults, delivered in groups in residential settings, that specifically included a language or communication activity. To explore the impact of such intervention on the specific domains of language, communication and social interaction. To determine whether behavioural mechanisms of action can be identified.\ud \ud Methods: Embase, Medline, Ovid Nursing database, Psych info, and CINAHL complete were searched and produced 158 records for screening, of which 22 remained for review. In order to identify and evaluate the quality of the evidence base presented the following research questions were posed: What research has been conducted in this area? What is the methodological quality of the studies identified? How complete is the intervention reporting? How was change measured in the domains of language, communication and social interaction? Is there evidence of efficacy, indicated by statistically significant improvement, in these domains? How did the interventions work? Synthesis tools employed included the PEDro-P Scale, the TIDieR checklist and the ITAX. \ud \ud Main Contribution: 22 studies met the criteria for review. One of the studies used solely language or communication interventions, but the remaining 21 studies used behavioural interventions which incorporated language and communication activities to varying degrees. Studies fell into 4 broad intervention types: Reminiscence or Life Review, Cognitive Stimulation, Narrative or Storytelling, and Multi-modality Group Communication. The majority of studies were of fair methodological quality, with a moderate level of detail provided in treatment reporting. Statistically significant improvement was reported by authors in all 4 intervention types and across language, communication and social domains. Social interaction, social support, and behavioural skills were the most consistent mechanisms of action in the reviewed behavioural interventions.\ud \ud Conclusion: Despite limitations in the evidence base there are important positive signs for the beneficial effects of supporting language and communication in care homes. Blinding of assessors, and the accuracy and accessibility of statistical reporting are important areas to address in order to improve the quality of the evidence base. \ud \ud What this paper adds\ud Aging can lead to reduced communication ability and activity, and in the care home setting, there may also be fewer communication opportunities. This situation is likely to negatively impact wellbeing. Previous reviews have found evidence of the effectiveness of behavioural interventions in increasing wellbeing. The communication skills of older adults living in care homes is an underexplored topic. No systematic review to date has focused specifically on the evidence base for group language and communication interventions in this population. This review reveals important positive signs for the beneficial effects of supporting language and communication in care homes. Social interaction, social support, and behavioural skills were the most consistent mechanisms of action in the reviewed behavioural interventions.

Introduction Amiodarone reduces recurrent ventricular tachyarrhythmias (VTA) but may worsen cardiovascular outcomes in heart failure (HF) patients. Cardiac resynchronization therapy (CRT) may also be antiarrhythmic. When patients with prior sustained VTA are upgraded to CRT defibrillators (CRT-D) from conventional implantable cardioverter-defibrillators (ICDs), should concomitant amiodarone be continued or is CRT's antiarrhythmic potential sufficient? Methods and results We identified 67 patients from a prospective CRT registry with spontaneous sustained VTA, New York Heart Association (NYHA) II-IV HF, and left bundle-branch block (LBBB) who were upgraded to CRT defibrillators from conventional ICDs. We compared changes in QRS duration and left ventricular ejection fraction (LVEF) pre- and post-CRT, time to death, transplant or ventricular assist device (VAD), and time to recurrent VTA therapies between 37 patients continuing amiodarone therapy and 30 amiodarone-naive patients. Amiodarone-treated patients had worse renal function and a higher prevalence of prior VTA storm compared with amiodarone-naive patients. After CRT, amiodarone-treated patients demonstrated less QRS narrowing (8 vs 20 ms; P = 0.021) and less LVEF improvement (-2.7 vs +5.2%; P = 0.006). Over 29 months, 31 (47%) patients died and 13 (20%) received transplant or VAD. Risk of death, transplant, or VAD was greater in amiodarone-treated than -naive patients (corrected hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.12-4.11; P = 0.022). Appropriate CRT-D therapies occurred in 37 (55%) patients; amiodarone use was not associated time to first therapy (HR, 1.13; 95% CI, 0.59-2.16; P = 0.72). Conclusion In patients with sustained VTA and LBBB upgraded from conventional ICDs to CRT defibrillators, concomitant amiodarone use is associated with less QRS narrowing, less LVEF improvement, greater risk of death, transplant, or VAD, and similar risk of recurrent VTA.

Ankyrins-R, -B, and -G are a family of membrane-associated adaptors required for localization of structurally diverse proteins to specialized membrane domains, including axon initial segments, cardiomyocyte T-tubules, and epithelial cell lateral membranes. Ankyrins are often co-expressed in the same cells and, although structurally similar, have non-overlapping functions. We previously determined that the regulatory domain of ankyrin-B defines specificity between ankyrins B and G in cardiomyocytes. Here, we identify key residues on the surface of an amphipathic α-helix unique to the regulatory domain of ankyrin-B that are essential for the function of ankyrin-B in cardiomyocytes. Using circular dichroism, we determined that a peptide representing the predicted helix folds as a helix in solution. Alanine-scanning mutagenesis revealed that residues 1773, 1777, 1780, 1784, and 1788 located in a patch on one surface the helix are critical for ankyrin-B function in cardiomyocytes. In a parallel set of experiments we determined that the molecular co-chaperone human DnaJ homologue 1 (Hdj1)/Hsp40 interacts with the ankyrin-B regulatory domain. Moreover, interaction of Hdj1/Hsp40 with the regulatory domain was mapped by random mutagenesis to same surface of the α-helix that is required for ankyrin-B function. These results provide new insight into the molecular basis for specificity between ankyrin-based pathways by defining a key α-helix structure in the divergent regulatory domain of ankyrin-B as well as interaction of the helix with Hdj1/Hsp40, the first downstream target for ankyrin-B-specific function.

This report describes a congenital myopathy and major loss of thymic lymphocytes in ankyrin-B (−/−) mice as well as dramatic alterations in intracellular localization of key components of the Ca2+ homeostasis machinery in ankyrin-B (−/−) striated muscle and thymus. The sacoplasmic reticulum (SR) and SR/T-tubule junctions are apparently preserved in a normal distribution in ankyrin-B (−/−) skeletal muscle based on electron microscopy and the presence of a normal pattern of triadin and dihydropyridine receptor. Therefore, the abnormal localization of SR/ER Ca ATPase (SERCA) and ryanodine receptors represents a defect in intracellular sorting of these proteins in skeletal muscle. Extrapolation of these observations suggests defective targeting as the basis for abnormal localization of ryanodine receptors, IP3 receptors and SERCA in heart, and of IP3 receptors in the thymus of ankyrin-B (−/−) mice. Mis-sorting of SERCA 2 and ryanodine receptor 2 in ankyrin-B (−/−) cardiomyocytes is rescued by expression of 220-kD ankyrin-B, demonstrating that lack of the 220-kD ankyrin-B polypeptide is the primary defect in these cells. Ankyrin-B is associated with intracellular vesicles, but is not colocalized with the bulk of SERCA 1 or ryanodine receptor type 1 in skeletal muscle. These data provide the first evidence of a physiological requirement for ankyrin-B in intracellular targeting of the calcium homeostasis machinery of striated muscle and immune system, and moreover, support a catalytic role that does not involve permanent stoichiometric complexes between ankyrin-B and targeted proteins. Ankyrin-B is a member of a family of adapter proteins implicated in restriction of diverse proteins to specialized plasma membrane domains. Similar mechanisms involving ankyrins may be essential for segregation of functionally defined proteins within specialized regions of the plasma membrane and within the Ca2+ homeostasis compartment of the ER.

This study analyzed the complex interactions of intact spectrin with bovine brain membranes by evaluating membrane associations of defined regions of beta G spectrin, the subunit responsible for high affinity membrane binding. Two regions of beta G spectrin were expressed in bacteria and demonstrated to contain fully functional binding site(s) for a subset of spectrin-binding sites in brain membranes depleted of peripheral proteins. One region, located near the NH2 terminus, was comprised of 106-residue repeats and required repeats 2-7 for full activity. The other binding domain was located at the COOH terminus, which is the most variable between beta G and beta R spectrins, is distinct from the 106-residue repeats, and contains a pleckstrin homology domain. NH2-terminal beta spectrin polypeptides interacted with a membrane site(s) that recognized both brain and erythrocyte isoforms of spectrin, was inhibited by calcium/calmodulin, and was not blocked by the COOH-terminal polypeptide. The COOH-terminal region associated with a membrane site(s) that was specific for brain spectrin, was not inhibited by calcium/calmodulin, and was not blocked by the NH2-terminal polypeptide. These observations demonstrate membrane association of spectrin with at least two independent sites, which differ with regard to regulation by calcium/calmodulin and in selectivity for spectrin isoforms.

This study of two forms of ankyrin (protein 2.1 and 2.2) from human erythrocytes has revealed a role for alternate exon usage at the level of regulation of protein interactions. The smaller form of ankyrin (protein 2.2), which lacks a portion of the regulatory domain due to alternative splicing of pre-mRNA, exhibits increased affinity for the cytoplasmic domain of the anion exchanger, spectrin, and tubulin. Direct evidence that at least one of these associations is modulated by the alternatively spliced segment of the regulatory domain is provided by experiments utilizing a polypeptide that is comprised of residues 1513-1674 corresponding to the portion of the regulatory domain missing from protein 2.2. Addition of this regulatory domain polypeptide to binding assays reversed the increase in affinity of protein 2.2 for the anion exchanger. The inhibitory activity of the regulatory domain polypeptide in these assays is accompanied by a direct interaction with a site that is available on the smaller form of ankyrin and is distinct from the binding site for the anion exchanger. These results support the idea that the alternatively spliced segment within the regulatory domain of erythrocyte ankyrin performs a repressor function and acts through an allosteric mechanism involving interaction(s) at a site separate from the binding site for the anion exchanger.

Erythrocyte ankyrin contains an 89-kDa domain (residues 2-827) comprised almost entirely of 22 tandem repeats of 33 amino acids which are responsible for the high affinity interaction of ankyrin with the anion exchanger (Davis, L., and Bennett, V. (1990) J. Biol. Chem. 265, 10589-10596). The question of whether the repeats are equivalent with respect to binding to the anion exchanger was addressed using defined regions of erythrocyte and brain ankyrins expressed in bacteria. The conclusion is that the repeats are not interchangeable and that the 44 residues from 722 to 765 are essential for high affinity binding between erythrocyte ankyrin and the anion exchanger. Residues 348-765 were active whereas a polypeptide of the same size (residues 305-721) but missing the 44 residues was not active. The difference between the active and inactive polypeptides was not caused by the degree of folding based on circular dichroism spectra. The 44 residues from 722 to 765 were not sufficient for binding since deletions of residues from 348 to 568 resulted in a 10-fold loss of activity. However, the role of residues 348-568 may be at the level of folding rather than a direct contact since the deleted sequences were not active in the absence of 722-765 and since circular dichroism spectra revealed significant loss of structure in the smaller polypeptides. Further evidence that the 33-residue repeats are not equivalent in ability to bind to the anion exchanger is that a region of human brain ankyrin containing 18 33-residue repeats with 67% overall sequence identity to erythrocyte ankyrin was 8-fold less active than a region of erythrocyte ankyrin containing only 12 repeats. The fact that the anion exchanger binds to certain repeats suggests that the other 33-amino acid repeats could interact with proteins distinct from the anion exchanger and provide ankyrin with the potential for considerable diversity in association with membrane proteins as well as cytoplasmic proteins. Tubulin was identified as one example of a protein that can interact with ankyrin repeats that are not recognized by the anion exchanger.

Spectrins are tetrameric actin-cross-linking proteins that form an elastic network, termed the membrane skeleton, on the cytoplasmic surface of cellular membranes. At the plasma membrane, the membrane skeleton provides essential support, preventing loss of membrane material to environmental shear stresses. The skeleton also controls the location, abundance, and activity of membrane proteins that are critical to cell and tissue function. The ability of the skeleton to modulate membrane stability and function requires adaptor proteins that bind the skeleton to membranes. The principal adaptors are the ankyrin proteins, which bind to the β-subunit of spectrin and to the cytoplasmic domains of numerous integral membrane proteins. Here, we present the crystal structure of the ankyrin-binding domain of human β2-spectrin at 1.95Å resolution together with mutagenesis data identifying the binding surface for ankyrins on β2-spectrin.

This report describes initial characterization of the binding sites of ankyrin for spectrin and the anion exchanger using defined subfragments isolated from purified ankyrin domains. The spectrin-binding domain of ankyrin is comprised of two subdomains: an acidic, proline-rich region (pI = 4) involving the amino-terminal 80 residues from 828 to 908 and a basic region (pI = 8.8) that extends from 898 to 1386. The amino-terminal 70 amino acids of the spectrin-binding domain are critical for association with spectrin, since a subfragment missing this region is only 5% as active as the intact domain in displacing binding of spectrin to inside-out membrane vesicles, while deletion of the first 38 residues of the acidic domain results in a 10-fold reduction in activity. The anion exchanger-binding site is confined to an 89-kDa domain that was isolated and characterized as a globular molecule with approximately 30% alpha-helical configuration. A subfragment of the 89-kDa domain extending from residues 403 to 779 (or possibly 740) retains ability to associate with the anion exchanger. The 89-kDa domain is comprised of a series of tandem repeats of 33 amino acids that extend from residues 35 to 778 (Lux, S., John, K., and Bennett, V. (1990) Nature 344, 36-42). The activity of residues 403-779 demonstrates that the 33-amino acid repeats of the 89-kDa domain are responsible for association between ankyrin and the anion exchanger. The 33-amino acid repeating sequence of ankyrin represents an ancient motif also found in proteins of Drosophila, yeast, and Caenor habditis elegans. The finding that the 33-amino acid repeating sequence is involved in interaction with the anion exchanger implies that this motif may perform a role in molecular recognition in diverse proteins.

E-cadherin is a ubiquitous component of lateral membranes in epithelial tissues and is required to form the first lateral membrane domains in development. Here, we identify ankyrin-G as a molecular partner of E-cadherin and demonstrate that ankyrin-G and beta-2-spectrin are required for accumulation of E-cadherin at the lateral membrane in both epithelial cells and early embryos. Ankyrin-G binds to the cytoplasmic domain of E-cadherin at a conserved site distinct from that of beta-catenin. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. In addition to restricting the membrane mobility of E-cadherin, ankyrin-G and beta-2-spectrin also are required for exit of E-cadherin from the trans-Golgi network in a microtubule-dependent pathway. Ankyrin-G and beta-2-spectrin co-localize with E-cadherin in preimplantation mouse embryos. Moreover, knockdown of either ankyrin-G or beta-2-spectrin in one cell of a two-cell embryo blocks accumulation of E-cadherin at sites of cell-cell contact. E-cadherin thus requires both ankyrin-G and beta-2-spectrin for its cellular localization in early embryos as well as cultured epithelial cells. We have recently reported that ankyrin-G and beta-2-spectrin collaborate in biogenesis of the lateral membrane ( Kizhatil, K., Yoon, W., Mohler, P. J., Davis, L. H., Hoffman, J. A., and Bennett, V. (2007) J. Biol. Chem. 282, 2029-2037 ). Together with the current findings, these data suggest a ankyrin/spectrin-based mechanism for coordinating membrane assembly with extracellular interactions of E-cadherin at sites of cell-cell contact.

Ankyrins are a family of adapter proteins required for localization of membrane proteins to diverse specialized membrane domains including axon initial segments, specialized sites at the transverse tubule/sarcoplasmic reticulum in cardiomyocytes, and lateral membrane domains of epithelial cells. Little is currently known regarding the molecular basis for specific roles of different ankyrin isoforms. In this study, we systematically generated alanine mutants of clusters of charged residues in the spectrin-binding domains of both ankyrin-B and -G. The corresponding mutants were evaluated for activity in either restoration of abnormal localization of the inositol trisphosphate receptor in the sarcoplasmic reticulum in mutant mouse cardiomyocytes deficient in ankyrin-B or in prevention of loss of lateral membrane in human bronchial epithelial cells depleted of ankyrin-G by small interfering RNA. Interestingly, ankyrin-B and -G share two homologous sites that result in loss of function in both systems, suggesting that common molecular interactions underlie diverse roles of these isoforms. Ankyrins G and B also exhibit differences; mutations affecting spectrin binding had no effect on ankyrin-B function but did abolish activity of ankyrin-G in restoring lateral membrane biogenesis. Depletion of beta(2)-spectrin by small interfering RNA phenocopied depletion of ankyrin-G and resulted in a failure to form new lateral membrane in interphase and mitotic cells. These results demonstrate that ankyrin-G and beta(2)-spectrin are functional partners in biogenesis of the lateral membrane of epithelial cells.

Publisher Summary Spectrin is a flexible rod-shaped molecule, comprising two subunits, aligned side-to-side to form hetero-dimers and head-to-head into tetramers that are capable of cross-linking actin, with binding sites, for actin on both ends. Two classes of protein interactions have been identified as an essential for the assembly of spectrin tetramers into a membrane-associated network; linkage of spectrin to the membrane and association of multiple spectrin molecules with actin to form a two-dimensional meshwork. Principal that can be derived, from the erythrocyte membrane, is that spectrin alone does not polymerize or assemble into higher order structures without the aid of accessory proteins. This chapter discusses ankyrins that comprise an important class of spectrin-organizing proteins that are candidates to link a number of integral membrane proteins to the spectrin skeleton in specialized plasma membrane domains. The chapter discusses ankyrin structure of ankyrins being a multigene family, functional diversity of ankyrin, because of alternative splicing of messenger RNA (mRNA) and of mapping the binding sites of ankyrin. Ankyrins are a family of structural proteins, associated with the plasma membrane, that are candidates to link integral membrane proteins to the spectrin skeleton. Ankyrin-binding proteins include three different ion channels: the anion exchanger of erythrocytes and kidney collecting ducts, the Na + /K + - adenosine triphosphate (ATP)ase of kidney distal tubules, and the voltage-dependent sodium channel of the brain.

Translator's note: The following passage, about the young narrator's love of the writer Bergotte, occurs about one hundred pages into The Way by Swann's (pp.92-95 in the Pleiade edition of Du cote de chez Swann). The character Bergotte, and his style of writing, are said to have been modeled at least in part by Proust on a writer much admired by him, John Ruskin, the nineteenth-century master stylist who wrote on art, architecture, and economic and social issues, and two of whose best known works are Modern Painters and The Stones of Venice. Proust himself, working with his mother, Jeanne Proust, and a young English artist, Marie Nordlinger, translated Ruskin's The Bible of Amiens and Sesame and Lilies into French. My procedure in translating Proust was to follow the original very closely, even word byword when possible, to reproduce the shape of its sentences, even including their punctuation when possible, and to avoid adding to the text, subtracting from it, or substituting my interpretations for the original. In my second and third drafts I compared my work closely with the major existing translation, C.K. Scott Moncrieff's Swann's Way. Despite the many good qualities of this translation, which has been the standard for decades, and despite the often positive effects of the revisions carried out on it by Terence Kilmartin and D.J. Enright, a close examination--which is what I gave it as I worked with it--reveals several features that point to the need for a new translation. There is a natural tendency, in translation, to inflate and overwrite, for a simple reason: you want to make a rhythmically pleasing sentence in English; often an easy way to improve the rhythm in English is by adding to or subtracting from the original; you will usually decide to add because a worse crime would be to subtract material from the original; and then if you add, you will usually choose to double or reinforce the meaning of the original rather than add new material of your own. Thus does your translation become redundant or repetitious--"his own" instead of "his' "he himself" instead of "he," "strange and haunting" instead of simply "strange." Although on its own terms, the Scott Moncrieff translation is quite successful and, because of the sheer size of the book, an astounding achievement, it does suffer consistently from over-interpretation and inflation. In the following passage, for instance, where Proust describes the narrator's remarks as "uninteresting," Moncrieff translates this more emphatically as "quite without interest": "without interest" is a good exact equivalent for sans interet, but here Moncrieff intensifies it by "quite?' In a more significant amplification, where Proust has "the writer's page" Moncrieff adds a concrete image, producing "his printed page?' Adding again, Moncrieff turns "confidence" into "newfound confidence": here he is taking what he has learned from the context (that the narrator was not confident before but is now confident) and adding it to the unadorned word that Proust actually wrote. French readers of the original will add their own understanding to the word; readers of the translation will be "helped?' Lastly, this time substituting, Moncrieff replaces pre retrouve--"father found again"--by "long-lost father?' Moncrieff is inferring that the father was lost from what Proust says--that the father was found again. This is legitimate enough if it is done silently by the reader--it is what readers do. But he is going farther when, as translator, he substitutes what he inferred for what Proust actually said. The replacement of Proust's choice, "lost:' by Moncrieff's, "found," is a significant one. (Think of the titles of the books: the general title, In Search of Lost Time, and the title of the last volume, Time Found Again.) And then he is also adding "long," a less justifiable inference. Most likely the father was "long-lost" but Proust chose not to specify. …