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At least 1,027 records · Page 57Linked to original sources
PubMed1996

Clock drawing in schizophrenia.

The Clock Drawing Test, a task sensitive to cognitive decline in neurological groups, was administered to 27 patients with schizophrenia. Clock drawings were scored for over-all global performance and the frequency of specific qualitative errors. Mean global performance scores indicated a small proportion of the sample was below the threshold typically used to identify dementia, and the patients displayed qualitative Clock Drawing deficits not fully represented in the global performance measure. Qualitative analyses indicated that size errors, graphic difficulty, and spatial planning problems were most common. Lastly, duration of illness was not related to global performance, suggesting that the latter might not reflect deterioration but the stable trajectory of impairment that may be constant through the schizophrenia illness.

Adult↗
PubMed2006

Interrater reliability of scores derived from two methods for scoring the clock drawing test.

Scores on the Clock Drawing Test have long been considered a useful screening tool for neuropsychological dysfunction, and a number of scoring methods have been developed to evaluate various aspects of performance. This study compared quantitative and qualitative scoring by briefly trained students on 145 clock drawings produced by patients in a geriatric psychiatry outpatient clinic to estimate the interrater reliability of the methods, user's acceptance of the methods, and whether the methods provide differential diagnosis. Both systems showed acceptable interrater reliability. Using the quantitative method, raters scored drawings by patients with organic mental disease as more impaired than those patients diagnosed as depressed or schizophrenic. Results suggest that the Clock Drawing Test is a reliable screening tool for cognitive impairment in a geropsychiatric population, but the scoring methods examined do not yet appear psychometrically sound enough to provide a differential diagnosis.

Aged↗
PubMed1999

Role of posttranscriptional regulation in circadian clocks: lessons from Drosophila.

Incredible progress has been made in the last few years in our understanding of the molecular mechanisms underlying circadian clocks. Many of the recent insights have been gained by the isolation and characterization of novel clock mutants and their associated gene products. As might be expected based on theoretical considerations and earlier studies that indicated the importance of temporally regulated macromolecular synthesis for the manifestation of overt rhythms, daily oscillations in the levels of "clock" RNAs and proteins are a pervasive feature of these timekeeping devices. How are these molecular rhythms generated and synchronized? Recent evidence accumulated from a wide variety of model organisms, ranging from bacteria to mammals, points toward an emerging trend; at the "heart" of circadian oscillators lies a cell autonomous transcriptional feedback loop that is composed of alternatively functioning positive and negative elements. Nonetheless, it is also clear that to bring this transcriptional feedback loop to "life" requires important contributions from posttranscriptional regulatory schemes. For one thing, there must be times in the day when the activities of negative-feedback regulators are separated from the activities of the positive regulators they act on, or else the oscillatory potential of the system will be dissipated, resulting in a collection of molecules at steady state. This review mainly summarizes the role of posttranscriptional regulation in the Drosophila melanogaster time-keeping mechanism. Accumulating evidence from Drosophila and other systems suggests that posttranscriptional regulatory mechanisms increase the dynamic range of circadian transcriptional feedback loops, overlaying them with appropriately timed biochemical constraints that not only engender these loops with precise daily periods of about 24 h, but also with the ability to integrate and respond rapidly to multiple environmental cues such that their phases are aligned optimally to the prevailing external conditions.

Animals↗
PubMed1999

Ten-point clock test sensitivity for Alzheimer's disease in patients with MMSE scores greater than 23.

The ten-point clock test is administered by tracing an 11.4 cm (4 1/2 inch) diameter circle on a piece of paper and asking the patient to 'Write the numbers in the face of a clock'. The patient is then asked to 'Make the clock say 10 minutes after 11'. The spacing of the numbers and the positions of the hands are used to score the test. A score of less than eight points identified 71% of patients with Alzheimer's disease who had a Mini-Mental State Examination score of greater than 23. The specificity measured in elderly controls was 82%. The test may prove useful in screening for early stage Alzheimer's disease.

Aged↗
PubMed1999

What makes the circadian clock tick: genes that keep time?

Intense activity in the field of circadian rhythms has led in recent years to a basic understanding of how an endogenous clock is generated. Oscillating products of the period (per) and timeless (tim) genes, which feed back to regulate their own synthesis, and transcription factors, which activate these genes, combine to generate a molecular loop that apparently drives behavioral and physiological rhythms. The best-characterized component of this system is the per gene, with considerable effort directed towards identifying the mechanisms that regulate cyclic expression of RNA and protein. Since the cycling of PER protein is controlled largely by post-transcriptional mechanisms, the relative importance of RNA versus protein cycling has been addressed in several studies that are discussed in this chapter. However, it now is clear that regulation of per cannot be dissociated from that of tim, since they are co-dependent components. The overt behavioral phenotype likely depends upon the effect that any perturbation has on both components, rather than on either alone. Major features of the feedback loop appear to be conserved, from fruit flies to mammals. One difference between the two systems is the manner in which the "molecular clock" responds to light. In flies, levels of TIM protein are reduced in response to light, while in mammals, per RNA is induced. The pathway that conducts light to the clock is poorly understood but there is increasing evidence in support of a dedicated pathway for circadian photoreception, as opposed to the sole use of the visual transduction system.

Animals↗
PubMed2000

A comparison of alternative approaches to the scoring of clock drawing.

Although a number of scoring procedures for clock drawing have emerged in the literature, no systematic comparison of the psychometric properties of various approaches has yet been conducted on a large sample of persons over 64 years of age diagnosed with dementia or deemed cognitively intact. The present study examined the reliability and validity of five scoring approaches (Doyon, Bouchard, Morin, Bourgeois, & Cote, 1991; Shulman, Shedletsky, & Silver, 1986; Tuokko, Hadjistavropoulos, Miller, & Beattie, 1992; Watson, Arfken, & Birge, 1993; Wolf-Klein, Silverstone, Levy, Brod, & Breuer, 1989) among the 493 participants of the Canadian Study of Health and Aging who completed clock drawing and who had a final diagnosis assigned at the conclusion of a comprehensive clinical examination. Inter- and intra-rater reliabilities were highest for the Tuokko et al. method. The Tuokko and Shulman scoring procedures had the highest sensitivities and relatively low specificities. The Wolf-Klein procedure had relatively low sensitivities and high specificities. Estimated areas under receiver operating curves were relatively high for all scoring methods. However, the area under the curve for the Watson procedure was significantly lower than the other procedures. All claims to the utility of clock drawing for differentiating between normal persons over 64 years of age and those with dementia appear validated.

Journal Article↗
PubMed2003

CK1 and GSK3 in the Drosophila and mammalian circadian clock.

Two kinases, DOUBLETIME and SHAGGY, have been shown to play a role in the circadian clock. DOUBLETIME, the Drosophila orthologue of casein kinase 1, can phosphorylate PERIOD in the cytoplasm and in the nucleus. This phosphorylation destabilizes PERIOD in both locations and sets patterns of both cytoplasmic accumulation and nuclear turnover. Cytoplasmic phosphorylation postpones accumulation of PERIOD and affects timing of nuclear accumulation of PERIOD/ TIMELESS complexes. SHAGGY, the Drosophila orthologue of glycogen synthase kinase 3, phosphorylates TIMELESS and promotes nuclear translocation of PERIOD/ TIMELESS complexes. Thus, the opposing effects of these two kinases in the cytoplasm are crucial for establishing the approximately 24 h period of circadian rhythmicity in Drosophila. Casein Kinase 1 has been shown to be a component of the circadian clock in mammals. Recent studies are also pointing to a role for glycogen synthase kinase 3 in the mammalian clock.

Amino Acid Sequence↗
PubMed2004

Precise circadian clocks in prokaryotic cyanobacteria.

Prokaryotic cyanobacteria express robust circadian (daily) rhythms under the control of a timing mechanism that is independent of the cell division cycle. This biological clock orchestrates global regulation of gene expression and controls the timing of cell division. Proteins that may be involved in input pathways have been identified. Mutational screening has identified three clock genes that are organized as a gene cluster. The structure of cyanobacterial clock proteins, their phosphorylation, and regulation is described. A new model for the core clockwork in cyanobacteria proposes that rhythmic changes in the status of the chromosome underlie the rhythms of gene expression. Mixed-strain experiments demonstrate that this timekeeper confers adaptive value when different strains compete against each other.

Bacterial Proteins↗
PubMed2005

The age of the angiosperms: a molecular timescale without a clock.

The age of the angiosperms has long been of interest to botanists and evolutionary biologists. Many early efforts to date the age of the angiosperms and evolutionary divergences within the angiosperm clade using a molecular clock have yielded age estimates that are grossly inconsistent with the fossil record. We investigated the age of angiosperms using Bayesian relaxed clock (BRC) and penalized likelihood (PL) approaches. Both of these methods allow the incorporation of multiple fossil constraints into the optimization procedure. The BRC method allows a range of values for among-lineage rate of substitution, from a nearly clocklike behavior to a condition in which each branch is allowed an optimal substitution rate, and also accounts for variation in molecular evolution across multiple genes. A topology derived from an analysis of genes from all three plant genomes for 71 taxa was used as a backbone. The effects on age estimates of different genes, single-gene versus concatenated datasets, and the inclusion and assumptions of fossils as age constraints were examined. In addition, the influence of prior distributions on estimates of divergence times was also explored. These results indicate that widely divergent age estimates can result from the different methods (198-139 million years ago), different sources of data (275-122 million years ago), and the inclusion of temporal constraints to topologies. Most dates, however, are between 180-140 million years ago, suggesting a Middle Jurassic-Early Cretaceous origin of flowering plants, predating the oldest unequivocal fossil angiosperms by about 45-5 million years. Nonetheless, these dates are consistent with other recent studies that have used methods that relax the assumption of a strict molecular clock and also agree with the hypothesis that the angiosperms may be somewhat older than the fossil record indicates.

Bayes Theorem↗
PubMed2006

[Regulation of adipose functions by molecular clocks].

Adipocytes play essential metabolic roles, not only serving as massive energy reserves but also secreting hormones and cytokines that regulate metabolic activities. The link between metabolic activity in adipocytes and circadian rhythm has long been studied, e.g., glucose and lipid homeostasis are well known to exhibit circadian variation. Therefore, molecular clock may play important roles in regulation of metabolic activity in adipocytes. In a previous study, we reported that white adipose tissue contains functional molecular clock and expression of several adipocytokines including leptin and plasminogen activator inhibitor-1 displays circadian rhythm. The diurnal rhythm in the level of these molecules suggests that molecular clock is, at least partly, associated with the onset of metabolic syndrome.

ARNTL Transcription Factors↗
PubMed1989

The mammalian circadian clock in the suprachiasmatic nuclei is reset in vitro by cAMP.

A circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus controls the daily behavioral and physiological rhythms of mammals. While the mammalian circadian system has been the focus of research for many years, very little work has been directed at understanding its underlying biochemical mechanisms. In these experiments we used the hypothalamic brain slice technique to investigate these mechanisms, focusing specifically on the intrinsic resetting properties of the circadian clock of the rat. We monitored a primary expression of the clock or pacemaker, the circadian rhythm of electrical activity of SCN neurons. This rhythm continues the oscillatory pattern seen in vivo for up to 60 hr in vitro, with an activity peak near midday that shows very little variation among SCN from different rats. The stability of the rhythm in vitro enabled us to use the time of peak activity to monitor the phase of the underlying pacemaker. Bath application of membrane-soluble cAMP analogs in 1 hr pulses induced robust advances in the phase of the rhythm that remained stable for 2 cycles. This effect depended on the phase of the pacemaker at the time of treatment: the peak was maximally advanced (4-6 hr) by treatments during the middle of the subjective day (projected from the donor's cycle); treatments during most of the subjective night and early subjective day induced no phase changes. Half-maximal phase resetting was induced at 1 x 10(-10) M concentrations of active cAMP analog.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

What starts an internal clock?

Five experiments with rats investigated under what conditions a stimulus is timed by the internal clock used in time-discrimination procedures. In Experiments 1-4, we trained rats to time one stimulus (e.g., light) and then asked whether they timed a stimulus from another modality (e.g., sound). The second stimulus was treated in three ways: exposed (presented alone), paired with food, and extinguished. Experiments 1 and 2 used the peak procedure, similar to a discrete-trial fixed-interval schedule, and paired the treated stimulus with food using instrumental training; Experiments 3 and 4 used a psychophysical choice procedure and paired the treated stimulus with food using classical conditioning. All four experiments found that there was cross-modal transfer of the time discrimination after pairing, but not after exposure or extinction. This suggests that the rat's internal clock timed the treated stimulus after pairing, but not after exposure or extinction. Experiment 5 tested a theory of extinction based on the results of Experiments 1-4; the results suggested that the decline of responding observed in extinction is not due to changes in timing. The main conclusion is that the internal clock apparently times stimuli with signal value (associative strength) and does not time stimuli without signal value.

Animals↗
PubMed1982

Cross-modal use of an internal clock.

Four experiments used time-discrimination procedures with rats to ask if light and sound are timed by the same internal clock and if measured durations of light and sound are stored in the same memory. Experiment 1 used a choice procedure and a cross-modal transfer-of-training design. Rats were trained to press one lever after a 1-sec signal, another lever after a 4-sec signal. At first, the signal was light (or sound); when performance was accurate, the signal was changed ot sound (or light). There was transfer of the time discrimination across modalities: To some extent, the rats treated the new signal (sound) as if it were the old signal (light). The rest of the experiments used the peak procedure, which is similar to a discrete-trials fixed-interval procedure. With the peak procedure, response rate reaches a maximum in the middle of the trial; the time of the maximum (peak time) is a measure of the clock and temporal memory. Experiment 2 found that changing the time of food during light (or sound) changed peak time during sound (or light). In Experiments 3 and 4, intervals of light (or sound) were followed by intervals of sound (or light). The interval of light decreased the peak time measured from the start to the interval of sound, whether the two intervals were adjacent (Experiment 3) or separated by 5 sec (Experiment 3). Experiments 1 and 2 suggest that measured durations of light and sound are stored by the same memory; Experiments 3 and 4 suggest that light and sound are timed by the same clock.

Animals↗
PubMed1997

Coupling of muscarinic cholinergic receptors and cGMP in nocturnal regulation of the suprachiasmatic circadian clock.

Acetylcholine has long been implicated in nocturnal phase adjustment of circadian rhythms, yet the subject remains controversial. Although the suprachiasmatic nucleus (SCN), site of the circadian clock, contains no intrinsic cholinergic somata, it receives choline acetyltransferase-immunopositive projections from basal forebrain and mesopontine tegmental nuclei that contribute to sleep and wakefulness. We have demonstrated that the SCN of inbred rats in a hypothalamic brain slice is sensitive to cholinergic phase adjustment via muscarinic receptors (mAChRs) only at night. We used this paradigm to probe the muscarinic signal transduction mechanism and the site(s) gating nocturnal responsiveness. The cholinergic agonist carbachol altered the circadian rhythm of SCN neuronal activity in a pattern closely resembling that for analogs of cGMP; nocturnal gating of clock sensitivity of each is preserved in vitro. Specific inhibitors of guanylyl cyclase (GC) and cGMP-dependent protein kinase (PKG), key elements in the cGMP signal transduction cascade, blocked phase shifts induced by carbachol. Further, carbachol administration to the SCN at night increased cGMP production and PKG activity. The carbachol-induced increase in cGMP was blocked both by atropine, an mAChR antagonist, and by LY83583, a GC inhibitor. We conclude that (1) mAChR regulation of the SCN is mediated via GC-->cGMP-->PKG, (2) nocturnal gating of this pathway is controlled by the circadian clock, and (3) a gating site is positioned downstream from cGMP. This study is among the first to identify a functional context for mAChR-cGMP coupling in the CNS.

Acetylcholine↗
PubMed1997

Role of neural cell adhesion molecule and polysialic acid in mouse circadian clock function.

The suprachiasmatic nuclei (SCN) express the highly polysialylated form of the neural cell adhesion molecule (NCAM) that has been proposed to promote plasticity in the adult brain. To investigate a role for NCAM in SCN circadian clock function, we examined the daily locomotor rhythm of mice homozygous for a mutation, Ncamtm1Cwr, which results in deletion of the NCAM-180 isoform that in brain carries polysialic acid (PSA). Mutant mice entrained well to a 12 hr light/dark cycle but exhibited a significantly shortened free-running period and longer activity duration under constant darkness (DD) than did wild-type mice. By the third week of DD treatment, circadian rhythmicity in the mutant was abolished. Immunocytochemical analyses of the mutant SCN revealed an abnormal number and distribution of vasoactive intestinal polypeptide-producing neurons, suggesting a developmental effect of the mutant phenotype; however, a direct physiological effect of the mutation on clock function was indicated by the fact that removal of PSA from adult wild-type SCN by microinjection of endoneuraminidase shortened the free-running period to a similar extent as in the mutant. Together, these data indicate critical roles for NCAM and PSA in the development and physiology of the mammalian SCN circadian clock.

Animals↗
PubMed1996

The molecular basis of carcinogenesis: understanding the cell cycle clock.

The cell cycle clock is the central controller of cell proliferation that governs the progress of the cell through its growth cycle, its exit from the active cycle, and its decision to differentiate. Components of the clock are found to be functioning in an aberrant fashion in many types of malignancies. Notable among these is the retinoblastoma protein, pRB, which acts to restrain proliferation in normal cells and suffers inactivation in many types of tumour cells. Its activity is controlled by D-type cyclins in various cell types. We have deleted one of these cyclins--cyclin D1--from the mouse germline and find that its absence leads to a limited range of defects including hypoplastic retinae and the inability of the mammary epithelium to respond to pregnancy-associated hormonal stimulation. Cyclin D1 is overexpressed in many human breast cancers, pointing to a highly specific association of this cell cycle clock component with mammary cell proliferation.

Activity Cycles↗
PubMedDate not supplied

Regulation of insulin-like growth factor binding protein-1 during the 24-hour metabolic clock and in response to hypoinsulinemia induced by fasting and Sandostatin in normal women.

OBJECTIVE: To establish the relation of insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) with 24-hour metabolic excursions in normal healthy women and in response to acute interruption of metabolic homeostasis by hypoinsulinemia. METHODS: Hourly blood samples during the 24-hour metabolic clock were obtained from seven normally cycling women. Uniform dietary composition (50% carbohydrate, 35% fat, and 15% protein) and timing of meals (8 AM, 12 PM, and 6 PM) were prescribed. Daytime hypoinsulinemia was induced by omitting meals and by Sandostatin (100 micrograms) administration. Changes in serum levels of glucose, insulin, cortisol, IGF-I, and IGFBP-1 were measured. RESULTS: The diurnal pattern of serum IGFBP-1 levels during the 24-hour metabolic clock was characterized by a rapid fall during the feeding phase of the day and a progressive 3.5-fold rise during nocturnal fasting; IGF-I levels were unchanged. Changes in IGFBP-1 levels were in parallel to those of cortisol and were inversely related to increases in glucose (80%) and insulin (tenfold) levels after each meal and to their decline during nocturnal fasting. Daytime fasting and administration of Sandostatin were accompanied by rapid and sustained increases in IGFBP-1 when insulin levels declined to 54 +/- 20 pmol/L. CONCLUSIONS: With constant levels of IGF-I, the diurnal rhythm of IGFBP-1 may subserve a physiologic function by coordinating insulin and IGF-I action with substrate availability. Fluctuations of insulin levels during the 24-hour metabolic clock in normal women appear to serve as a signal, with an inhibitory effect on IGFBP-1 production when levels are above 70 pmol/L and a stimulatory effect at levels below 70 pmol/L. These findings provide a basis for future investigations in women with nutritionally related reproductive disorders.

Adult↗
PubMed1998

[Clock drawing test: qualitative and quantitative evaluation methods].

INTRODUCTION: The interest about the Clock Drawing Test (CDT) is justified because the importance of praxic disorders and especially the constructive apraxias in demented patients. Generally, this kind of deficits or intellectual losses has been less studied than aphasisas and agnosias. Nevertheless, praxias are usually affected in demential processes, even in initial stages. OBJECTIVE: We try to determine if the CDT can be useful as an assessment tool for dementia. We have used two assessment systems of the clock drawing in order to select an useful and reliable method of correction. PATIENTS AND METHODS: The sample is made up of 35 subjects older than 60 years, they were administered the Mini Cognitive Examination (MCE) and the CDT. Patients with previous diagnosis of dementia, others with physical pathology without neurological affectation and, finally, subjects without any kind of pathology were included in order to get a wide rank of punctuations. We carried out a reliability analysis between two raters and the discriminant validity of the CDT compared to the Spanish adaptation of the Mini Mental Examination. RESULTS: We achieve a high reliability inter examiner rates. Quantitative criteria of both scales are more objective than qualitative ones, therefore, these last should be more operativized. CONCLUSIONS: The results obtained in this work suggest that the clock drawing allow a rapid evaluation of cognitive function as the presence of cognitive impairment.

Aged↗