Screening for Neuroligin 4 (NLGN4) truncating and transmembrane domain mutations in schizophrenia.
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Adult↗
Biomedical subjects
P Sand
Publications and source records attributed to P Sand.
Investigation of the DAOA/G30 locus in panic disorder.
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Carrier Proteins↗
Cholecystokinin- and cholecystokinin-B-receptor gene polymorphisms in panic disorder.
Panic disorder like other neuropsychiatric disorders is believed to be caused by multiple psychosocial and biological factors. Several lines of evidence point to a role for the peptide neurotransmitter cholecystokinin in the pathogenesis of panic disorder. We therefore determined the allele and genotype frequencies of a single nucleotide polymorphism in the CCK gene (-36C>T) and one CT repeat polymorphism in the CCK-B-receptor gene in a German panic disorder sample (n = 115 for CCK gene polymorphism, n = 111 for CCK-B-receptor polymorphism) and compared them with gender and age matched controls. The length of the polymorphic CT repeat alleles varies between 146 bp and 180 bp. We first analysed the results by a permutation test which provided evidence for heterogeneity between patients and controls (p=0.002). We then analysed the data as a di-allelic polymorphism with a short (146-162bp) and a long (164-180bp) allele and as a tetra-allelic polymorphism with 4 alleles (146-154bp, 156-162bp, 164-170bp, 172-180bp). In the di-allelic analysis as well as in the tetra-allelic analysis there was an excess of the longer allele (p = 0.001) or the two longer alleles (p = 0.041) respectively in patients with panic disorder. No difference between groups was observed for the -36C > T polymorphism. Our findings are consistent with the notion that genetic variation in the CCK neurotransmitter system contributes to the pathogenesis of panic disorder.
Adult↗
Hypotonic stress activates an intermediate conductance K+ channel in human colonic crypt cells.
AIM: To investigate the effect of hypotonic stress on human colonic crypts cells in terms of ion channel activity and intracellular Ca2+ concentration. METHODS: Single crypts were isolated from biopsies taken during colonoscopy. The patch clamp technique was used (in the cell-attached mode) to observe the activity of ion channels during hypotonic stress. Calcium measurements were made using the fluophores Fluo 3 or 4. RESULTS: The intermediate conductance (29 pS), Ca2+ -sensitive, K+ channel (also known as KCNN4) previously described (Sandle et al. 1994) was seen in 54 of 149 patches (36%) when the crypts were bathed in normal extracellular solution (290 mOsm kg(-1)). Forty-one patches could be used for further analysis. Activation of one or several 29 pS channels was seen in 15 of 41 patches (39%) after 30 s to 4 min of exposure to hypotonic solution (160 mOsm kg(-1)). The open probability increased from 0.0043 in control solution to 0.44 at 5 min of hypotonic stress. When the crypts were exposed to hypotonic solution, an increase in intracellular Ca2+ could be seen. The increase in intracellular Ca2+ emanates mainly from intracellular stores. CONCLUSION: The 29 pS K+ channel takes part in volume regulation in human colonic crypt cells. The activation of this channel is mediated through an increase in intracellular Ca2+.
Calcium↗
Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder.
Panic disorder is an anxiety disorder with an estimated heritability of 48%. Variation in the gene of the nuclear transcription factor "cAMP-responsive element modulator" (CREM) might contribute to its pathogenesis. CREM knock-out mice exhibit significantly less anxiety behavior than wild-type mice and the alternative CREM gene product "inducible cAMP early repressor" (ICER) plays a pivotal role in the hypothalamo-pituitary-adrenal (HPA) axis, which is disturbed in panic disorder. We characterized the genomic organization of the human CREM gene and performed a systematic mutation screening by means of single stranded conformational analysis (SSCA) in a sample of 40 German patients with panic disorder (DSM-III-R). Four novel single nucleotide polymorphisms in CREM promoters P 1 and P 4, one trinucleotide (ATT)-repeat polymorphism in CREM promoter P 2-generating the ICER isoform-and a rare amino acid substitution in CREM exon glut 2 were identified. Association analysis in an extended sample of German patients (n = 88) revealed a significant excess of the shorter CREM P 2 promoter eight-repeat trinucleotide allele and of genotypes containing the eight-repeat trinucleotide allele in panic disorder (P = 0.02), in particular in panic disorder without agoraphobia (P = 0.001). A replication study in independent Italian (n = 76) and Spanish (n = 62) samples, however, failed to confirm this observation. This suggests that the CREM P 2 promoter trinucleotide polymorphism is not a major susceptibility factor in the pathogenesis of panic disorder. Functional analysis of the observed CREM P 2 promoter polymorphism as well as studies in independent panic disorder samples are necessary.
Agoraphobia↗
Untangling the human estrogen receptor gene structure.
Awareness of estrogen's neuroprotective and behavioral effects is broadening rapidly and has served as an incentive to investigate estrogen signaling in central nervous system disorders. The present analysis focuses on two human nuclear estrogen receptors, ER alpha and ER beta, which have been shown to play key roles in the complex integration of estrogen's genomic and non-genomic modes of action. The corresponding genes are estimated to have diverged from an ancestral ER gene over 450 million years ago and are candidate genes for a variety of brain disorders. Recent progress in the Human Genome Project has greatly aided our understanding of the molecular blueprint and provides the means for reassessing both genes' genomic organization. Analyses of multiple alternatively spliced transcripts, large untranslated sequences and neighbouring genes reveal several novel features which suggest an increasingly versatile transcriptional machinery. We outline additional exons in the genes' 5'- and 3'-untranslated regions, a new polymorphic ER alpha microsatellite and a nested gene which lend themselves to further evolutionary and functional studies.
Base Sequence↗
Naturally occurring benzodiazepines may codetermine chronotypes.
Determinants of individual differences in sleep-wake cycles and vigilance are being recognized as major factors of influence in both physical and mental health. Alterations of an accustomed circadian sleep-wake rhythm are commonly seen in the early stages of the majority of psychiatric disorders and, by themselves, predispose to significant morbidity even in the absence of an underlying illness. While it is well known that disruptions of sleep respond favourably to benzodiazepines, agents which have been prescribed for insomnia since their industrial synthesis in the early 1960s, little attention has been paid to putative central nervous system effects of naturally occurring benzodiazepines. These molecules were found in various nutritive plants and have been quantified in human brain and peripheral blood of drug-naive individuals at trace amounts. There is agreement that elevated concentrations of naturally occurring benzodiazepines participate in the complex pathophysiology of hepatic encephalopathy, a condition asssociated with progressive impairment of consciousness and, ultimately, coma. In the present study, we address the relationship between naturally occurring benzodiazepines and time-of-day effects on the behavior of healthy subjects.
Adult↗
Transvaginal bladder neck suspension to Cooper's ligament.
Numerous surgeries have been proposed for the treatment of genuine stress incontinence, with the goals to improve functional outcome and decrease complications and their associated morbidity. Two new, minimally invasive procedures, transvaginal retropubic urethropexy and transvaginal Cooper's ligament sling, are reviewed in this article. These procedures provide a completely transvaginal approach, without the use of abdominal incisions or bone anchors. The anterior point of suspension is Cooper's ligament. The transvaginal retropubic urethropexy is used for the treatment of genuine stress incontinence with urethral hypermobility, and the transvaginal sling also may be used in the presence of intrinsic sphincteric deficiency. The procedures are described and the recent outcomes discussed.
Aged↗
Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study.
OBJECTIVE: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder. SUBJECTS AND METHODS: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. RESULTS: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups. CONCLUSIONS: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.
Aged↗
Identification of benzodiazepines in Artemisia dracunculus and Solanum tuberosum rationalizing their endogenous formation in plant tissue.
Sterile cultivated plant cell tissues and cell regenerates of several species were tested for their binding affinity to the central human benzodiazepine receptor. Binding activity was found in extracts of Artemisia dracunculus cell tissue (IC(50) = 7 microg/ml) and, to a lesser extent, in plant regenerates of potato herb (Solanum tuberosum). Preparative HPLC led to the isolation of fractions with a significant displacing potency in the benzodiazepine receptor binding assay. Using on-line HPLC-electrospray-tandem mass spectrometry (HPLC-ESI-MS/MS) in the "selected reaction monitoring" (SRM) mode, delorazepam and temazepam were found in amounts of about 100 to 200 ng/g cell tissue of Artemisia dracunculus, whereas sterile potato herb contained temazepam and diazepam ranging approximately from 70 to 450 ng/g cell tissue. It is the first report on the endogenous formation of benzodiazepines by plant cells, as any interaction of microorganisms and environmental factors was excluded.
Artemisia↗
Naturally occurring benzodiazepines: current status of research and clinical implications.
Naturally occurring benzodiazepines (BZDs) were first detected in mammalian tissues in 1986. They comprise a variety of 1,4-benzodiazepines corresponding to drugs commercially available for the treatment of anxiety disorders, sleep disturbances and epileptic seizures. Several biosynthetic pathways leading to the formation of BZDs are currently being discussed and have led to the proposition of possible precursor molecules. For years, the identification of naturally occurring BZDs in mammalian organisms was mostly confined to post mortem CNS material for sensitivity reasons. While radioimmunoassay and radioreceptor assay techniques have been tentatively applied to quantitations of genuine BZDs from human milk and cerebrospinal fluid, accurate measurements in peripheral blood have only recently become accessible, e. g., by gas chromatography/selected ion monitoring-mass spectrometry (GC/SIM-MS). This review summarizes existing evidence of benzodiazepines' occurrence in nature and discusses implications for neuropsychiatric disorders.
Animals↗
Polymorphic MAO-A and 5-HT-transporter genes: analysis of interactions in panic disorder.
Recurrent panic attacks, anticipatory anxiety and phobic avoidance characterise panic disorder. The influence of genetic factors on liability to the disease has been the object of several linkage and association studies and appears to relate to an oligo- or polygenic rather than a monogenic mode of inheritance. Recently, an excess of high activity monoamine oxidase A (MAO-A) gene promoter alleles was found in female patients with panic disorder. An analysis of possible synergistic effects of the MAO-A gene promoter variant and the short serotonin transporter (5-HTT) gene promoter variant in panic disorder was performed in a German and an Italian sample (combined panic disorder n = 144, combined controls n = 175). There was no significant difference in odds ratios, suggesting that the observed increase of genetic liability by the long MAO-A gene promoter allele is not modified by the 5-HTT gene promoter polymorphism.
Adult↗
Macrocurrents of voltage gated Na+ and K+ channels from the crayfish stretch receptor neuronal soma.
Currents from the slowly adapting stretch receptor neuron of the crayfish (Pacifastacus leniusculus) were studied in a cell attached configuration using patch pipettes with an opening diameter of 2-10 microm. The neuronal membrane was enzymatically freed from the glial layer. The voltage gated Na+ and K+ channels seemed to be more concentrated in the lower part of soma close to the axon hillock. The Na+ and K+ currents could be analysed by fitting the currents to a fourth-order exponential function for Na+ current and a second-order exponential function for the K+ current. The macropatch recordings of enzymatically treated neurons are superior to two electrode voltage clamp recordings when analyzing voltage gated Na+ and K+ currents.
Animals↗
Osteomyelitis of the pubis following suspension of the neck of the bladder with use of bone anchors. A report of four cases.
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Aged↗
Carbachol induces oscillations in membrane potential and intracellular calcium in a colonic tumor cell line, HT-29.
The patch-clamp technique was used to study the effects of carbachol (CCh) on HT-29 cells. During CCh exposure, the cells (n = 23) depolarized close to the equilibrium potential for Cl- (E(Cl-); -48 mV) and the membrane potential then started to oscillate (16/23 cells). In voltage-clamp experiments, similar oscillations in whole cell currents could be demonstrated. The whole cell conductance increased from 225 +/- 25 pS in control solution to 6,728 +/- 1,165 pS (means +/- SE, n = 17). In substitution experiments (22 mM Cl- in bath solution, E(Cl-) = 0 mV), the reversal potential changed from -41.6 +/- 2.2 mV (means +/- SE, n = 9) to -3.2 +/- 2.0 mV (means +/- SE, n = 7). When the cells were loaded with the calcium-sensitive fluorescent dye, fluo 3, and simultaneously patch clamped, CCh caused a synchronous oscillating pattern of fluorescence and membrane potential. In cell-attached patches, the CCh-activated currents reversed at a relative membrane potential of 1.9 +/- 3.7 mV (means +/- SE, n = 11) with control solution in the pipette and at 46.2 +/- 5.3 mV (means +/- SE, n = 10) with a 15 mM Cl- solution in the pipette. High K+ (144 mM) did not change the reversal potential significantly (P < or = 0.05, n = 8). In inside-out patches, calcium-dependent Cl- channels could be demonstrated with a conductance of 19 pS (n = 7). It is concluded that CCh causes oscillations in membrane potential that involve calcium-dependent Cl- channels and a K+ permeability.
Calcium↗
Psychopathological and neuropsychological effects of 8-days' corticosteroid treatment. A prospective study.
Corticosteroids often induce a variety of psychiatric symptoms, such as alterations of mood, neuropsychological deficits and even psychotic states. To date, only a few studies have specifically addressed behaviour as well as cognitive functioning in patients under steroid treatment. Fifty ophthalmologic patients participated in this prospective study. They received methylprednisolone or fluocortolone at doses of 119 +/- 41 mg/day in the beginning and 75 +/- 22 mg after 8 days of treatment. Psychopathology and neuropsychological functioning were examined before and after steroid therapy, mood was self-rated on days 0, 3, 5 and 8. No marked psychopathological abnormalities such as psychosis, dementia or delirious states were observed. However, a significant proportion of patients suffered from an organic mood disorder, 26-34% experienced a hypomanic syndrome, 10-12% a depressive syndrome. Most neuropsychological tests did not reveal significant effects of steroid treatment. Performance of Word Fluency and Trail Making A improved, while the Auditory-Verbal-Learning and the Digit-Symbol showed a worsening. Psychopathological and neuropsychological effects were not significantly correlated.
Administration, Oral↗
Effectiveness of a urinary control insert in the management of stress urinary incontinence: early results of a multicenter study.
OBJECTIVES: The purpose of this study was to test the safety and effectiveness of a urethral insert for managing stress or mixed urinary incontinence. METHODS: We performed a prospective, multicenter study of 135 female patients who were treated for 4 months with the Reliance Urinary Control Insert. The effectiveness of the insert was measured objectively at the time of first use and after 4 months' use by standardized pad weight studies. Insert effectiveness was also measured by reports of symptom improvement during patient interviews and on patient diaries. Urine microscopy and culture were obtained monthly; cystoscopy and urodynamics were conducted at study entry and at 4 months. RESULTS: Significant improvement in involuntary urine loss was observed. Objective measurement of urine loss revealed that 80% of the patients were completely dry, and 95% of the patients achieved greater than an 80% decrease in urine loss. In addition, patients' perceptions of acceptability, incontinence symptom improvement, ease of learning, comfort, and time to habituation also showed improvements. Untoward events reported during the study included hematuria, bacteriuria, and bladder irritation. These events did not require significant medical intervention and did not result in any long-term clinical sequelae. CONCLUSIONS: These preliminary results indicate that the Reliance Urinary Control Insert may be a safe, effective, and well-tolerated alternative to other available methods for the management of stress or mixed incontinence in women. Additional long-term follow-up will be required to substantiate this conclusion.
Adolescent↗
Successful treatment with flupenthixol decanoate of a patient with both schizophrenia and alcoholism.
There is growing evidence that substance abuse is a major problem in patients with schizophrenia. With respect to alcohol, alledegly the most frequently abused drug among schizophrenics, clinical and epidemiological studies would suggest that the risk of alcoholism is approximately four times greater (Cuffel, 1992; Mueser et al., 1990; Soyka et al., 1993; Soyka, 1994). A variety of hypotheses have been proposed to explain this phenomenon, including the so-called "self-medication hypothesis". Some authors feel that substance abuse in schizophrenics might be due to extrapyramidal and other side-effects caused by neuroleptic treatment or inadequate remission of psychotic symptoms. There remains, at present, an obvious lack of both psychosocial and psychopharmacological studies of treatment in "dual diagnosis" schizophrenics (Mueser et al., 1992). Changes in dopaminergic neurotransmission and dopamine-receptor dysfunction have been linked both to the development of psychotic symptoms and to alcoholism/substance abuse, and thus give rise to the question as to whether some dual diagnosis patients might benefit from neuroleptic treatment in both domains. A number of dopamine receptor subtypes in different regions of the brain seems to be involved in the development of schizophrenia and substance abuse. Modifications of D2-receptor subtype function have been implicated in psychotic symptoms, and changes in the D1- and D2-receptor function in substance abuse such as cocaine abuse and alcoholism (Spealman et al., 1990; 1991; 1992), especially in the mesolimbic dopaminergic reward system. Accordingly, the "ideal" neuroleptic drug for dual diagnosis schizophrenics should be effective in both receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗