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PubMed1990

Post-traumatic epilepsy: cellular mechanisms and implications for treatment.

Epilepsy complicates severe head trauma. Development of persistent seizures appears to correlate with the extent of trauma. Although early reports suggested that prophylactic administration of antiepileptic drugs would prevent epileptogenesis, controlled studies have failed to corroborate this assumption. Head trauma initiates a sequence of responses that includes altered blood flow and vasoregulation, disruption of the blood-brain barrier, increases in intracranial pressure, focal or diffuse ischemia, hemorrhage, inflammation, necrosis, and disruption of fiber tracts. The presence of an intracranial hematoma has a robust association with the development of post-traumatic epilepsy. Extravasation of blood is followed by hemolysis and deposition of heme-containing compounds into the neuropil, initiating a sequence of univalent redox reactions and generating various free radical species, including superoxides, hydroxyl radicals, peroxides, and perferryl ions. Free radicals initiate peroxidation reactions by hydrogen abstraction from methylene groups adjacent to double bonds of fatty acids and lipids within cellular membranes. Intrinsic enzymatic mechanisms for control of free radical reactions include activation of catalase, peroxidase, and superoxide dismutase. Steroids, proteins, and tocopherol also terminate peroxidative reactions. Tocopherol and selenium are effective in preventing tissue injury initiated by ferrous chloride and heme compounds. Treatment strategies for prevention or prophylaxis of post-traumatic epilepsy must await absolute knowledge of mechanisms. Antioxidants and chelators may be useful, given the speculation that peroxidative reactions may be an important component of brain injury responses. However, potential treatment strategies involving gamma-aminobutyric acid (GABA) agonists, NMDA receptor antagonists, and barbiturates need further scientific assessment.

Brain↗

PubMed1991

[Morbidity studies in children's nurseries].

In 1986-1988 the indices of absence morbidity taken from monthly reports of crèches were registered in 8 crèches of Dresden and were compared with the real total morbidity, which had been registered with help of a symptom catalogue for one year. The total morbidity amounted to more than the double of absence morbidity, the total of the illness days per case amounted to 8.42 days and the days of absence morbidity amounted 7.3. The description of infection groups with help of quarters (according to Adam) on the basis of the registered total morbidity showed differences with regard to: average illness period per case (children susceptible to infections: 9.33 d; children robust to infections: 6.82 d) and average recurrence period (children susceptible to infections: 15.7 d; children robust to infections: 78.2 d). Probable causes of susceptibility to infections and conclusions hence to be drawn.

Child Day Care Centers↗

PubMed1994

Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn's Relapse Prevention Trial Study Group.

BACKGROUND/AIMS: Quality of life (QOL), a subjective index of health perception and function, embraces physical, social, and emotional performance but has not had a prominent role in clinical trials of inflammatory bowel disease (IBD). To test the robustness of the Inflammatory Bowel Disease Questionnaire (IBDQ), a disease-specific QOL index, this study assessed its validity, reliability, and responsiveness during a multicenter trial. METHODS: Three hundred five patients with stable Crohn's disease received cyclosporin or placebo for 18 months. IBDQ and dimensional scores (bowel, social, systemic, and emotional) were correlated with disease activity (Crohn's disease activity index [CDAI] and Harvey-Bradshaw index). Concordance of IBDQ scores was tested in 280 stable subjects. Linear regression evaluated change in IBDQ scores over time. RESULTS: IBDQ scores correlated highly with CDAI (r = -0.67; P < 0.0001). The reliability coefficient for IBDQ score was 0.70 vs. 0.66 for CDAI and 0.55 for Harvey-Bradshaw index. Regression line slopes of IBDQ scores were significantly different in patients who deteriorated from those who remained stable ([b] < 0.15; P < 0.0001). QOL scores were lower in patients who required surgery. CONCLUSIONS: The IBDQ is a valid reliable assessment tool that reflects important changes in the health status of patients with IBD. The IBDQ is a robust measure of therapeutic efficacy and should be used in future clinical trials in IBD.

Adult↗

PubMed2001

Efficacy of corticosteroids in acute experimental irritant contact dermatitis?

BACKGROUND/AIMS: Topical corticoids are used to treat irritant contact dermatitis (ICD) in humans. However, their clinical efficacy remains sub judice. This study was designed to assess the efficacy of low- and medium-potency corticosteroids on irritant dermatitis. METHODS: We induced an acute ICD via open application of sodium lauryl sulphate (SLS) on the hands of subjects. The dorsal side of hands was irritated with 10% SLS five times in one day. Once on day 1 and twice daily on days 2-5, 1% hydrocortisone, 0.1% betamethasone-17-valerate and vehicle cream (petrolatum) were applied subsequently. Visual grading, bioengineering techniques and squamometry were used to quantify skin response. RESULTS: Corticosteroids were found ineffective in treating the surfactant-induced irritant dermatitis when compared with the vehicle and with the untreated control. CONCLUSION: The counterintuitive result (in a relatively realistic and robust model) should be interpreted with caution until verified with other irritants of varying physicochemical properties.

Adult↗

PubMed1994

Coadministration of fluvoxamine increases serum concentrations of haloperidol.

Four patients with chronic schizophrenia were treated with a combination of fluvoxamine, haloperidol, and benztropine. The combination significantly impaired performance on tests of delayed recall memory and attentional function. Haloperidol concentrations in serum were monitored in three patients and were robustly elevated by fluvoxamine.

Adult↗

PubMedDate not supplied

Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels.

OBJECTIVE: Caffeine increases cortisol secretion in people at rest or undergoing mental stress. It is not known whether tolerance develops in this response with daily intake of caffeine in the diet. We therefore tested the cortisol response to caffeine challenge after controlled levels of caffeine intake. METHODS: Men (N = 48) and women (N = 48) completed a double-blind, crossover trial conducted over 4 weeks. On each week, subjects abstained for 5 days from dietary caffeine and instead took capsules totaling 0 mg, 300 mg, and 600 mg/day in 3 divided doses. On day 6, they took capsules with either 0 mg or 250 mg at 9:00 AM, 1:00 PM, and 6:00 PM, and cortisol was sampled from saliva collected at 8 times from 7:30 AM to 7:00 PM. RESULTS: After 5 days of caffeine abstinence, caffeine challenge doses caused a robust increase in cortisol across the test day (p < .0001). In contrast, 5 days of caffeine intake at 300 mg/day and 600 mg/day abolished the cortisol response to the initial 9:00 AM caffeine dose, although cortisol levels were again elevated between 1:00 PM and 7:00 PM (p = .02 to .002) after the second caffeine dose taken at 1:00 PM. Cortisol levels declined to control levels during the evening sampling period. CONCLUSION: Cortisol responses to caffeine are reduced, but not eliminated, in healthy young men and women who consume caffeine on a daily basis.

Adult↗

PubMed2004

The acute effect of methylphenidate in Brazilian male children and adolescents with ADHD: a randomized clinical trial.

OBJECTIVE: To evaluate the acute efficacy of methylphenidate (MPH) in Brazilian male children and adolescents with ADHD. METHOD: In a 4-day, double-blind, placebo-controlled, randomized, fix dose escalating, parallel-group trial, 36 ADHD children and adolescents were allocated to two groups: MPH (n = 19) and placebo (n = 17). Participants were evaluated pre- and posttreatment using the 10-item Conners Abbreviated Rating Scale (ABRS), the Children's Global Assessment Scale (CGAS), and a simplified version of the Continuous Performance Test (CPT). RESULTS: The MPH group had a significantly greater decrease in ABRS scores and a significantly higher increase in CGAS scores than the placebo group (p < 0.01). The MPH group showed also a significantly higher proportion of patients with a robust improvement (decrement of at least 50% in the ABRS score after the intervention) than the placebo group (p < 0.01). The MPH effect size for the ABRS was 1.05 (95% CI = 0.73-1.37). CONCLUSION: Our results extend the efficacy of MPH on the ADHD core symptoms extensively demonstrated in clinical trials with samples from some developed countries to a sample from a developing country where a diverse culture may modulate the clinical presentation of the disorder.

Adolescent↗

PubMed1999

Gene expression in proliferating human erythroid cells.

A complete understanding of human erythropoiesis will require a robust description of transcriptional activity in hematopoietic cells that proliferate and differentiate in response to erythropoietin (EPO). For this purpose, we cultured peripheral blood mononuclear cells in the presence or in the absence of EPO and examined the transcriptional profile of those cells arising only in response to EPO. A distinct population of CD71( +) cells that demonstrated an average of six additional doublings in suspension culture and erythroid colony formation in methylcellulose was isolated. Suppression subtractive hybridization of mRNA isolated from those cells permitted the identification of transcribed genes. A summary of 719 expressed sequence tags (ESTs) describing 505 independent transcripts is provided here with a full analysis of each EST available at http://hembase.niddk.nih.gov. Several transcripts that matched genes previously reported in the context of erythroid differentiation including 4 cell surface proteins were expressed at this developmental stage. Active chromatin remodeling was suggested by the identification of 4 histone proteins, 4 high-mobility group proteins, 13 transcription factors, and 6 genes involved in DNA recombination and repair. Numerous genes associated with leukemic translocations were also recognized including topoisomerases I and II, nucleophosmin, Translin, EGR1, dek, pim-1, TFG, and MLL. In addition to known transcripts, 44 novel EST were discovered. This transcriptional profile provides the first genomic-scale description of gene activity in erythroid progenitor cells.

Antigens, CD↗

PubMed2002

Long-term potentiation is increased in the CA1 area of the hippocampus of APP(swe/ind) CRND8 mice.

The present study reports changes in synaptic function and plasticity [long-term potentiation (LTP)] in a recently developed mouse model of Alzheimer's disease (CRND8 line) harboring a double amyloid precursor protein mutation (APP(swe/ind)). In 9-week-old preplaque transgenic (Tg) mice brain slices, basal synaptic function in the hippocampal CA1 area was unchanged. Only one of three different LTP induction protocols revealed early influence of genotype on synaptic plasticity. By 20 weeks of age, there were numerous plaques in the hippocampus from Tg mice associated with more robust evidence for genotype-related effects in synaptic function. Field potential maximum slope was consistently decreased and LTP was increased, irrespective of the stimulation protocol used. In addition, there was clear evidence of increased synaptic excitability in Tg mice. Furthermore, the maximum amplitude of evoked IPSCs was decreased whereas the maximum amplitude of evoked EPSCs was increased in 20-week-old Tg mice. Collectively, these results suggest a number of APP genotype-related changes in the fine-tuning of the CA1 area circuitry, some of which are likely to contribute to the pathology-dependent effects on LTP observed in CRND8 mice.

Aging↗

PubMed2002

A DNA vector-based RNAi technology to suppress gene expression in mammalian cells.

Double-stranded RNA-mediated interference (RNAi) has recently emerged as a powerful reverse genetic tool to silence gene expression in multiple organisms including plants, Caenorhabditis elegans, and Drosophila. The discovery that synthetic double-stranded, 21-nt small interfering RNA triggers gene-specific silencing in mammalian cells has further expanded the utility of RNAi into mammalian systems. Here we report a technology that allows synthesis of small interfering RNAs from DNA templates in vivo to efficiently inhibit endogenous gene expression. Significantly, we were able to use this approach to demonstrate, in multiple cell lines, robust inhibition of several endogenous genes of diverse functions. These findings highlight the general utility of this DNA vector-based RNAi technology in suppressing gene expression in mammalian cells.

Animals↗

PubMed2004

Bifurcation analysis of the regulatory modules of the mammalian G1/S transition.

MOTIVATION: Mathematical models of the cell cycle can contribute to an understanding of its basic mechanisms. Modern simulation tools make the analysis of key components and their interactions very effective. This paper focuses on the role of small modules and feedbacks in the gene-protein network governing the G1/S transition in mammalian cells. Mutations in this network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network. RESULTS: We identify various positive and negative feedback loops in the network controlling the G1/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator-inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G1/S phase transition point. Thus, core modules can explain major features of the complex G1/S network and have a robust decision taking function.

Animals↗

PubMed2006

Information security system by iterative multiple-phase retrieval and pixel random permutation.

A novel information security system based on multiple-phase retrieval by an iterative Fresnel-transform algorithm and pixel random permutation (PRP) technique is proposed. In this method a series of phase masks cascaded in free space are employed and the phase distributions of all the masks are adjusted simultaneously in each iteration. It can achieve faster convergence and better quality of the recovered image compared with double-phase encoding and a similar approach in the spatial-frequency domain with the same number of phase masks and can provide a higher degree of freedom in key space with more geometric parameters as supplementary keys. Furthermore, the security level of this method is greatly improved by the introduction of the PRP technique. The feasibility of this method and its robustness against occlusion and additional noise attacks are verified by computer simulations. The performance of this technique for different numbers of phase masks and quantized phase levels is investigated systematically with the correlation coefficient and mean square error as convergence criterions.

Journal Article↗

PubMed1997

Global measures of outcome in a controlled comparison of pharmacological and psychological treatment of panic disorder and agoraphobia in primary care.

BACKGROUND: Panic disorder, with and without agoraphobia, is a prevalent condition which presents primarily in general practice. Previous clinical outcome studies have been conducted mainly in specialist university departments or hospital settings, and have tended to employ complex rating scales that are not well suited for use as outcome measures in primary care. AIM: To evaluate the outcome, in a primary care setting, of fluvoxamine versus cognitive behaviour therapy, each used alone and in combination in a double-blind placebo-controlled framework, balanced for therapist contact. METHOD: A total of 149 patients satisfying DSMIII-R criteria for panic disorder were randomly allocated to receive one of the following: fluvoxamine, placebo, fluvoxamine plus cognitive behaviour therapy, placebo plus cognitive behaviour therapy, and cognitive behaviour therapy alone. These five treatment groups represent the minimum number acceptable for such a comparison to be made. All patients received an identical schedule of contact over 13 weeks. Measures of symptom severity, general health and social disruption were taken at entry point and end point; measures of change in symptoms were taken at end point only. Outcome was reported in terms of brief global ratings of severity of illness and change in symptoms, and of ratings of general health and social disruption that are suitable for use in general practice. RESULTS: All active treatment groups showed statistically significant advantages over placebo over a range of outcome ratings. The groups employing cognitive behaviour therapy showed the most robust and consistent response. CONCLUSION: The brief global measures reported here proved adequate to the task of assessing treatment outcome. Results indicate that treatments including cognitive behaviour therapy can be effective in the treatment of panic disorder and agoraphobia in primary care.

Adolescent↗

PubMed2026

Intravenous Ketamine reduces psychological pain in suicidal inpatients: A secondary analysis of a six-week randomized placebo-controlled trial.

BACKGROUND: Psychological pain has been conceptualized as an unbearable inner experience and a possible precondition for suicidal ideation. No randomized placebo-controlled study has specifically investigated psychological pain as a treatment target in psychiatric populations. We examined ketamine's effect on psychological pain in suicidal psychiatric inpatients. METHODS: This secondary analysis used KETIS, a 6-week randomized, double-blind, placebo-controlled trial. Participants received two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (0.9% saline) 24 h apart, alongside usual care and medication. Psychological and physical pain were assessed at baseline, repeatedly during 96 h, and at weeks 2, 4, and 6 using the self-rated PPP-VAS. Longitudinal mixed models compared pain trajectories. RESULTS: The trial randomized suicidal inpatients to ketamine (n = 73) or placebo (n = 83). Psychological pain decreased in both groups but was lower with ketamine during the first 96 h. Pointwise scores were lower with ketamine from 40 min to 96 h, largest at 40 min, 2 h, 4 h, and 24 h (all p < 0.001), but not at weeks 2, 4, or 6. This early difference remained significant after adjustment for depressive symptoms and hopelessness. The early reduction appeared more pronounced in the bipolar subgroup. No robust baseline predictors of outcome were identified. CONCLUSIONS: Intravenous ketamine was associated with a greater reduction in psychological pain than placebo in suicidal inpatients, with the clearest effects emerging within the first hours after treatment and remaining evident through the first 96 h. Ketamine may represent a clinically relevant option as a psychological pain reliever in psychiatric patients.

Humans↗

PubMed2006

Familiality of factor analysis-derived YBOCS dimensions in OCD-affected sibling pairs from the OCD Collaborative Genetics Study.

BACKGROUND: Identification of familial, more homogenous characteristics of obsessive-compulsive disorder (OCD) may help to define relevant subtypes and increase the power of genetic and neurobiological studies of OCD. While factor-analytic studies have found consistent, clinically meaningful OCD symptom dimensions, there have been only limited attempts to evaluate the familiality and potential genetic basis of such dimensions. METHODS: Four hundred eighteen sibling pairs with OCD were evaluated using the Structured Clinical Interview for DSM-IV and the Yale-Brown Obsessive Compulsive Scale (YBOCS) Symptom Checklist and Severity scales. RESULTS: After controlling for sex, age, and age of onset, robust sib-sib intraclass correlations were found for two of the four YBOCS factors: Factor IV (hoarding obsessions and compulsions (p = .001) and Factor I (aggressive, sexual, and religious obsessions, and checking compulsions; p = .002). Smaller, but still significant, familiality was found for Factor III (contamination/cleaning; p = .02) and Factor II (symmetry/ordering/arranging; p = .04). Limiting the sample to female subjects more than doubled the familiality estimates for Factor II (p = .003). Among potentially relevant comorbid conditions for genetic studies, bipolar I/II and major depressive disorder were strongly associated with Factor I (p < .001), whereas ADHD, alcohol dependence, and bulimia were associated with Factor II (p < .01). CONCLUSIONS: Factor-analyzed OCD symptom dimensions in sibling pairs with OCD are familial with some gender-dependence, exhibit relatively specific relationships to comorbid psychiatric disorders and thus may be useful as refined phenotypes for molecular genetic studies of OCD.

Comorbidity↗

PubMed2005

Asymmetric probability densities in symmetrically modulated bistable devices.

A Brownian particle hopping in a symmetric double-well potential can be statistically confined into a single well by the simultaneous action of (a) two periodic input signals, one tilting the minima and the other one modulating the barrier height, and (b) an additive and a purely multiplicative random signal, generated by a unique source and thus preserving a certain degree of statistical correlation. The underlying gating mechanism is quite robust when compared, for instance, with biharmonic rocking. In view of technological implementation, asymmetric confinement through gating can be conveniently maximized by tuning the input signal parameters (correlation time, phase-time lag, amplitudes), thus revealing a resonant localization mechanism of general applicability.

Journal Article↗

PubMed2006

Zero-field kondo splitting and quantum-critical transition in double quantum dots.

Double quantum dots offer unique possibilities for the study of many-body correlations. A system containing one Kondo dot and one effectively noninteracting dot maps onto a single-impurity Anderson model with a structured (nonconstant) density of states. Numerical renormalization-group calculations show that, while band filtering through the resonant dot splits the Kondo resonance, the singlet ground state is robust. The system can also be continuously tuned to create a pseudogapped density of states and access a quantum-critical point separating Kondo and non-Kondo phases.

Journal Article↗

PubMed1997

What happens to anxiety levels on giving up smoking?

OBJECTIVE: DSM-IV lists increased anxiety as a nicotine withdrawal symptom. Increased anxiety has been reported to follow smoking cessation in most but not all studies. Indeed, there is some evidence for a reduction in anxiety, compared with precessation levels, after the first few weeks of abstinence. This study reports data from 101 smokers who attempted to stop smoking and who satisfied DSM-III-R criteria for nicotine dependence. METHOD: Unlike most studies in this area, a strict criterion of lapse-free abstinence was adopted. It is argued that lapses during an attempt at cessation may underlie a transient increase in anxiety. Anxiety was measured both by a single rating typical in withdrawal studies and by the State-Trait Anxiety Inventory--State Form X. Patients were rated 2 weeks and 1 week before cessation, immediately before cessation, 24 hours after cessation, and 1, 2, 3, and 4 weeks after cessation. RESULTS: Seventy patients were abstinent for the 4-week follow-up period. There was no evidence of an increase in anxiety following smoking cessation. However, there was a significant decrease in anxiety from the first week of abstinence. CONCLUSIONS: The results weaken the view that increased anxiety is a robust and central element of the nicotine withdrawal syndrome and suggest that giving up smoking is quite rapidly followed by a reduction in anxiety that may reflect removal of an anxiogenic agent, nicotine.

Adolescent↗