An evaluation of community-based cognitive stimulation therapy: a pilot study with an Irish population of people with dementia.

OBJECTIVES: Research shows that cognitive stimulation therapy (CST) improves cognitive function, quality of life, and well-being of people with mild-moderate dementia. Despite consistent evidence and recommendations, CST is not routinely available in Ireland post-diagnosis. The aim of the current research was to develop and evaluate community-based CST for people with mild-moderate dementia, run by the Alzheimer Society of Ireland across four pilot sites in Ireland. METHODS: Participants with mild-moderate dementia attended once weekly CST sessions for 14 weeks. Baseline and post-intervention assessments were completed by CST participants, carers, and CST facilitators. Primary outcomes of interest for CST participants included quality of life (Quality of Life in Alzheimer Disease Scale), cognitive function (Montreal Cognitive Assessment), and subjective cognitive function (Memory Awareness Rating Scale-Functioning Subscale). Secondary outcomes included well-being, cognitive ability, satisfaction with cognitive performance, and engagement and confidence of CST participants; well-being of carers; and job satisfaction of facilitators. Post-intervention interviews supplemented quantitative analyses. RESULTS: In total, 20 CST participants, 17 carers, and six CST facilitators completed evaluation assessments. Results showed that CST improved participants' satisfaction with cognitive performance (p=0.002), level of engagement (p=0.046), level of confidence (p=0.026). Improvements on subjective cognitive function just fell short of significance (p=0.055). Qualitative analysis of interview data identified consistent themes of cognitive and overall benefits of CST; and provided support for quantitative data. CONCLUSIONS: Community-based CST positively impacted the lives of people with dementia and their families. This study supports prior recommendations that CST should be made routinely available to people with mild-moderate dementia, particularly in light of the lack of post-diagnostic interventions currently offered in Ireland.

Silica hydride intermediate for octadecylsilica and phenyl bonded phase preparation via heterogeneous hydrosilation in supercritical carbon dioxide.

Investigations into the preparation of silica hydride intermediate in supercritical carbon dioxide (sc-CO(2)) that avoids the use of organic solvents such as toluene or dioxane are described. The effects of reaction temperature, pressure and time on the surface coverage of the supercritical fluid generated silica hydride intermediate were studied. Under optimised supercritical conditions of 120°C, 483 bar and 3 h reaction time, silica hydride (Si-H) conversion efficiencies of ca. 40% were achieved for the hydride intermediate prepared from a monofunctional silane reagent (dimethylmethoxysilane). Si-H conversion efficiencies (as determined from (29)Si CP-MAS NMR spectral analysis) for the hydride intermediate prepared from triethoxysilane (TES) in sc-CO(2) were found to be comparable to those obtained using a TES silanisation approach in an organic solvent. (13)C and (29)Si CP-MAS-NMR spectroscopy was employed to provide a complete structural assignment of the silica hydride intermediates. Furthermore, supercritical CO(2) was subsequently employed as a reaction medium for the heterogenous hydrosilation of silica hydride with octadecene and with styrene, in the presence of a free radical initiator. These supercritical fluid generated reversed-phase materials were prepared in a substantially reduced reaction time (3 h) compared to organic solvent based methods (100 h reaction time). Silica functionalisation in sc-CO(2) presents an efficient and clean alternative to organic solvent based methods for the preparation of important silica hydride intermediate and silica bonded stationary phases via a hydrosilation approach.

Primary pulmonary meningioma: report of a case and review of the literature.

Ten cases of benign primary pulmonary meningioma have been reported in the English literature. We describe herein an additional case of a benign meningioma arising in the lung showing comparable histologic features of sheets and whorls of epithelioid and meningothelial cells with numerous psammoma bodies. Immunohistochemistry showed that the tumor expressed vimentin and epithelial membrane antigen and was negative for keratin, CD34, glial fibrillary acidic protein, CAM 5.2 and S-100, in keeping with previously reported findings. Our review of the literature reveals similar clinical presentations and follow-up behavior and, where reported, similar electron microscopic and immunostaining features.

Absorption, pharmacokinetics and metabolism of 14C-sumatriptan following intranasal administration to the rat.

1. Studies have been carried out to investigate the absorption of sumatriptan after intranasal administration to rats. The pharmacokinetics, metabolism and excretion of 14C-sumatriptan were compared following intranasal and intravenous dosing to male and female albino rats using an aqueous buffered formulation at pH 5.5. 2. Following intravenous administration sumatriptan was eliminated from plasma with a half-life of about 1.1 h. After intranasal administration there was rapid absorption of part of the dose and two peak plasma concentrations were observed, initially at 0.5 and then at 1.5-2 h. The elimination half-life after the second peak was estimated as being about 4 h. 3. Radioactivity was largely excreted in urine (up to 89% of dose in 168 h) after both intravenous and intranasal administration, with a faster rate of excretion after intravenous dosage (73% males, 64% females within 6 h) than after intranasal dosage (37% males, 40% females within 6 h). 4. 14C-sumatriptan was the major component in urine and in extracts of faeces after both intravenous and intranasal administration. The major metabolite excreted in urine and faeces was GR49336, the indole acetic acid analogue. 5. The results of this in vivo rat study suggest that absorption of the dose via the nasal mucosa is incomplete after intranasal administration and that there is a secondary absorption phase probably reflecting oral absorption of part of the dose. The bioavailability is estimated as about 30%, for the period 0-6 h.

Kinetics and disposition of picumeterol in animals.

1. The pharmacokinetics and disposition of picumeterol, a novel beta 2 receptor agonist agent, have been studied in the rat and dog following administration by inhalation, intravenous and oral routes at various dose levels. 2. Picumeterol was found to be transferred across the lung of the rat and dog following inhalation dosage. After i.v. dosage picumeterol was eliminated from plasma with a half-life of about 1 h in the rat and about 2 h in the dog. Plasma clearance in the rat was about twice liver blood flow and the plasma levels of picumeterol were low after oral administration. 3. Following instillation of 14C-picumeterol to the trachea of isolated respiring rat lung preparations radioactivity was transferred from the airways to perfusion media as unchanged drug within 2 min. After 2 h perfusion, no metabolites were detected in the recirculation perfusate or lung. 4. Picumeterol was extensively metabolized in vivo in the rat (about 95%) and dog (about 90%) and in vitro in microsomal preparations of rat, dog and human liver. O-dealkylation and beta-oxidation are important as routes of metabolism. 5. Radioactivity was largely excreted in the urine of the rat and dog (> 50% of dose), as metabolites, following i.v. administration. There was some excretion of radioactivity in dog bile. Extensive first-pass metabolism was found after oral administration in the rat.

Cell surface beta 1,4 galactosyltransferase on primary spermatocytes facilitates their initial adhesion to Sertoli cells in vitro.

The Sertoli cell maintains the cytoarchitecture of the seminiferous epithelium and provides support for the developing germ cells through specialized adhesive junctions. Despite the importance of this adhesive interaction, our understanding of germ cell-Sertoli cell interactions is limited. Previous studies have shown that beta 1,4 galactosyltransferase (GalTase) is present on the surface of mature sperm, where it mediates sperm binding to the egg zona pellucida. Since GalTase is present on the surface of early spermatogenic cells long before it is required for sperm-egg recognition, we determined in this study whether GalTase on developing germ cells functions during adhesion to Sertoli cells. Consistent with such a function, GalTase was localized by indirect immunofluorescence to areas of putative germ cell-Sertoli cell contact. More directly, anti-GalTase IgG and Fab fragments inhibited the initial adhesion of spermatocytes to Sertoli cell monolayers; however, anti-GalTase antibodies were less able to inhibit spermatocyte-Sertoli cell adhesions after prolonged co-culture, presumably due to stabilization of the intercellular adhesion. After meiosis, surface GalTase begins to acquire its final distribution overlying the intact acrosome; there it was no longer able to facilitate germ cell adhesion to Sertoli cells. Indirect immunofluorescence and direct enzyme assays showed that Sertoli cells also expressed surface GalTase; however, most GalTase was confined to the basal cell surface where it was inaccessible to germ cells, but where it may function in adhesion to the underlying basal lamina. Preblocking studies confirmed that surface GalTase on the spermatocyte surface, rather than on the exposed apical Sertoli surface, mediated germ cell-Sertoli cell adhesion, presumably by binding to glycoside ligands on the Sertoli cell.

Tests of sperm function for evaluation of the male: Penetrak and Tru-Trax.

OBJECTIVE: To evaluate the Penetrak (Serono Laboratories, Norwell, MA) and Tru-Trax (Humagen, Charlottesville, VA) bovine cervical mucus (CM) penetration assays and to correlate results to parameters of semen analysis and male factor diagnosis. DESIGN: Prospective, nonrandomized, controlled study. PARTICIPANTS: Two hundred thirty-six males undergoing evaluation for male factor infertility and 37 fertile semen donors. MAIN OUTCOME MEASURES: Human sperm penetration in bovine CM measured by the Penetrak and Tru-Trax assay systems correlated to sperm density, motility, forward progression, and clinical diagnosis. RESULTS: Two parameters of semen analysis, motility and density were correlated to the distance traversed by the vanguard sperm in both Penetrak and Tru-Trax assays. Penetrak results were significantly correlated to male factor infertility diagnosis. CONCLUSIONS: Both assays were reliable and highly reproducible, and the Tru-Trax assay was correlated to its predecessor, Penetrak. Although Penetrak and Tru-Trax were correlated to motility and density, no correlation coefficient was > 0.6, suggesting that these assays measure a facet of sperm function that is independent of semen analysis.

Intraoperative transesophageal echocardiography.

Intraoperative echocardiography in patients undergoing cardiac surgery was first described in 1972. Interest in intraoperative echocardiography has grown in recent years due to the extensive information provided by 2-dimensional (2-D) and color-flow Doppler imaging via the transesophageal approach. The value of this technique also has been verified in large clinical studies involving patients undergoing cardiac surgery. Intraoperative transesophageal echocardiography (TEE) is very useful in preoperative formulation of surgical plans and in immediate post-operative assessment of surgical results in patients undergoing valve surgery.

Less than lobar resections for bronchogenic carcinoma.

We performed less than lobar resections for peripheral clinical Stage I primary lung cancers on 170 patients treated between 1973 and 1987 at two university centers, one in Hawaii and one in Israel. Most patients were poor risks and several had FEV1 < 1 liter. There were 6 (3.5%) hospital deaths. There were 58 segmental resections, 97 wedge resections and 15 less than lobar resections not otherwise specified. Seventy-three patients (43%) are living free of cancer from 5 to 11 years postoperatively and 20 additional patients died of causes unrelated to lung cancer after 5 years; thus disease free five year survival was 54.7%. Patients with adenocarcinoma had poorer prognosis than other cell types. Twenty-three patients (13.5%) had synchronous or metachronous second primary lung cancers. Nine of these patients are long term survivors. Twenty-four patients (14.1%) developed local recurrences with or without distant metastases. This promising long term cancer-free survival and the frequency of second primary lung cancers justifies less than lobar resection for peripheral, Stage I bronchogenic carcinoma, especially in the poor risk patient.

Coronary atherectomy: report of the first experience in Hawaii.

Since Andreas Gruentzig first introduced percutaneous transluminal coronary angioplasty (PTCA) in 1977, the ability to revascularize occluded coronary vessels with a catheter has enjoyed an explosive and unimaginable growth. As the equipment and operator experience improved, the possibilities appeared boundless. However, balloon angioplasty is hampered by a significant restenosis rate in the dilated vessel (approximately 30%), which is higher in selected locations (up to 60% in the proximal left anterior descending artery), even in the best of hands. This fundamental limitation may in part be due to the actual nature of the technique itself--stretching the vessel and fissuring the plaque causing remodeling without removal. The uneven, exposed vessel surface post-plaque rupture may contribute to activation of the hemostatic system, with acute thrombosis and release of various platelet and endothelial-derived growth factors, leading to long-term tissue proliferation and restenosis. Atherectomy, the mechanical removal of plaque from the vessel wall, appears to be an answer. This process actually debulks the culprit tissue and leaves behind a smoother, presumably less thrombogenic surface. We wish to report our first experience with a specific form of this technique in 4 consecutive patients, with a brief discussion of its promises and limitations.

Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly.

Ondansetron is a 5-hydroxytryptamine3 receptor antagonist for the treatment of chemotherapy- and radiotherapy-induced nausea and emesis. A sensitive, accurate, and precise HPLC method for the determination of ondansetron in plasma is described. Samples are prepared by solid-phase extraction and, after chromatography of the extracts on a silica analytical column, ondansetron is detected by UV absorbance at 305 nm. The method is sensitive down to 1 ng/mL, at which concentration the coefficient of variation was 6.2% in a single assay run. Repeated analyses of quality control samples, nominally at 2 ng/mL, were carried out over a number of assay runs with a coefficient of variation of 5.5%. The method is specific for ondansetron with respect to endogenous plasma components, identified phase I metabolites, and some co-administered chemotherapeutic drugs. In sustained use over several months, and in support of the clinical development of ondansetron, the method has been shown to be robust. An application of the assay in the investigation of the pharmacokinetics of ondansetron in the young and elderly is described.

The pharmacodynamics and pharmacokinetics of a novel thromboxane receptor blocking drug vapiprost (GR32191) after single intravenous doses in healthy subjects.

1 The effect of single, serially increasing, intravenous doses of a specific thromboxane receptor blocking drug, vapiprost, upon platelet aggregation induced ex vivo by the thromboxane A2 mimetic, U-46619, was examined in 12 healthy males. 2 Subjects received either 1 (n = 1 subject), 2 (n = 6), 3 (n = 2), or 4 (n = 3) administrations of vapiprost within the dose range 0.125 to 16 mg and, in random order, placebo on separate study days at intervals of at least 48 h. 3 All doses of vapiprost produced an immediate antagonism of U-46619-induced platelet aggregation in whole blood. Both the magnitude and duration of the rightward displacement of the concentration-effect curves increased with dose. Although lower doses produced parallel displacements of these curves, with the higher doses the maximum response to U-46619 was reduced such that 50% platelet aggregation was not achieved. After the 16 mg dose of vapiprost, virtually complete suppression of platelet aggregation (up to a concentration of 30 microM) was seen. This degree of inhibition was maintained for 2 h after dosing, following which there was a gradual return to pre-dose U-46619 sensitivity over the next 12 to 24 h. U-46619-induced platelet aggregation was unaffected by placebo. 4 Across the dose range, vapiprost was rapidly cleared from plasma, with an elimination half-life of 69-84 min and a plasma clearance of 514-721 ml min-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated galactosyltransferase activity on t-bearing sperm segregates with T/t-complex distorter loci-2.

Sperm bearing complete t-haplotypes are preferentially transmitted during fertilization from heterozygous +/t males, often in excess of 95% relative to their (+)-bearing meiotic partner. Sperm from t-bearing males have an approximate two- to fourfold increase in beta 1,4-galactosyltransferase (GalTase) activity, a cell surface protein that mediates sperm binding to the egg zona pellucida. The elevated GalTase activity strictly correlates with the preferential transmission of t-sperm from +/t males, since eight other enzymes show normal levels of activity on t-sperm. Furthermore, sperm bearing proximal partial t-haplotypes, which are no longer favoured during fertilization, have normal levels of GalTase activity. Nevertheless, it has been unclear whether the elevated sperm GalTase activity on t-sperm is due to specific loci in the distal segment of the T/t-complex, or rather, is an indirect consequence of the abnormal sperm function characteristic of +/t and tx/ty males. In this study, it is shown that the elevated sperm GalTase activity is due specifically to factors that reside within the distal segment of the T/t complex, which also contains Tcd-2, the strongest of the distorter loci. Since the structural locus for GalTase is located on mouse chromosome 4, these results also show that T/t-complex alleles on chromosome 17 are regulatory in nature and affect the expression of sperm surface components critical for normal fertilization. Models are presented to explain how elevated GalTase activity could contribute to sperm transmission distortion.

Automatic implantable cardioverter defibrillator: report of the first two implants in Hawaii.

Sudden cardiac death is the major cause of death in the United States today, claiming over 400,000 victims each year, or one per minute. In the majority of cases, the underlying mechanism is malignant ventricular tachyarrhythmia, with the common substrate being abnormal myocardium from ischemic heart disease or congestive cardiomyopathy.

Stage-specific increase in cell surface galactosyltransferase activity during spermatogenesis in mice bearing t alleles.

Mouse sperm surface galactosyltransferase (GalTase) mediates fertilization by binding to its appropriate glycoconjugate substrate in the egg zona pellucida. GalTase is present throughout all stages of spermatogenesis, during which time it redistributes within the plasma membrane from a uniform, diffuse distribution on primary spermatocytes to a restricted domain overlying the dorsal surface of the acrosome. Previously, we have shown that GalTase activity is elevated on transmission-distorting t-bearing sperm populations, relative to normal sperm, and in this paper, we define the stage when surface GalTase activity becomes elevated during t spermatogenesis. GalTase specific activity is equal between normal and t-bearing primary spermatocytes, but following meiosis, surface GalTase activity becomes elevated nearly fourfold on t-bearing round spermatids. The increased GalTase activity on t-bearing spermatids is not due to decreased hydrolysis of the GalTase substrates, and is appropriately localized over the acrosomal region, even on misshapen sperm heads occasionally seen in t-sperm populations. These studies define the stage when a specific biochemical defect associated with mutant alleles of the T/t complex first becomes detectable. The t factors that elevate GalTase activity on round spermatids may be similar to previously identified t-specific testicular proteins that are maximally expressed at the same developmental stage, and which map to the same portion of the T/t complex.

Spatial and temporal expression of cell surface galactosyltransferase during mouse spermatogenesis and epididymal maturation.

We have previously shown that sperm-egg recognition in the mouse is mediated by the binding of galactosyltransferase (GalTase) on the sperm surface to its appropriate glycoside substrate in the egg zona pellucida [L. C. Lopez, E. M. Bayna, D. Litoff, N. L. Shaper, J. H. Shaper, and B. D. Shur (1985) J. Cell Biol. 101, 1501-1510]. In the present study, we have defined the spatial and temporal expression of surface GalTase during spermatogenesis and epididymal maturation. Purified populations of spermatogenic cells were isolated by unit gravity sedimentation, and surface GalTase expression was determined by indirect immunofluorescence and by direct enzymatic assay. GalTase is present on the surface of all spermatogenic cells assayed. During differentiation, there is a progressive redistribution of GalTase from an initially diffuse and uniform localization on the surface of primary spermatocytes to a restricted plasma membrane domain overlying the dorsal aspect of the mature acrosome. This apparent redistribution of surface GalTase was confirmed by direct enzymatic assays, which show that surface GalTase activity, normalized per cell, remains relatively constant throughout spermatogenesis, despite a drastic reduction in cell surface area. When normalized to the relevant cell surface area, the GalTase concentration per square micrometer increases 77-fold from pachytene spermatocytes to cauda epididymal sperm. Cell surface GalTase is thought to be a cytoskeletally associated transmembrane protein [N. L. Shaper, P. L. Mann, and J. H. Shaper (1985) J. Cell Biochem. 28, 229-239]; consequently we examined whether cytoskeletal components may be involved in the redistribution of GalTase during spermatogenesis. beta-Tubulin, monomeric actin, and filamentous actin were found to be present during spermatogenesis, as assayed by indirect immunofluorescence and by Western immunoblotting. alpha-Actinin and vinculin were not detectable under these conditions and served as negative controls. During spermatogenesis, the distribution of tubulin coincides with the appearance of the mitotic spindle, flagellum, and manchette. On the other hand, the distribution of filamentous actin coincides with surface GalTase, suggesting that actin-containing microfilaments may participate in the redistribution of surface GalTase during spermatogenesis.

Cell surface galactosyltransferase as a recognition molecule during development.

Recent results from our laboratory suggest that a variety of cellular interactions during development are mediated, in part, by the binding of a cell surface enzyme, galactosyltransferase (GalTase), to its specific lactosaminoglycan (LAG) substrate on adjacent cell surfaces and in the extracellular matrix. Our present interest in surface GalTase developed from earlier biochemical studies of a series of morphogenetic mutations in the mouse which map to the T/t-complex. These studies identified a specific defect in the regulation of surface GalTase activity on morphogenetically abnormal cells, while eight other enzymes showed normal activity. This led us to consider the unique function of surface GalTase in those cell interactions that are influenced by mutations of the T/t-complex. By using a multidisciplinary approach, which included genetic, biochemical and immunological probes, we have found that GalTase functions as a surface receptor during fertilization, early embryonic cell adhesions, and embryonic cell migration on basal lamina matrices. Recently, we have examined the expression of surface GalTase during spermatogenesis, as well as the fate of sperm GalTase following the acrosome reaction. This paper summarizes the results of these studies, as well as others, which suggest that GalTase functions as a surface receptor during those cell interactions regulated by the T/t-complex alleles.

Tissue distribution and subunit structures of the multiple forms of glutathione S-transferase in the rat.

A study of the subunit structures of the multiple forms of glutathione S-transferase in rat kidney, testis, lung and spleen is shown to be consistent with a proteolytic model for the generation of the multiple forms.