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PubMed1997

A New Approach to Assessing Regional and Global Myocardial Contractility.

A number of studies that assessed myocardial contractility by noninvasive means have been conducted in the past. However, many of these studies are limited because they assessed the velocity of fiber shortening-afterload relationship at only a single location in the ventricle, thus assuming uniform contractility throughout the ventricle. This is often not the case, particularly in patients with coronary disease. The present study provides a new approach to assessing regional and global function that will be applicable to patients with nonuniform contractile function and makes use of entirely noninvasively obtained data. In addition, the method proposed will permit the question of linearity or nonlinearity of shortening rate-afterload relationship to be addressed in a more detailed, quantitative manner.

Journal Article↗

PubMed2005

Efficacy of combining levodopa with entacapone on quality of life and activities of daily living in patients experiencing wearing-off type fluctuations.

OBJECTIVES: To compare the efficacy of levodopa/dopa decarboxylase inhibitor (DDCI) plus entacapone with levodopa/DDCI plus placebo on measures of parkinsonian disability and health-related quality of life (QoL) in subjects with Parkinson's disease (PD) experiencing motor fluctuations. MATERIALS AND METHODS: A double-blind, placebo-controlled phase IV study was performed in 270 PD patients randomized to receive either entacapone 200 mg or placebo with each dose of their current levodopa regimen. The primary variables were the Unified Parkinson's Disease Rating Scale (UPDRS) part II activities of daily living (ADL) and the Parkinson's Disease Questionnaire (PDQ)-39 summary index. UPDRS parts I, III-VI, Global Assessment of Change, PDQ-39 subscores, and the Short-Form (SF)-36 and the European Quality of Life five-dimension questionnaire (EQ-5D) were included as secondary variables. RESULTS: There was a significant improvement in ADL scores with levodopa/DDCI/entacapone compared with levodopa/DDCI/placebo at 5 and 13 weeks (-2.3 vs -0.7, respectively; P = 0.0001). However, no significant differences were observed between treatments using the PDQ-39 summary index. UPDRS part III (motor) scores significantly decreased in the levodopa/DDCI/entacapone group compared with the levodopa/DDCI/placebo group (-5.0 vs -2.9, respectively; P = 0.03). Similarly, the change in the investigators Global Assessment was significantly greater (P = 0.004) in the levodopa/DDCI/entacapone group. There were no significant differences between treatments for any of the PDQ-39 subscores, the SF-36 variables or the EQ-5D utility score. CONCLUSIONS: Levodopa combined with entacapone demonstrated good efficacy in terms of ADL, global function, motor performance and was well tolerated. However, this short-term study did not generate significant improvements in QoL.

Activities of Daily Living↗

PubMed1997

Hopelessness and first-episode psychosis: a longitudinal study.

Hopelessness has not been adequately studied in first-episode psychotic patients, although it is already present at the early stages, especially in schizophrenic patients. We have studied 96 neuroleptic-naive psychotic patients (49 schizophrenic patients and 47 other non-affective psychotic patients) over a period of 12 months after their first admission. The total score on the Hopelessness Scale (HS) at first admission was higher in the schizophrenic patients, and correlated with younger age and with negative symptoms. High HS scores at baseline predicted poor short-term outcome in schizophrenic patients, as evidenced by worse global functioning at the 12-month follow-up. These correlations were not observed in the other psychoses group. Our results suggest that young, severely affected schizophrenic patients who experience hopelessness might be at higher risk of poor outcome.

Adolescent↗

PubMed1998

Chronic patients in psychiatric institutions: psychopathology, level of functioning and need for care.

A total of 107 chronic in-patients in a catchment area of 106,000 inhabitants were rated for psychopathology on the Brief Psychiatric Rating Scale expanded version (BPRS-E), for level of functioning on the Rehabilitation Evaluation Hall And Baker (REHAB), and for geriatric problems on the Geriatric Rating Scale (GRS). The results showed low levels of severe psychopathology and low to moderate levels of functioning, indicating that the main obstacle to community placement was the lack of functioning. Global assessment by ward nurses with regard to the future level of care needed divided the patients into three categories: 40 patients in need of a psychiatric nursing home, 30 patients in need of a general nursing home, and 37 patients who could potentially be discharged to apartments with community support. This study indicates that the REHAB may help to identify patients who are potential candidates for community placement, while the BPRS-E may help to identify patients who are still in need of care in a psychiatric institution.

Activities of Daily Living↗

PubMed1990

Acute cerebral hemorrhage changes the nocturnal surge of plasma melatonin in humans.

The diurnal rhythm of plasma melatonin was studied in 46 Chinese patients with acute cerebral hemorrhage. The state of consciousness of each patient was assessed clinically. The individual sites of lesion were determined by computerized tomography scanning. One to five days after stroke, blood samples were collected by venipuncture at 1000 and 1400 h in the daytime and 0200 and 0400 h at night. Plasma melatonin was extracted by dichloromethane and determined by radioimmunoassay. It was found that patients with lesions in the brain stem or in the third and lateral ventricles had melatonin levels significantly different from the other subjects in that these values were lower and lacking a nocturnal rise. These results are consistent with the presumptive retina-pineal pathway proposed in humans. Dramatic blunting or obliteration of the nocturnal melatonin surge in the blood was also observed in some patients with lesions in the frontal lobe, fronto-parietal lobe, parieto-temporal lobe, and basal ganglia. These brain regions are not involved in the retina-pineal pathway described in rodents or humans. Thus, our results suggest that brain regions other than the presumptive retina-pineal neural pathway may play an important role in the generation and/or regulation of the diurnal production and/or secretion of pineal melatonin in humans. However, a global functional disturbance caused by cerebral hemorrhage cannot be ruled out in some cases. It should be noted that many of the lesions leading to a change in the nocturnal rise of plasma melatonin were unilateral lesions. The significance of this finding is presently unknown. In addition, patients without a nocturnal rise of plasma melatonin were mostly comatose. They had lesions in the basal ganglion, fronto-parietal lobe, brain stem, and lateral and third ventricles. The latter findings suggest that in the brain, certain regions responsible for the state of consciousness of the individual may also be important to the dirunal rhythm of pineal melatonin secretion.

Acute Disease↗

PubMedDate not supplied

Consultative intervention to improve outcomes of high utilizers in a public mental health system.

PURPOSE: To examine the effectiveness of an academic consultation on outcomes among consumers in a public mental health system and to compare outcomes between high-cost/high-utilizer and midcost consumers. METHODS: Participants (N = 36) completed all questionnaires during three semistructured interviews. Using a repeated-measures experimental design, the outcomes of global functioning, quality of life, service use and need, costs, and consumer satisfaction were examined. FINDINGS: The hypothesis that consultation would change medication practices and reduce costs was supported. CONCLUSIONS: Consultation with a senior clinician helped change medication practices and reduced costs. Consultation may lead to recognition of a new diagnosis (medical, neurologic, or psychiatric) or suggestions for modifying a treatment regimen that could improve functioning and QOL. In a busy public mental health system, there is often little time for consultation and little thought to second opinions. For clients who cost the system the greatest amount, the small additional cost of a consultation is a good potential investment.

Adult↗

PubMed1997

Clinical trials in dementia with propentofylline.

The mode of action of propentofylline (a xanthine derivative) suggested that it would have beneficial effects in patients with Alzheimer's disease or vascular dementia. In four double-blind, placebo-controlled, randomized studies, 901 patients with mild to moderate Alzheimer's disease and 359 patients with mild to moderate vascular dementia were treated for up to 12 months (daily dose of propentofylline: 3 x 300 mg taken 1 hr before food). Patients were assessed at regular intervals for efficacy and safety of the drug. Efficacy variables covered cognitive and global functions as well as activities of daily living. Propentofylline showed statistically significant, clinically relevant improvements over placebo in efficacy assessments, both in patients with Alzheimer's disease and in patients with vascular dementia. The drug was also well tolerated. It had no significant effects on laboratory findings and the adverse events that were considered to be related to the study medication were mostly minor, transient, and affected the digestive and nervous systems.

Adenosine↗

PubMed2005

Metachronal propagation of motoneurone burst activation in isolated spinal cord of newborn rat.

Adequate locomotor and postural activity in mammals results from the coordinated activation of assemblies of spinal cord networks. In order to assess the global functioning of spinal circuitry, multisite recordings were made from an isolated spinal cord preparation of the newborn rat. Motor activity, elicited in a disinhibited network by bath-applying strychnine (glycinergic blocker) and bicuculline (GABAergic blocker), consisted of slow spontaneous bursting. Under these conditions, the recorded bursts were coordinated in 1: 1 relationships at all segmental levels. For each cycle, a leading segment initiated the activity that then propagated in a metachronal way through adjacent segments along the length of spinal cord. There was both regional non-linearity and directional asymmetry in this burst propagation: motor bursts propagated most rapidly in the thoracic spinal cord and the rostro-caudal wave travelled faster than the caudo-rostral one. Propagation involved both long projecting fibres and local intersegmental connections. These results suggest that the mammalian spinal cord contains propriospinal pathways subserving a metachronal transmission of motor information and that normally it may be involved in coordinating various parts of the body. The simple model developed here could be useful in unravelling more general mechanisms of neuronal circuit coupling.

Animals↗

PubMed2000

The matched-phase coherent multi-frequency matched-field processor

Coherent multi-frequency matched-field processing is investigated using a matched-phase coherent matched-field processor. Its main difference from previous coherent processors is that the relative phases of the Fourier components contained within the recorded signal are not assumed to be known a priori. Rather they are considered free parameters that can be determined using a global functional minimization algorithm. Additionally, this processor uses only the cross-frequency terms, making it less susceptible to the detrimental effects of ambient noise; in one example, this processor shows a five decibel improvement over a similar coherent processor. Along with its increased sensitivity with respect to the broadcast source levels, this coherent processor exhibits superior range resolution as compared with multi-frequency incoherent processors, due to the cross-frequency interference of the vertical eigenmodes. Within this work we explore the efficacy of the algorithms used to determine the relative phases along with the performance of the matched-phase coherent processor itself, performed within the context of data collected during an event from the SWellEx-96 experiment. Performance comparisons between this processor, an incoherent processor, and another coherent processor are demonstrated using this data set.

Journal Article↗

PubMed2000

Saccharomyces cerevisiae sigma 1278b has novel genes of the N-acetyltransferase gene superfamily required for L-proline analogue resistance.

We discovered on the chromosome of Saccharomyces cerevisiae Sigma 1278b novel genes involved in L-proline analogue L-azetidine-2-carboxylic acid resistance which are not present in the standard laboratory strains. The 5.4 kb-DNA fragment was cloned from the genomic library of the L-azetidine-2-carboxylic acid-resistant mutant derived from a cross between S. cerevisiae strains S288C and Sigma 1278b. The nucleotide sequence of a 4.5-kb segment exhibited no identity with the sequence in the genome project involving strain S288C. Deletion analysis indicated that one open reading frame encoding a predicted protein of 229 amino acids is indispensable for L-azetidine-2-carboxylic acid resistance. The protein sequence was found to be a member of the N-acetyltransferase superfamily. Genomic Southern analysis and gene disruption showed that two copies of the novel gene with one amino acid change at position 85 required for L-azetidine-2-carboxylic acid resistance were present on chromosomes X and XIV of Sigma 1278b background strains. When this novel MPR1 or MPR2 gene (sigma 1278b gene for L-proline analogue resistance) was introduced into the other S. cerevisiae strains, all of the recombinants were resistant to L-azetidine-2-carboxylic acid, indicating that both MPR1 and MPR2 are expressed and have a global function in S. cerevisiae.

Amino Acid Sequence↗

PubMed2001

CpG binding protein is crucial for early embryonic development.

Epigenetic modification of DNA via CpG methylation is essential for the proper regulation of gene expression during embryonic development. Methylation of CpG motifs results in gene repression, while CpG island-containing genes are maintained in an unmethylated state and are transcriptionally active. The molecular mechanisms involved in maintaining the hypomethylation of CpG islands remain unclear. The transcriptional activator CpG binding protein (CGBP) exhibits a unique binding specificity for DNA elements that contain unmethylated CpG motifs, which makes it a potential candidate for the regulation of CpG island-containing genes. In order to assess the global function of this protein, mice lacking CGBP were generated via homologous recombination. No viable mutant mice were identified, indicating that CGBP is required for murine development. Mutant embryos were also absent between 6.5 and 12.5 days postcoitum (dpc). Approximately, one-fourth of all implantation sites at 6.5 dpc appeared empty with no intact embryos present. However, histological examination of 6.5-dpc implantation sites revealed the presence of embryo remnants, indicating that CGBP mutant embryos die very early in development. In vitro blastocyst outgrowth assays revealed that CGBP-null blastocysts are viable and capable of hatching and forming both an inner cell mass and a trophectoderm. Therefore, CGBP plays a crucial role in embryo viability and peri-implantation development.

Animals↗

PubMed2006

The relationship between histone H3 phosphorylation and acetylation throughout the mammalian cell cycle.

During interphase, histone amino-terminal tails play important roles in regulating the extent of DNA compaction. Post-translational modifications of the histone tails are intimately associated with regulating chromatin structure: phosphorylation of histone H3 is associated with proper chromosome condensation and dynamics during mitosis, while multiple H2B, H3, and H4 tail acetylations destabilize the chromatin fiber and are sufficient to decondense chromatin fibers in vitro. In this study, we investigate the spatio-temporal dynamics of specific histone H3 phosphorylations and acetylations to better understand the interplay of these post-translational modifications throughout the cell cycle. Using a panel of antibodies that individually, or in combination, recognize phosphorylated serines 10 and 28 and acetylated lysines 9 and 14, we define a series of changes associated with histone H3 that occur as cells progress through the cell cycle. Our results establish that mitosis appears to be a period of the cell cycle when many modifications are highly dynamic. Furthermore, they suggest that the upstream histone acetyltransferases/deacetylases and kinase/phosphatases are temporally regulated to alter their function globally during specific cell cycle time points.

Acetylation↗

PubMed2000

Left ventricular mass and volume: fast calculation with guide-point modeling on MR images.

The authors describe a fast method for calculating left ventricle (LV) mass and volumes from multiplanar magnetic resonance (MR) images. Mathematic models were fitted to a small number of user-selected guide points in 15 healthy volunteers, 13 patients after myocardial infarction, and a canine model of mitral regurgitation in eight dogs. Errors between model and manual contours were small (LV mass, 1.8 g +/- 4.9 [mean +/- SD]; end-diastolic volume, 2.2 mL +/- 4.6; end-systolic volume, 2.3 mL +/- 3.8). Estimates of global function could be obtained in 6 minutes, a time saving of 5-10 times over estimates with manual contouring.

Adolescent↗

PubMed1993

Effects of cardiac contraction and cavity pressure on myocardial blood flow.

Regional impairment of cardiac contraction uncouples force generation from left ventricular pressure (LVP) and may alter the determinants of the phasic pattern and transmural distribution of coronary flow. In anesthetized, open-chest dogs with maximal coronary vasodilation, we studied the effects of abolishing local contraction and changing cavity pressure on phasic myocardial inflow and net transmural flow in a region of left ventricular free wall. With contraction present, the normalized amplitude of distal phasic coronary velocity (NAmp) was not significantly different at normal vs. low LVP (1.00 vs. 0.92 +/- 0.09, respectively, intracoronary lidocaine, however, NAmp varied with LVP (1.62 +/- 0.25 at normal LVP, 0.85 +/- 0.22 at low LVP, P < 0.0001). With contraction present, inner-to-outer flow ratio was not consistently different at normal vs. low LVP (0.47 +/- 0.15 vs. 0.64 +/- 0.28, respectively, P = NS) but was consistently higher at low than at normal LVP with contraction absent (1.01 +/- 0.30 vs. 1.84 +/- 0.38, respectively, P < 0.0001). During uniform global function, contraction is the main determinant of phasic amplitude and transmural distribution of myocardial flow. When regional contraction is abolished, allowing passive deformation of the wall during systole, LVP assumes a powerful role.

Animals↗

PubMed2001

Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions.

This study was performed to explore changes in gene expression as a consequence of exercise training at two levels of intensity under normoxic and normobaric hypoxic conditions (corresponding to an altitude of 3,850 m). Four groups of human subjects trained five times a week for a total of 6 wk on a bicycle ergometer. Muscle biopsies were taken, and performance tests were carried out before and after the training period. Similar increases in maximal O(2) uptake (8.3-13.1%) and maximal power output (11.4-20.8%) were found in all groups. RT-PCR revealed elevated mRNA concentrations of the alpha-subunit of hypoxia-inducible factor 1 (HIF-1) after both high- (+82.4%) and low (+78.4%)-intensity training under hypoxic conditions. The mRNA of HIF-1alpha(736), a splice variant of HIF-1alpha newly detected in human skeletal muscle, was shown to be changed in a similar pattern as HIF-1alpha. Increased mRNA contents of myoglobin (+72.2%) and vascular endothelial growth factor (+52.4%) were evoked only after high-intensity training in hypoxia. Augmented mRNA levels of oxidative enzymes, phosphofructokinase, and heat shock protein 70 were found after high-intensity training under both hypoxic and normoxic conditions. Our findings suggest that HIF-1 is specifically involved in the regulation of muscle adaptations after hypoxia training. Fine-tuning of the training response is recognized at the molecular level, and with less sensitivity also at the structural level, but not at global functional responses like maximal O(2) uptake or maximal power output.

Acyl-CoA Dehydrogenase↗

PubMedDate not supplied

A 6-month, double-blind, placebo-controlled trial of eptastigmine in Alzheimer's disease.

OBJECTIVES: To evaluate the efficacy and safety of eptastigmine as a treatment for patients with mild-to-moderate Alzheimer's disease (AD). PATIENTS AND METHODS: The study was designed as a randomized, double-blind, placebo-controlled, parallel-group study. It was performed in 26 Italian and American geriatric and neurological centers. The study group comprised 349 outpatients with a diagnosis of probable AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association. Patients were assigned to one of the three study groups: placebo (n = 119), eptastigmine 10 mg t.i.d. (n = 115) or eptastigmine 12 mg t.i.d. (n = 115) for 25 weeks. The AD Assessment Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB) were the primary outcome measures for efficacy. RESULTS: The two doses of eptastigmine produced similar results and are presented together. Percentages of patients completing double-blind treatment were 82 and 87% in the placebo and eptastigmine groups, respectively. At the end of treatment, the intent to-treat analysis on 342 patients showed a statistically significant effect of eptastigmine compared to placebo on both ADAS-Cog (p = 0.047) and CDR-SB (p = 0.010). Patients on eptastigmine performed significantly better than placebo-treated patients also on the Mini-Mental State Examination (p < 0.001). The drug was well tolerated with 5% of patients withdrawing due to adverse events versus 3% on placebo. Adverse events were recorded in 46% of the patients on placebo compared to 52% of the patients taking eptastigmine. Cholinergic side effects (nausea, vomiting, diarrhea and abdominal pain) were reported with similar frequency in the eptastigmine and placebo-treated patients. CONCLUSION: Eptastigmine doses up to 12 mg t.i.d. for 25 weeks are well tolerated. The drug positively affects cognitive performance and global function of patients with mild-to-moderate AD.

Aged↗

PubMedDate not supplied

Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer's disease.

OBJECTIVE: To compare rates of cognitive decline between probable Alzheimer's disease (AD) patients treated with long-duration cholinesterase inhibitors (ChE-Is) and those who remained untreated. BACKGROUND: ChE-Is, including donepezil and tracrine, have shown beneficial effects on cognition and global functioning in patients with AD. The duration of these benefits is unknown because the longest double-blind placebo-controlled studies reported were only approximately 6 months long. Ethical concerns regarding randomization of patients to placebo for long periods make it difficult to undertake trials of longer duration. METHODS: We identified patients in 4 AD centers who were or were not consistently treated with ChE-Is and who had demographic, psychometric and follow-up data. We compared 205 ChE-I-treated and 218 untreated AD patients on baseline variables hypothesized to differ between these groups, on baseline Mini Mental Status Examination (MMSE) scores and on rates of MMSE change at 1 year. The analysis was performed initially with all ChE-I-treated patients as a single group versus untreated subjects, and then with donepezil versus untreated subjects and tacrine versus untreated subjects. RESULTS: As expected, treated and untreated patients differed with respect to age, education, ethnicity, percentage of community dwelling and exact days of follow-up (ANOVA and chi2) in several comparisons, but did not differ on baseline MMSE score. These baseline variables were highly intercorrelated. MMSE scores declined significantly more slowly after 1 year of ChE-I treatment compared to untreated patients (p = 0.05) after controlling for baseline differences in age, education, ethnicity and percentage of community dwelling. Slowing of decline was significant in the donepezil-treated patients (p = 0.007) but not in the tacrine-treated group (p = 0.33). CONCLUSIONS: This study, utilizing concurrent, nonrandomized controls, suggests that donepezil continues to have efficacy over at least the first year of therapy. Other studies are needed to determine whether the benefits are maintained beyond 1 year.

Aged↗

PubMed1999

Clinical profile of donepezil in the treatment of Alzheimer's disease.

Although the underlying pathogenesis of Alzheimer's disease (AD) is not fully understood, one of its key features is the widespread loss of central cholinergic innervation, known to be fundamental for cognitive processes. This finding led to the hypothesis that pharmacological enhancement of acetylcholine (ACh) neurotransmission may alleviate the symptoms of AD. Currently, cholinergic therapy, particularly cholinesterase (ChE) inhibition, represents the most realistic approach to the symptomatic treatment of AD. Donepezil HCl, for example, is a piperidine-based, reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other ChE inhibitors and rationally designed for the symptomatic treatment of AD. It is highly selective for centrally acting AChE, with little or no affinity for butyrylcholinesterase, present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favourable pharmacokinetic, pharmacodynamic and safety profile with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. Furthermore, its long half-life supports a simple and convenient once-daily dosing regimen. Subsequent to encouraging phase II clinical trial results, two pivotal, randomized, double-blind phase III trials (of 15 and 30 weeks' duration) demonstrated highly significant improvements in cognition and global function in mild to moderately severe AD patients treated with either 5 or 10 mg/day donepezil compared with placebo. Adverse events in the phase II and III trials, primarily cholinergic in nature, were transient and generally mild in severity and resolved during continued donepezil administration. Thus, the donepezil clinical trials programme has shown that this drug is a clinically effective and well-tolerated, once-daily treatment for the symptoms of mild to moderately severe AD.

Aged↗