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PubMed1990

The effects of caffeine on blood pressure in the work environment.

The ambulatory blood pressure and heart rate of twelve healthy volunteers were monitored on two separate days in the participants' work environment. All subjects were studied in a double-blind crossover design while they consumed caffeinated or decaffeinated coffee. We examined them at rest, during a standardized mental arithmetic task, and for 6 h of ambulatory monitoring in their regular work setting (research facility and hospital). On days of drinking caffeinated coffee, both systolic and diastolic blood pressure were consistently elevated at all time points (P less than .0005). In response to the mental arithmetic task, the increase in systolic blood pressure over the resting value was particularly exaggerated on caffeinated coffee (P = .0003). For heart rate, there were no effects from caffeine. The study demonstrates that the blood pressure-elevating effects of caffeine, well-known from laboratory studies, are sufficiently robust to be evident in patients' uncontrolled work environments. It implies the importance of caffeine restriction for hypertensive patients. It also indicates the utility of ambulatory blood pressure techniques in studying the blood pressure effects of various nutritional factors taken ad lib in the real world.

Adult↗
PubMed2000

Multicenter double-blind comparison of sertraline and desipramine for concurrent obsessive-compulsive and major depressive disorders.

BACKGROUND: Serotonin reuptake inhibitors (SRIs) have demonstrated consistent efficacy in the treatment of obsessive-compulsive disorder (OCD), while agents that are primarily norepinephrine reuptake inhibitors have not. Comparable efficacy has been demonstrated for SRI and non-SRI antidepressants in uncomplicated major depressive disorder (MDD). This multicenter trial is the first comparison of an SRI (sertraline) and a non-SRI antidepressant (desipramine) in the treatment of OCD with concurrent MDD. METHODS: One hundred sixty-six patients diagnosed using structured clinical interviews and recruited from 16 treatment sites were randomly assigned to double-blind treatment with either sertraline (up to 200 mg/d) or desipramine (up to 300 mg/d) over 12 weeks. Measures of severity of OCD and MDD symptoms, as well as adverse effects of the medications, were monitored over the course of the treatment period. RESULTS: Patients assigned to sertraline responded significantly better at end point on measures of OCD and MDD symptoms compared with patients assigned to desipramine. Sertraline was also associated with a significantly greater number of patients who achieved a "robust" improvement in OCD symptoms (> or =40% reduction) compared with desipramine. More patients receiving desipramine than sertraline discontinued treatment because of adverse events. CONCLUSIONS: The SRI sertraline was more effective in reducing MDD and OCD symptoms than the primarily norepinephrine reuptake inhibitor desipramine for patients with concurrent OCD and MDD.

Adrenergic Uptake Inhibitors↗
PubMed2006

A new configuration of the Zeiss LSM 510 for simultaneous optical separation of green and red fluorescent protein pairs.

The power and simplicity of genetically encoded fluorophores (fluorescent proteins, FPs) have drawn many molecular biologists to light microscopy. First generation FPs suffered from overlapping excitation and emission spectra, which limited their use together in pairs (Patterson et al., J Cell Sci 2001;114 (Part 5):837-838). Image acquisition and processing techniques, collectively known as linear unmixing, have been developed to separate overlapping fluorescence signals encountered in the imaging of FP pairs and also in FRET. These specialized techniques are not without their potential drawbacks, including limitations on sensitivity and time-resolution for live cell imaging, and the risk of artifact in the hands of nonspecialists. With the advent of a new generation of red-shifted FPs (Shaner et al., Nat Biotechnol 2004;22:1567-1572; Verkhusha and Lukyanov, Nat Biotechnol 2004;22:289-296) careful selection of excitation sources and emission filters obviate the need for linear unmixing when simple two channel imaging of FPs is required. Here we introduce a new configuration of the Zeiss LSM 510 laser scanning confocal microscope, optimized for live cell imaging of green fluorescent protein (GFP) together with spectral variants such as mRFP1 and mCherry using standard photo-multipliers. A 2 mW, 594 nm HeNe laser was chosen as the excitation source for the red FP. This wavelength efficiently excites the aforementioned red variants without limiting the detection range of GFP emission during simultaneous two-channel imaging. Compared to excitation of GFP and mCherry at 488 and 543 nm, excitation at 488 and 594 nm approximately doubles the sensitivity of GFP detection and eliminates bleed-through of GFP into the mCherry channel. However, sensitivity of mCherry detection is decreased by 30%, suggesting the need for red FPs having longer emission peaks. Practical advantages to the simultaneous optical separation of FPs with nonoverlapping emission spectra include simplicity, robustness, reduced risk of artifact, and increased sensitivity during live cell imaging.

Diagnostic Imaging↗
PubMed2026

LiCl induces GSK-3β mediated autophagy, DNA damage, and cell cycle arrest in HPV driven cervical cancer cells.

High-risk HPV infections induce cervical cancer progression by disrupting cellular homeostasis and survival pathways, including autophagy. Targeting autophagy represents a promising therapeutic strategy. Lithium chloride (LiCl), extensively studied for its neuroprotective properties, can be investigated for its potential anticancer effects in HPV-driven cervical cancer cells. Treatment with 30 mM LiCl induced significant phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, inducing functional inhibition and downstream signal alterations. This modulation of GSK-3β activity compromised genomic integrity, validated by increased double strand DNA breaks, increased oxidative and cellular stress, and reduced antioxidant enzyme activity. Consequently, LiCl treated cells exhibited significant G2/M phase arrest, indicating disruption in cell cycle progression. Interestingly, the observed cytotoxicity occurred independently of classical apoptotic pathways, suggesting the activation of alternative cell death mechanisms. Mechanistic studies revealed a robust autophagic flux, with GSK-3β mediated autophagy, validated through siRNA mediated knockdown experiments. These findings highlight a novel cytotoxic mechanism of LiCl and propose its potential repurposing from neurobiology to targeted cancer therapeutics.

Humans↗
PubMed2004

Improving solid-state NMR dipolar recoupling by optimal control.

We present the first solid-state NMR experiments developed using optimal control theory. Taking heteronuclear dipolar recoupling in magic-angle-spinning NMR as an example, it proves possible to significantly improve the efficiency of the experiments while introducing robustness toward instrumental imperfections such as radio frequency inhomogeneity. The improvements are demonstrated by numerical simulations as well as practical experiments on a 13Calpha,15N-labeled powder of glycine. The experiments demonstrate a gain of 53% in the efficiency for 15N to 13Calpha coherence transfer relative to the typically double-cross-polarization experiments.

Carbon Isotopes↗
PubMed2005

Linear-After-The-Exponential (LATE)-PCR: primer design criteria for high yields of specific single-stranded DNA and improved real-time detection.

Traditional asymmetric PCR uses conventional PCR primers at unequal concentrations to generate single-stranded DNA. This method, however, is difficult to optimize, often inefficient, and tends to promote nonspecific amplification. An alternative approach, Linear-After-The-Exponential (LATE)-PCR, solves these problems by using primer pairs deliberately designed for use at unequal concentrations. The present report systematically examines the primer design parameters that affect the exponential and linear phases of LATE-PCR amplification. In particular, we investigated how altering the concentration-adjusted melting temperature (Tm) of the limiting primer (TmL) relative to that of the excess primer (TmX) affects both amplification efficiency and specificity during the exponential phase of LATE-PCR. The highest reaction efficiency and specificity were observed when TmL - TmX 5 degrees C. We also investigated how altering TmX relative to the higher Tm of the double-stranded amplicon (TmA) affects the rate and extent of linear amplification. Excess primers with TmX closer to TmA yielded higher rates of linear amplification and stronger signals from a hybridization probe. These design criteria maximize the yield of specific single-stranded DNA products and make LATE-PCR more robust and easier to implement. The conclusions were validated by using primer pairs that amplify sequences within the cystic fibrosis transmembrane regulator (CFTR) gene, mutations of which are responsible for cystic fibrosis.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed2001

Contextual equilibrium effects in DNA molecules.

The thermodynamic parameters of DNA triplex formation between oligonucleotides and double-stranded DNA segments containing adenine runs (A-tracts) were investigated to explore equilibrium structural effects exerted by flanking segments upon the A-tracts. Results obtained from isothermal titration calorimetry, temperature-dependent circular dichroism (CD), and UV melting experiments indicate that A-tracts, considered as a uniquely robust and inflexible DNA motif, can be structurally perturbed by neighboring sequences in a way that significantly affects the propensity of this motif to interact with triplex-forming oligonucleotides. These contextual equilibrium effects, which depend upon the composition and location of the flanking sequences, are likely to apply not only to the interaction of A-tracts with single-stranded DNA molecules but also to interactions with drugs and proteins. As such, the current results refine the guidelines for the design of triplex-forming oligonucleotides used for antigene strategies. More generally, they substantiate the notion that significant data might be encoded by structural DNA parameters.

Base Sequence↗
PubMed2000

The triad targeting signal of the skeletal muscle calcium channel is localized in the COOH terminus of the alpha(1S) subunit.

The specific localization of L-type Ca(2+) channels in skeletal muscle triads is critical for their normal function in excitation-contraction (EC) coupling. Reconstitution of dysgenic myotubes with the skeletal muscle Ca(2+) channel alpha(1S) subunit restores Ca(2+) currents, EC coupling, and the normal localization of alpha(1S) in the triads. In contrast, expression of the neuronal alpha(1A) subunit gives rise to robust Ca(2+) currents but not to triad localization. To identify regions in the primary structure of alpha(1S) involved in the targeting of the Ca(2+) channel into the triads, chimeras of alpha(1S) and alpha(1A) were constructed, expressed in dysgenic myotubes, and their subcellular distribution was analyzed with double immunofluorescence labeling of the alpha(1S)/alpha(1A) chimeras and the ryanodine receptor. Whereas chimeras containing the COOH terminus of alpha(1A) were not incorporated into triads, chimeras containing the COOH terminus of alpha(1S) were correctly targeted. Mapping of the COOH terminus revealed a triad-targeting signal contained in the 55 amino-acid sequence (1607-1661) proximal to the putative clipping site of alpha(1S). Transferring this triad targeting signal to alpha(1A) was sufficient for targeting and clustering the neuronal isoform into skeletal muscle triads and caused a marked restoration of Ca(2+)-dependent EC coupling.

Action Potentials↗
PubMed2006

Translation of the flavivirus kunjin NS3 gene in cis but not its RNA sequence or secondary structure is essential for efficient RNA packaging.

Our previous studies using trans-complementation analysis of Kunjin virus (KUN) full-length cDNA clones harboring in-frame deletions in the NS3 gene demonstrated the inability of these defective complemented RNAs to be packaged into virus particles (W. J. Liu, P. L. Sedlak, N. Kondratieva, and A. A. Khromykh, J. Virol. 76:10766-10775). In this study we aimed to establish whether this requirement for NS3 in RNA packaging is determined by the secondary RNA structure of the NS3 gene or by the essential role of the translated NS3 gene product. Multiple silent mutations of three computer-predicted stable RNA structures in the NS3 coding region of KUN replicon RNA aimed at disrupting RNA secondary structure without affecting amino acid sequence did not affect RNA replication and packaging into virus-like particles in the packaging cell line, thus demonstrating that the predicted conserved RNA structures in the NS3 gene do not play a role in RNA replication and/or packaging. In contrast, double frameshift mutations in the NS3 coding region of full-length KUN RNA, producing scrambled NS3 protein but retaining secondary RNA structure, resulted in the loss of ability of these defective RNAs to be packaged into virus particles in complementation experiments in KUN replicon-expressing cells. Furthermore, the more robust complementation-packaging system based on established stable cell lines producing large amounts of complemented replicating NS3-deficient replicon RNAs and infection with KUN virus to provide structural proteins also failed to detect any secreted virus-like particles containing packaged NS3-deficient replicon RNAs. These results have now firmly established the requirement of KUN NS3 protein translated in cis for genome packaging into virus particles.

Animals↗
PubMed2004

Branched-chain amino acids increase p70S6k phosphorylation in human skeletal muscle after resistance exercise.

The aim of the study was to investigate the effect of resistance exercise alone or in combination with oral intake of branched-chain amino acids (BCAA) on phosphorylation of the 70-kDa S6 protein kinase (p70(S6k)) and mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/2), and p38 MAPK in skeletal muscle. Seven male subjects performed one session of quadriceps muscle resistance training (4 x 10 repetitions at 80% of one repetition maximum) on two occasions. In a randomized order, double-blind, crossover test, subjects ingested a solution of BCAA or placebo during and after exercise. Ingestion of BCAA increased plasma concentrations of isoleucine, leucine, and valine during exercise and throughout recovery after exercise (2 h postexercise), whereas no change was noted after the placebo trial. Resistance exercise led to a robust increase in p70(S6k) phosphorylation at Ser(424) and/or Thr(421), which persisted 1 and 2 h after exercise. BCAA ingestion further enhanced p70(S6k) phosphorylation 3.5-fold during recovery. p70(S6k) phosphorylation at Thr(389) was unaltered directly after resistance exercise. However, during recovery, Thr(389) phosphorylation was profoundly increased, but only during the BCAA trial. Furthermore, phosphorylation of the ribosomal protein S6 was also increased in the recovery period only during the BCAA trial. Exercise led to a marked increase in ERK1/2 and p38 MAPK phosphorylation, which was completely suppressed upon recovery and unaltered by BCAA. In conclusion, BCAA, ingested during and after resistance exercise, mediate signal transduction through p70(S6k) in skeletal muscle.

Administration, Oral↗
PubMed2000

Dynamics of the follicle-stimulating hormone (FSH)-inhibin B feedback loop and its role in regulating spermatogenesis in the adult male rhesus monkey (Macaca mulatta) as revealed by unilateral orchidectomy.

The purpose of this study was to document the morphological changes in the seminiferous epithelium that underlie the compensatory testicular hypertrophy observed in response to unilateral orchidectomy (UO) in the adult rhesus monkey and to describe the concomitant response in the endocrine feedback loops controlling testicular function in this species. Adult male monkeys were implanted with indwelling venous catheters; seven animals were then subjected to UO (data are presented from six) and three to sham UO. Profiles of circulating concentrations of FSH, LH, testosterone (T), inhibin B, and pro-alpha-C were monitored in 12-h series of sequential blood samples collected before, on the day of UO (day 0), and on days 1, 2, 4, 8, 16, 32, and 42 or 43 after UO. In the UO monkeys, the remaining testis was taken on day 44. Sertoli and germ cells in the removed and remaining testes were counted and expressed either as number per testis or, in the case of the differentiated spermatogonia (B1, B2, B3, and B4), as number per cross-section of the seminiferous tubule. UO was associated with a marked increase in the number of all germ cells more mature than undifferentiated spermatogonia (Ap) in the remaining testis. Sertoli cell number, on the other hand, did not change, and it is therefore reasonable to propose that the primary locus of the spermatogenic compensation was the differentiated spermatogonia. The additional finding that the relationship between the number of Sertoli cells and total germ cells in the remaining testis became robust (r = 0.92; P < 0.01 vs. r = 0.44; P > 0.05 for the removed testis) indicated that in the monkey, spermatogenesis does not normally operate at its ceiling. The increased drive to the seminiferous tubule of the remaining testis is hypothesized to be mediated by the sustained increase in FSH secretion that was observed after UO, although a role for increased testicular T production cannot be excluded. The stimulus for increased FSH secretion was presumably provided by the abrupt, 50% decline in circulating inhibin B levels. Interestingly, inhibin B secretion by the remaining testis was not dramatically affected by UO, and therefore, the deficit in circulating levels of this hormone and thus the error signal to FSH secretion were maintained for the duration of the experiment. In contrast, the changes in circulating LH and T concentrations were only transient, and within 48 h of UO, these hormonal parameters had returned to control values. The mechanisms by which the remaining testis rapidly acquires the capacity to double T production in the face of an unchanging LH drive remains to be determined. The foregoing body of evidence suggests that sperm output by the monkey testis is regulated by the circulating concentration of FSH and that in physiological situations, FSH secretion is insufficient to stimulate spermatogenesis to its ceiling. The results also indicate that FSH secretion is controlled by a feedback system in which the feedforward arm (FSH-inhibin B) is less robust than the feedback loop (inhibin B-FSH). Thus, a decrease in the inhibin B feedback signal results in a sustained increase in FSH secretion that drives the testes toward their spermatogenic ceiling, which is presumably set by Sertoli cell number.

Animals↗
PubMedDate not supplied

Psychosis of Alzheimer disease: validity of the construct and response to risperidone.

OBJECTIVE: The authors evaluated the efficacy of risperidone in reducing psychotic and aggressive symptoms in a subgroup of patients who fulfilled operationalized criteria for psychosis of dementia. METHODS: Authors conducted a subgroup analysis of patients in the risperidone database arising from a previous double-blind, randomized, placebo-controlled study. In the primary study, patients age 55 or older, with a DSM-IV diagnosis of Alzheimer disease and/or vascular dementia were randomized to placebo or 0.5 mg, 1.0 mg, or 2.0 mg/day of risperidone. For this analysis, patients were selected who fulfilled operationalized criteria for psychosis of dementia. These criteria were then validated. The primary outcome measures were the newly developed Psychosis and Aggression Severity Indices, derived from Parts 1 and 2 of the BEHAVE-AD rating scale. RESULTS: At Week 12 and endpoint, patients with psychosis of dementia receiving 1 mg or 2 mg/day of risperidone showed significantly more improvement on the Psychosis Severity and Aggressiveness Severity Indices than those receiving placebo. CONCLUSIONS: The construct of psychosis of dementia was validated, and the severity of both psychosis and aggressiveness was reduced with risperidone treatment in a robust and dose-related way, with a continuing response over the 12-week trial period.

Aged↗
PubMed1999

Structural characterization of triacylglycerols as lithiated adducts by electrospray ionization mass spectrometry using low-energy collisionally activated dissociation on a triple stage quadrupole instrument.

We describe features of tandem mass spectra of lithiated adducts of triacylglycerol (TAG) species obtained by electrospray ionization mass spectrometry (ms) with low-energy collisionally activated dissociation (CAD) on a triple stage quadrupole instrument. The spectra distinguish isomeric triacylglycerol species and permit assignment of the mass of each fatty acid substituent and positions on the glycerol backbone to which substituents are esterified. Source CAD-MS2 experiments permit assignment of double bond locations in polyunsaturated fatty acid substituents. The ESI/MS/MS spectra contain [M + Li - (RnCO2H)]+, [M + Li - (RnCO2Li)]+, and RnCO+ ions, among others, that permit assignment of the masses of fatty acid substituents. Relative abundances of these ions reflect positions on the glycerol backbone to which substituents are esterified. The tandem spectra also contain ions reflecting combined elimination of two adjacent fatty acid residues, one of which is eliminated as a free fatty acid and the other as an alpha, beta-unsaturated fatty acid. Such combined losses always involve the sn-2 substituent, and this feature provides a robust means to identify that substituent. Fragment ions reflecting combined losses of both sn-1 and sn-3 substituents without loss of the sn-2 substituent are not observed. Schemes are proposed to rationalize formation of major fragment ions in tandem mass spectra of lithiated TAG that are supported by studies with deuterium-labeled TAG and by source CAD-MS2 experiments. These schemes involve initial elimination of a free fatty acid in concert with a hydrogen atom abstracted from the alpha-methylene group of an adjacent fatty acid, followed by formation of a cyclic intermediate that decomposes to yield other characteristic fragment ions. Determination of double bond location in polyunsaturated fatty acid substituents of TAG is achieved by source CAD experiments in which dilithiated adducts of fatty acid substituents are produced in the ion source and subjected to CAD in the collision cell. Product ions are analyzed in the final quadrupole to yield information on double bond location.

Fatty Acids↗
PubMed1995

Estrogen-receptive neurons in the anteroventral periventricular nucleus are synaptic targets of the suprachiasmatic nucleus and peri-suprachiasmatic region.

The anteroventral periventricular nucleus (AVPv) in the rat preoptic area is a key site underlying control of the steroid dependent preovulatory gonadotropin surge. Estrogen and progesterone receptor-containing neurons in the preoptic/hypothalamic continuum, particularly those in the AVPv, are believed to transduce steroidal signals and, in turn convey this information to the LHRH system, which lacks steroid receptors. In addition to the influence of the gonadal steroids, the precise timing of the preovulatory gonadotropin surge is believed to be regulated by the hypothalamic suprachiasmatic nucleus (SCN). The SCN and peri-SCN neurons send efferent projections rostrally to the anterior preoptic area suggesting that circadian signals are communicated synaptically to steroid-responsive neurons in the AVPv. To test this hypothesis, ultrastructural double label immunocytochemistry was conducted to determine whether SCN efferents contact estrogen receptor-immunoreactive neurons in the AVPv. Brain sections with SCN injections of phaseolus vulgaris leucoagglutinin (PHA-L) were immunostained for estrogen receptors and PHA-L. Light and electron microscopic data show that the anterior preoptic area received robust PHA-L-immunoreactive efferents from SCN neurons and immediately adjacent subparaventricular zone. In particular, the AVPv contained abundant labeled fibers and terminal boutons. Ultrastructurally, SCN- and subparaventricular zone-derived terminals synaptically contacted the perikaryon of many estrogen receptor-immunoreactive neurons in the AVPv. The perikarya of unlabeled neurons were also contacted, but the majority of the labeled contacts were observed upon neuronal processes. These results demonstrate that estrogen responsive AVPv neurons are regulated by SCN efferents. Furthermore, the present data provide strong support to the idea of collective control of pituitary gonadotropin release by steroid sensitive and circadian signal neural pathways.

Animals↗
PubMed2004

Hydrodynamics and electrokinetics of spherical liposomes with coatings of terminally anchored poly(ethylene glycol): numerically exact electrokinetics with self-consistent mean-field polymer.

A detailed theoretical model is presented to interpret electrokinetic experiments performed on colloids with uncharged polymer layers. The methodology removes many of the degrees of freedom that otherwise have to be accounted for by adopting multiple empirical fitting parameters. Furthermore, the level of detail provides a firm basis for future studies examining liposome surface chemistry and charge, surface-charge mobility, and the dynamics of adsorbed polymer on fluidlike membranes. The model predictions are compared with experimental measurements of the electrophoretic mobility of stealth liposomes with molecular weights of terminally anchored poly(ethylene glycol) (PEG) in the range 0.35-10 kg mol(-1) [J.A. Cohen and V.A. Khorosheva, Colloids Surf. A 195, 113 (2001)]. The experimental data are interpreted by drawing upon self-consistent mean-field calculations of the polymer segment density distributions and numerically exact solutions of the governing transport equations [R.J. Hill, D.A. Saville, and W.B. Russel, J. Colloid Interface Sci. 258, 56 (2003)]. The approach leads to excellent agreement between theory and experiment with one adjustable parameter--the hydrodynamic size (Stokes radius) a(s) approximately equal to 0.175 A of the statistical PEG segments with (Kuhn) length l=7.1 A . The remarkably small Stokes radius is demonstrated to be consistent with other applications of the well-known Debye-Brinkman model and, consequently, this work reveals important limitations of the mean-field hydrodynamic model. Despite such limitations, the "full" electrokinetic model is robust in its predictive capacity. The molecular weights of the terminally anchored PEG span the range where the coatings undergo a transition from mushroomlike to brushlike conformations, and the hydrodynamic size and electrophoretic mobility of the liposomes are demonstrated to be sensitive to the PEG chain length and the effects of double-layer polarization.

Coated Materials, Biocompatible↗
PubMed2003

The prevalence and causes of dementia in people under the age of 65 years.

OBJECTIVES: To determine the prevalence of dementia in people under the age of 65 in a large catchment area, and use these figures to estimate the number of younger people affected by dementia in the UK. DESIGN: Epidemiological catchment area prevalence survey. SETTING: The London boroughs of Kensington and Chelsea, Westminster, and Hillingdon with a total population of 567500 people. PARTICIPANTS: All residents of the catchment area with dementia, where the illness began before the age of 65 years. Participants were notified to the study by medical and care professionals. The diagnosis and age of onset was established from all available health and social care records. In total, 227 people were identified, of whom 185 fulfilled the inclusion criteria of having a dementia which started before their 65th birthday. MAIN OUTCOME MEASURES: Diagnosis of dementia and differential diagnosis of the cause of the dementia. RESULTS: The prevalence of dementia in those aged 30-64 was 54.0 per 100000 (95% CI 45.1 to 64.1 per 100000). For those aged 45-64 years, the prevalence was 98.1 per 100000 (95% CI 81.1 to 118.0 per 100000). From the age of 35 onwards, the prevalence of dementia approximately doubled with each 5 year increase in age. Extrapolating these figures nationally suggests that there are 18319 (15296-21758) people with dementia under the age of 65 in the UK. CONCLUSIONS: The study confirms previous "guestimates" of the number of younger people affected by dementia in UK. The prevalence figures generated are robust, and are supported by other smaller and targeted prevalence surveys. The prevalence figures provided by this study will allow health planners to accurately estimate need and plan services.

Adult↗
PubMed1997

Extended release of adenovirus from polymer microspheres: potential use in gene therapy for brain tumors.

Current protocols for the treatment of intracerebral glioma are inadequate, with limited reduction in morbidity or mortality. As such, gene therapy paradigms have been developed. Initial progress in rodent models using in situ introduction of retroviral vector producer cells to transfer a cytotoxic gene product led to phase I clinical trials with limited success, due in part to immune responses to murine producer cells along with low level gene transfer. We and others have initiated studies to determine the effectiveness of adenoviral vectors to deliver cytotoxic and/or immuno-stimulatory gene products directly to tumor. Adenoviral vectors can be purified to high titers, are relatively stable upon formulation and storage, and can infect both dividing and non-dividing tumor cells. Also, they can be introduced in situ without helper virus or producer cells. However, gene transfer to glioma tissue with recombinant adenoviruses is not efficient, with multiplicities of infection greater than 50 infectious units/cell required for efficacy. At these doses the virus induces a potent immune response that further reduces gene transfer following re-administration. The inflammatory response to low doses of recombinant adenoviral vectors is less robust and does not preclude re-administration. Thus, strategies to increase efficiency coupled to low dose administration are desirable. To accomplish low dose administration we have developed a method to formulate recombinant adenoviral vectors in biodegradable microspheres. Poly (lactic-glycolic) acid (PLGA) microspheres containing recombinant adenovirus were prepared using a double emulsion technique, and viable virus released for greater than 10 days.

Journal Article↗
PubMed1993

Similarities in the detection of stimulus symmetry by individuals with and without mental retardation.

Intelligence-related differences in the detection of stimulus organization previously identified by Soraci, Carlin, Deckner, and Baumeister (1990) were examined further to determine whether they would (a) extend to similar checkerboard stimuli varying solely with respect to symmetry and (b) generalize to form-like polygon stimuli. Detection performances of 10 individuals with mild mental retardation, 10 CA-matched, and 10 MA-matched individuals were assessed on a rapid presentation a two-choice match-to-sample task. The organizations of the target and distractor stimuli were varied across four levels of symmetry: double, vertical, horizontal, and asymmetrical. Results indicated that detection rates for each group were highest when the target stimulus was vertically symmetrical or when target-distractor structural disparity was maximal. However, no significant main effects of subject group or stimulus type (i.e., checkerboard vs. polygon) were found, thereby arguing for the robustness of the symmetry effect across groups differing in intelligence and physically dissimilar stimulus types.

Adolescent↗