Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington's Disease Knock-In Mice.

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Neto, João Luís; Lee, Jong-Min; Afridi, Ali; Gillis, Tammy; Guide, Jolene R; Dempsey, Stephani; Lager, Brenda; Alonso, Isabel; Wheeler, Vanessa C; Pinto, Ricardo Mouro

2017-02-01

Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability. Copyright © 2017 by the Genetics Society of America.

Interferon β induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice.

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Chort, Alice; Alves, Sandro; Marinello, Martina; Dufresnois, Béatrice; Dornbierer, Jean-Gabriel; Tesson, Christelle; Latouche, Morwena; Baker, Darren P; Barkats, Martine; El Hachimi, Khalid H; Ruberg, Merle; Janer, Alexandre; Stevanin, Giovanni; Brice, Alexis; Sittler, Annie

2013-06-01

We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival.

Erythroblast differentiation at spleen in Q137E mutant ribosomal protein S19 gene knock-in C57BL/6J mice.

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Yamanegi, Koji; Yamada, Naoko; Nakasho, Keiji; Nishiura, Hiroshi

2018-01-01

We recently found that erythroblast-like cells derived from human leukaemia K562 cells express C5a receptor (C5aR) and produce its antagonistic and agonistic ligand ribosomal protein S19 (RP S19) polymer, which is cross-linked between K122 and Q137 by tissue transglutaminases. RP S19 polymer binds to the reciprocal C5aRs on erythroblast-like cells and macrophage-like cells derived from human monocytic THP-1 cells and promotes differentiation into reticulocyte-like cells through enucleation in vitro. To examine the roles of RP S19 polymer in mouse erythropoiesis, we prepared Q137E mutant RP S19 gene knock-in C57BL/6J mice. In contrast to wild-type mice, erythroblast numbers at the preliminary stage (CD71 high /TER119 low ) in spleen based on transferrin receptor (CD71) and glycophorin A (TER119) values and erythrocyte numbers in orbital artery bloods were not largely changed in knock-in mice. Conversely, erythroblast numbers at the early stage (CD71 high /TER119 high ) were significantly decreased in spleen by knock-in mice. The reduction of early erythroblast numbers in spleen was enhanced by the phenylhydrazine-induced pernicious anemia model knock-in mice and was rescued by a functional analogue of RP S19 dimer S-tagged C5a/RP S19. These data indicated that RP S19 polymer plays the roles in the early erythroblast differentiation of C57BL/6J mouse spleen. Copyright © 2017 Elsevier GmbH. All rights reserved.

Generation of Knock-in Mouse by Genome Editing.

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Fujii, Wataru

2017-01-01

Knock-in mice are useful for evaluating endogenous gene expressions and functions in vivo. Instead of the conventional gene-targeting method using embryonic stem cells, an exogenous DNA sequence can be inserted into the target locus in the zygote using genome editing technology. In this chapter, I describe the generation of epitope-tagged mice using engineered endonuclease and single-stranded oligodeoxynucleotide through the mouse zygote as an example of how to generate a knock-in mouse by genome editing.

Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations.

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Ihara, Yukiko; Tomonoh, Yuko; Deshimaru, Masanobu; Zhang, Bo; Uchida, Taku; Ishii, Atsushi; Hirose, Shinichi

2016-01-01

The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+) bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT) littermates, at 63-100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg) were recorded using a video-electroencephalography (EEG) monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine's scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations.

Reduced hypoxic ventilatory response in newborn mice knocked-out for the progesterone receptor.

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Potvin, Catherine; Rossignol, Orlane; Uppari, NagaPraveena; Dallongeville, Arnaud; Bairam, Aida; Joseph, Vincent

2014-11-01

Recent studies showed that progesterone stimulates the hypoxic ventilatory response and may reduce apnoea frequency in newborn rats, but so far we still do not know by what mechanisms and whether endogenous progesterone might contribute to respiratory control in neonates. We therefore determined the role of the nuclear progesterone receptor (PR; member of the steroid receptor superfamily) by using wild-type (WT) and PR knock-out (PRKO) mice at postnatal days (P) 1, 4 and 10. We measured the hypoxic ventilatory response (14 and 12% O2, 20 min each) and apnoea frequency in both male and female mice by using whole-body plethysmography. In response to hypoxia, WT male mice had a marked hypoxic ventilatory response at P1 and P10, but not at P4. At P1 and P10, PRKO male mice had a lower hypoxic ventilatory response than WT males. Wild-type female mice had a marked hypoxic ventilatory response at P10, but not at P1 and P4. At P1 and P10, PRKO female mice had a lower hypoxic ventilatory response than WT females. In basal conditions, apnoea frequency was similar in WT and PRKO mice at P1, P4 and P10. During hypoxia, apnoea frequency was higher in WT male mice compared with PRKO male mice and WT female mice at P1. We conclude that PR is a key contributor to the hypoxic ventilatory response in newborn mice, but PR deletion does not increase the frequency of apnoea during normoxia or hypoxia. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

Lethal Zika Virus Disease Models in Young and Older Interferon α/β Receptor Knock Out Mice

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Andrea Marzi

2018-04-01

Full Text Available The common small animal disease models for Zika virus (ZIKV are mice lacking the interferon responses, but infection of interferon receptor α/β knock out (IFNAR−/− mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR−/− mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV-Paraiba by different routes established a uniformly lethal model only in young mice (4-week old upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR−/− mice (10–12-weeks old. In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage.

Effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and on atherogenesis in apolipoprotein E knock-out mice

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Portugal L.R.

2006-01-01

Full Text Available Elevated blood cholesterol is an important risk factor associated with atherosclerosis and coronary heart disease. Several studies have reported a decrease in serum cholesterol during the consumption of large doses of fermented dairy products or lactobacillus strains. The proposed mechanism for this effect is the removal or assimilation of intestinal cholesterol by the bacteria, reducing cholesterol absorption. Although this effect was demonstrated in vitro, its relevance in vivo is still controversial. Furthermore, few studies have investigated the role of lactobacilli in atherogenesis. The aim of the present study was to determine the effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and the possible hypocholesterolemic and antiatherogenic action of these bacteria using atherosclerosis-prone apolipoprotein E (apo E knock-out (KO mice. For this purpose, Swiss/NIH germ-free mice were monoassociated with L. delbrueckii and fed a hypercholesterolemic diet for four weeks. In addition, apo E KO mice were fed a normal chow diet and treated with L. delbrueckii for 6 weeks. There was a reduction in cholesterol excretion in germ-free mice, which was not associated with changes in blood or liver cholesterol concentration. In apo E KO mice, no effect of L. delbrueckii was detected in blood, liver or fecal cholesterol. The atherosclerotic lesion in the aorta was also similar in mice receiving or not these bacteria. In conclusion, these results suggest that, although L. delbrueckii treatment was able to reduce cholesterol excretion in germ-free mice, no hypocholesterolemic or antiatherogenic effect was observed in apo E KO mice.

Exacerbation of spontaneous autoimmune nephritis following regulatory T cell depletion in B cell lymphoma 2-interacting mediator knock-out mice.

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Wang, Y M; Zhang, G Y; Wang, Y; Hu, M; Zhou, J J; Sawyer, A; Cao, Q; Wang, Y; Zheng, G; Lee, V W S; Harris, D C H; Alexander, S I

2017-05-01

Regulatory T cells (T regs ) have been recognized as central mediators for maintaining peripheral tolerance and limiting autoimmune diseases. The loss of T regs or their function has been associated with exacerbation of autoimmune disease. However, the temporary loss of T regs in the chronic spontaneous disease model has not been investigated. In this study, we evaluated the role of T regs in a novel chronic spontaneous glomerulonephritis model of B cell lymphoma 2-interacting mediator (Bim) knock-out mice by transient depleting T regs . Bim is a pro-apoptotic member of the B cell lymphoma 2 (Bcl-2) family. Bim knock-out (Bim -/- ) mice fail to delete autoreactive T cells in thymus, leading to chronic spontaneous autoimmune kidney disease. We found that T reg depletion in Bim -/- mice exacerbated the kidney injury with increased proteinuria, impaired kidney function, weight loss and greater histological injury compared with wild-type mice. There was a significant increase in interstitial infiltrate of inflammatory cells, antibody deposition and tubular damage. Furthermore, the serum levels of cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17α, interferon (IFN)-γ and tumour necrosis factor (TNF)-α were increased significantly after T reg depletion in Bim -/- mice. This study demonstrates that transient depletion of T regs leads to enhanced self-reactive T effector cell function followed by exacerbation of kidney disease in the chronic spontaneous kidney disease model of Bim-deficient mice. © 2017 British Society for Immunology.

Anti-human tissue factor antibody ameliorated intestinal ischemia reperfusion-induced acute lung injury in human tissue factor knock-in mice.

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Xiaolin He

Full Text Available BACKGROUND: Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS. Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: Human tissue factor knock-in (hTF-KI transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859 were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro-coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v. attenuated the severity of lung tissue injury, decreased the total cell counts and protein concentration in bronchoalveolar lavage fluid, and reduced Evans blue leakage. In addition, the treatment significantly reduced alveolar fibrin deposition, and decreased tissue factor and plasminogen activator inhibitor-1 activity in the serum. This treatment also down-regulated cytokine expression and reduced cell death in the lung. CONCLUSIONS: This novel anti-hTF antibody showed beneficial effects on intestinal ischemia-reperfusion induced acute lung injury, which merits further investigation for clinical usage. In addition, the use of knock-in transgenic mice to test the efficacy of antibodies against human-specific proteins is a novel strategy for preclinical studies.

Effects of short-term Western diet on cerebral oxidative stress and diabetes related factors in APP x PS1 knock-in mice.

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Studzinski, Christa M; Li, Feng; Bruce-Keller, Annadora J; Fernandez-Kim, Sun Ok; Zhang, Le; Weidner, Adam M; Markesbery, William R; Murphy, M Paul; Keller, Jeffrey N

2009-02-01

A chronic high fat Western diet (WD) promotes a variety of morbidity factors although experimental evidence for short-term WD mediating brain dysfunction remains to be elucidated. The amyloid precursor protein and presenilin-1 (APP x PS1) knock-in mouse model has been demonstrated to recapitulate some key features of Alzheimer's disease pathology, including amyloid-beta (Abeta) pathogenesis. In this study, we placed 1-month-old APP x PS1 mice and non-transgenic littermates on a WD for 4 weeks. The WD resulted in a significant elevation in protein oxidation and lipid peroxidation in the brain of APP x PS1 mice relative to non-transgenic littermates, which occurred in the absence of increased Abeta levels. Altered adipokine levels were also observed in APP x PS1 mice placed on a short-term WD, relative to non-transgenic littermates. Taken together, these data indicate that short-term WD is sufficient to selectively promote cerebral oxidative stress and metabolic disturbances in APP x PS1 knock-in mice, with increased oxidative stress preceding alterations in Abeta. These data have important implications for understanding how WD may potentially contribute to brain dysfunction and the development of neurodegenerative disorders such as Alzheimer's disease.

A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8.

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Bouhy, Delphine; Juneja, Manisha; Katona, Istvan; Holmgren, Anne; Asselbergh, Bob; De Winter, Vicky; Hochepied, Tino; Goossens, Steven; Haigh, Jody J; Libert, Claude; Ceuterick-de Groote, Chantal; Irobi, Joy; Weis, Joachim; Timmerman, Vincent

2018-01-01

Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot-Marie-Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and muscular phenotypes and if a common pathogenesis lies behind these diseases. Growing evidence points towards a role of HSPB8 in chaperone-associated autophagy, which has been shown to be a determinant for the clearance of poly-glutamine aggregates in neurodegenerative diseases but also for the maintenance of skeletal muscle myofibrils. To test this hypothesis and better dissect the pathomechanism of mutant HSPB8, we generated a new transgenic mouse model leading to the expression of the mutant protein (knock-in lines) or the loss-of-function (functional knock-out lines) of the endogenous protein Hspb8. While the homozygous knock-in mice developed motor deficits associated with degeneration of peripheral nerves and severe muscle atrophy corroborating patient data, homozygous knock-out mice had locomotor performances equivalent to those of wild-type animals. The distal skeletal muscles of the post-symptomatic homozygous knock-in displayed Z-disk disorganisation, granulofilamentous material accumulation along with Hspb8, αB-crystallin (HSPB5/CRYAB), and desmin aggregates. The presence of the aggregates correlated with reduced markers of effective autophagy. The sciatic nerve of the homozygous knock-in mice was characterized by low autophagy potential in pre-symptomatic and Hspb8 aggregates in post-symptomatic animals. On the other hand, the sciatic nerve of the homozygous knock-out mice presented a normal morphology and their distal muscle displayed accumulation of abnormal mitochondria but intact myofiber and Z-line organisation. Our data, therefore, suggest that toxic gain-of-function of mutant Hspb8 aggregates is a major contributor to the peripheral neuropathy and the myopathy. In addition, mutant Hspb8 induces

Contribution of PPARγ in modulation of acrolein-induced inflammatory signaling in gp91phox knock-out mice.

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Yousefipour, Zivar; Chug, Neha; Marek, Katarzyna; Nesbary, Alicia; Mathew, Joseph; Ranganna, Kasturi; Newaz, Mohammad A

2017-08-01

Oxidative stress and inflammation are major contributors to acrolein toxicity. Peroxisome proliferator activated receptor gamma (PPARγ) has antioxidant and anti-inflammatory effects. We investigated the contribution of PPARγ ligand GW1929 to the attenuation of oxidative stress in acrolein-induced insult. Male gp91 phox knock-out (KO) mice were treated with acrolein (0.5 mg·(kg body mass) -1 by intraperitoneal injection for 7 days) with or without GW1929 (GW; 0.5 mg·(kg body mass) -1 ·day -1 , orally, for 10 days). The livers were processed for further analyses. Acrolein significantly increased 8-isoprostane and reduced PPARγ activity (P acrolein-treated WT mice, and was reduced by GW1929 (by 65%). KO mice exhibited higher xanthine oxidase (XO). Acrolein increased XO and COX in WT mice and XO in KO mice. GW1929 significantly reduced COX in WT and KO mice and reduced XO in KO mice. Acrolein significantly reduced the total antioxidant status in WT and KO mice (P acrolein-treated WT mice. GW1929 reduced NF-κB levels (by 51%) in KO mice. Acrolein increased CD36 in KO mice (by 43%), which was blunted with GW1929. Data confirms that the generation of free radicals by acrolein is mainly through NAD(P)H, but other oxygenates play a role too. GW1929 may alleviate the toxicity of acrolein by attenuating NF-κB, COX, and CD36.

Lentivirus-ABCG1 instillation reduces lipid accumulation and improves lung compliance in GM-CSF knock-out mice

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Malur, Anagha; Huizar, Isham; Wells, Greg; Barna, Barbara P.; Malur, Achut G.; Thomassen, Mary Jane

2011-01-01

Highlights: ► Lentivirus-ABCG1 reduces lipid accumulation in lungs of GM-CSF knock-out mice. ► Up-regulation of ABCG1 improves lung function. ► Upregulation of ABCG1 improves surfactant metabolism. -- Abstract: We have shown decreased expression of the nuclear transcription factor, peroxisome proliferator-activated receptor-gamma (PPARγ) and the PPARγ-regulated ATP-binding cassette transporter G1 (ABCG1) in alveolar macrophages from patients with pulmonary alveolar proteinosis (PAP). PAP patients also exhibit neutralizing antibodies to granulocyte–macrophage colony stimulating factor (GM-CSF), an upregulator of PPARγ. In association with functional GM-CSF deficiency, PAP lung is characterized by surfactant-filled alveolar spaces and lipid-filled alveolar macrophages. Similar pathology characterizes GM-CSF knock-out (KO) mice. We reported previously that intratracheal instillation of a lentivirus (lenti)-PPARγ plasmid into GM-CSF KO animals elevated ABCG1 and reduced alveolar macrophage lipid accumulation. Here, we hypothesized that instillation of lenti-ABCG1 might be sufficient to decrease lipid accumulation and improve pulmonary function in GM-CSF KO mice. Animals received intratracheal instillation of lenti-ABCG1 or control lenti-enhanced Green Fluorescent Protein (eGFP) plasmids and alveolar macrophages were harvested 10 days later. Alveolar macrophage transduction efficiency was 79% as shown by lenti-eGFP fluorescence. Quantitative PCR analyses indicated a threefold (p = 0.0005) increase in ABCG1 expression with no change of PPARγ or ABCA1 in alveolar macrophages of lenti-ABCG1 treated mice. ABCG1 was unchanged in control lenti-eGFP and PBS-instilled groups. Oil Red O staining detected reduced intracellular neutral lipid in alveolar macrophages from lenti-ABCG1 treated mice. Extracellular cholesterol and phospholipids were also decreased as shown by analysis of bronchoalveolar lavage fluid. Lung compliance was diminished in untreated GMCSF KO mice

Generation of CRISPR/Cas9-mediated bicistronic knock-in ins1-cre driver mice.

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Hasegawa, Yoshikazu; Hoshino, Yoshikazu; Ibrahim, Abdelaziz E; Kato, Kanako; Daitoku, Yoko; Tanimoto, Yoko; Ikeda, Yoshihisa; Oishi, Hisashi; Takahashi, Satoru; Yoshiki, Atsushi; Yagami, Ken-Ichi; Iseki, Hiroyoshi; Mizuno, Seiya; Sugiyama, Fumihiro

2016-07-29

In the present study, we generated novel cre driver mice for gene manipulation in pancreatic β cells. Using the CRISPR/Cas9 system, stop codon sequences of Ins1 were targeted for insertion of cre, including 2A sequences. A founder of C57BL/6J-Ins1(em1 (cre) Utr) strain was produced from an oocyte injected with pX330 containing the sequences encoding gRNA and Cas9 and a DNA donor plasmid carrying 2A-cre. (R26GRR x C57BL/6J-Ins1(em1 (cre) Utr)) F1 mice were histologically characterized for cre-loxP recombination in the embryonic and adult stages; cre-loxP recombination was observed in all pancreatic islets examined in which almost all insulin-positive cells showed tdsRed fluorescence, suggesting β cell-specific recombination. Furthermore, there were no significant differences in results of glucose tolerance test among genotypes (homo/hetero/wild). Taken together, these observations indicated that C57BL/6J-Ins1(em1 (cre) Utr) is useful for studies of glucose metabolism and the strategy of bicistronic cre knock-in using the CRISPR/Cas9 system could be useful for production of cre driver mice.

The kick-in system: a novel rapid knock-in strategy.

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Tomonoh, Yuko; Deshimaru, Masanobu; Araki, Kimi; Miyazaki, Yasuhiro; Arasaki, Tomoko; Tanaka, Yasuyoshi; Kitamura, Haruna; Mori, Fumiaki; Wakabayashi, Koichi; Yamashita, Sayaka; Saito, Ryo; Itoh, Masayuki; Uchida, Taku; Yamada, Junko; Migita, Keisuke; Ueno, Shinya; Kitaura, Hiroki; Kakita, Akiyoshi; Lossin, Christoph; Takano, Yukio; Hirose, Shinichi

2014-01-01

Knock-in mouse models have contributed tremendously to our understanding of human disorders. However, generation of knock-in animals requires a significant investment of time and effort. We addressed this problem by developing a novel knock-in system that circumvents several traditional challenges by establishing stem cells with acceptor elements enveloping a particular genomic target. Once established, these acceptor embryonic stem (ES) cells are efficient at directionally incorporating mutated target DNA using modified Cre/lox technology. This is advantageous, because knock-ins are not restricted to one a priori selected variation. Rather, it is possible to generate several mutant animal lines harboring desired alterations in the targeted area. Acceptor ES cell generation is the rate-limiting step, lasting approximately 2 months. Subsequent manipulations toward animal production require an additional 8 weeks, but this delimits the full period from conception of the genetic alteration to its animal incorporation. We call this system a "kick-in" to emphasize its unique characteristics of speed and convenience. To demonstrate the functionality of the kick-in methodology, we generated two mouse lines with separate mutant versions of the voltage-dependent potassium channel Kv7.2 (Kcnq2): p.Tyr284Cys (Y284C) and p.Ala306Thr (A306T); both variations have been associated with benign familial neonatal epilepsy. Adult mice homozygous for Y284C, heretofore unexamined in animals, presented with spontaneous seizures, whereas A306T homozygotes died early. Heterozygous mice of both lines showed increased sensitivity to pentylenetetrazole, possibly due to a reduction in M-current in CA1 hippocampal pyramidal neurons. Our observations for the A306T animals match those obtained with traditional knock-in technology, demonstrating that the kick-in system can readily generate mice bearing various mutations, making it a suitable feeder technology toward streamlined phenotyping.

An anticholinergic reverses motor control and corticostriatal LTD deficits in Dyt1 ΔGAG knock-in mice

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Dang, Mai T.; Yokoi, Fumiaki; Cheetham, Chad C.; Lu, Jun; Vo, Viet; Lovinger, David M.; Li, Yuqing

2011-01-01

DYT1 early-onset generalized torsion dystonia is an inherited movement disorder associated with mutations in DYT1 that codes for torsinA protein. The most common mutation seen in this gene is a trinucleotide deletion of GAG. We previously reported a motor control deficit on a beam-walking task in our Dyt1 ΔGAG knock-in heterozygous mice. In this report we show the reversal of this motor deficit with the anticholinergic trihexyphenidyl (THP), a drug commonly used to treat movement problems in ...

Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice.

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Noah Saederup

2010-10-01

Full Text Available Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents.We created CCR2-red fluorescent protein (RFP knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6C(hi/CCR2(hi monocytes. Surprisingly, neutrophils, not Ly6C(lo monocytes, largely replaced Ly6C(hi cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia.These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations.

Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice.

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Nakata, Daisuke; Masaki, Tsuneo; Tanaka, Akira; Yoshimatsu, Mie; Akinaga, Yumiko; Asada, Mari; Sasada, Reiko; Takeyama, Michiyasu; Miwa, Kazuhiro; Watanabe, Tatsuya; Kusaka, Masami

2014-01-15

TAK-385 (relugolix) is a novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist, which builds on previous work with non-peptide GnRH antagonist TAK-013. TAK-385 possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared with TAK-013. Both TAK-385 and TAK-013 have low affinity for the rat GnRH receptor, making them difficult to evaluate in rodent models. Here we report the human GnRH receptor knock-in mouse as a humanized model to investigate pharmacological properties of these compounds on gonadal function. Twice-daily oral administration of TAK-013 (10mg/kg) for 4 weeks decreased the weights of testes and ventral prostate in male knock-in mice but not in male wild-type mice, demonstrating the validity of this model to evaluate antagonists for the human GnRH receptor. The same dose of TAK-385 also reduced the prostate weight to castrate levels in male knock-in mice. In female knock-in mice, twice-daily oral administration of TAK-385 (100mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomized levels and downregulated GnRH receptor mRNA in the pituitary after 4 weeks. Gonadal function of TAK-385-treated knock-in mice began to recover after 5 days and almost completely recovered within 14 days after drug withdrawal in both sexes. Our findings demonstrate that TAK-385 acts as an antagonist for human GnRH receptor in vivo and daily oral administration potently, continuously and reversibly suppresses the hypothalamic-pituitary-gonadal axis. TAK-385 may provide useful therapeutic interventions in hormone-dependent diseases including endometriosis, uterine fibroids and prostate cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

Lentivirus-ABCG1 instillation reduces lipid accumulation and improves lung compliance in GM-CSF knock-out mice

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Malur, Anagha; Huizar, Isham [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Wells, Greg [Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States); Barna, Barbara P. [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Malur, Achut G. [Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States); Thomassen, Mary Jane, E-mail: thomassenm@ecu.edu [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States)

2011-11-18

Highlights: Black-Right-Pointing-Pointer Lentivirus-ABCG1 reduces lipid accumulation in lungs of GM-CSF knock-out mice. Black-Right-Pointing-Pointer Up-regulation of ABCG1 improves lung function. Black-Right-Pointing-Pointer Upregulation of ABCG1 improves surfactant metabolism. -- Abstract: We have shown decreased expression of the nuclear transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) and the PPAR{gamma}-regulated ATP-binding cassette transporter G1 (ABCG1) in alveolar macrophages from patients with pulmonary alveolar proteinosis (PAP). PAP patients also exhibit neutralizing antibodies to granulocyte-macrophage colony stimulating factor (GM-CSF), an upregulator of PPAR{gamma}. In association with functional GM-CSF deficiency, PAP lung is characterized by surfactant-filled alveolar spaces and lipid-filled alveolar macrophages. Similar pathology characterizes GM-CSF knock-out (KO) mice. We reported previously that intratracheal instillation of a lentivirus (lenti)-PPAR{gamma} plasmid into GM-CSF KO animals elevated ABCG1 and reduced alveolar macrophage lipid accumulation. Here, we hypothesized that instillation of lenti-ABCG1 might be sufficient to decrease lipid accumulation and improve pulmonary function in GM-CSF KO mice. Animals received intratracheal instillation of lenti-ABCG1 or control lenti-enhanced Green Fluorescent Protein (eGFP) plasmids and alveolar macrophages were harvested 10 days later. Alveolar macrophage transduction efficiency was 79% as shown by lenti-eGFP fluorescence. Quantitative PCR analyses indicated a threefold (p = 0.0005) increase in ABCG1 expression with no change of PPAR{gamma} or ABCA1 in alveolar macrophages of lenti-ABCG1 treated mice. ABCG1 was unchanged in control lenti-eGFP and PBS-instilled groups. Oil Red O staining detected reduced intracellular neutral lipid in alveolar macrophages from lenti-ABCG1 treated mice. Extracellular cholesterol and phospholipids were also decreased as shown by

Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice.

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Silvia Fre

Full Text Available The conserved role of Notch signaling in controlling intestinal cell fate specification and homeostasis has been extensively studied. Nevertheless, the precise identity of the cells in which Notch signaling is active and the role of different Notch receptor paralogues in the intestine remain ambiguous, due to the lack of reliable tools to investigate Notch expression and function in vivo. We generated a new series of transgenic mice that allowed us, by lineage analysis, to formally prove that Notch1 and Notch2 are specifically expressed in crypt stem cells. In addition, a novel Notch reporter mouse, Hes1-EmGFP(SAT, demonstrated exclusive Notch activity in crypt stem cells and absorptive progenitors. This roster of knock-in and reporter mice represents a valuable resource to functionally explore the Notch pathway in vivo in virtually all tissues.

A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice.

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Sabine M Hölter

Full Text Available Huntington's disease (HD is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

An anticholinergic reverses motor control and corticostriatal LTD deficits in Dyt1 ΔGAG knock-in mice.

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Dang, Mai T; Yokoi, Fumiaki; Cheetham, Chad C; Lu, Jun; Vo, Viet; Lovinger, David M; Li, Yuqing

2012-01-15

DYT1 early-onset generalized torsion dystonia is an inherited movement disorder associated with mutations in DYT1 that codes for torsinA protein. The most common mutation seen in this gene is a trinucleotide deletion of GAG. We previously reported a motor control deficit on a beam-walking task in our Dyt1 ΔGAG knock-in heterozygous mice. In this report we show the reversal of this motor deficit with the anticholinergic trihexyphenidyl (THP), a drug commonly used to treat movement problems in dystonia patients. THP also restored the reduced corticostriatal long-term depression (LTD) observed in these mice. Corticostriatal LTD has long been known to be dependent on D2 receptor activation. In this mouse model, striatal D2 receptors were expressed at lower quantities in comparison to wild-type mice. Furthermore, the mice were also partially resistant to FPL64176, an agonist of L-type calcium channels that have been previously reported to cause severe dystonic-like symptoms in wild-type mice. Our findings collectively suggest that altered communication between cholinergic interneurons and medium spiny neurons is responsible for the LTD deficit and that this synaptic plasticity modification may be involved in the striatal motor control abnormalities in our mouse model of DYT1 dystonia. Copyright © 2011 Elsevier B.V. All rights reserved.

Role of interferon-gamma in the pathogenesis of LCMV-induced meningitis: unimpaired leucocyte recruitment, but deficient macrophage activation in interferon-gamma knock-out mice

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Nansen, A; Christensen, Jan Pravsgaard; Röpke, C

1998-01-01

, a viral peptide could also elicit a T cell mediated inflammatory response in virus-primed IFN-gamma knock-out mice, indicating that redundancy of this cytokine as a proinflammatory mediator is not restricted to inflammatory reactions triggered by an active infection. Thus, T cell mediated inflammation may...

Knocking out or pharmaceutical inhibition of fatty acid binding protein 4 (FABP4) alleviates osteoarthritis induced by high-fat diet in mice.

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Zhang, C; Chiu, K Y; Chan, B P M; Li, T; Wen, C; Xu, A; Yan, C H

2018-06-01

Adipokines play roles in the pathogenesis of osteoarthritis (OA). Fatty acid binding protein 4 (FABP4) is a novel adipokine that is closely associated with obesity and metabolic diseases. The aim of this study was to discover the potential role of FABP4 in OA. Seventy-two FABP4 knockout mice (KO) in C57BL/6N background and wild-type littermates (WT) (male, 6-week-old) were fed with a high-fat diet (HFD, 60% calorie) or standard diet (STD, 11.6% calorie) for 3 months, 6 months and 9 months (n = 6 each). In the parallel study, forty-eight 6-week-old male WT mice were fed with HFD or STD, and simultaneously treated with daily oral gavage of selective FABP4 inhibitor BMS309403 (15 mg/kg/d) or vehicle for 4 months and 6 months (n = 6 each). Serum FABP4 and cartilage oligomeric matrix protein (COMP) concentration was quantified. Histological assessment of knee OA and micro-CT analysis of subchondral bone were performed. HFD induced obesity in mice. After 3 months and 6 months of HFD, KO mice showed alleviated cartilage degradation and synovitis, with significantly lower COMP, modified Mankin OA score, and MMP-13/ADAMTS4 expression. After 6 months and 9 months of HFD, KO mice showed less osteophyte formation and subchondral bone sclerosis. Chronic treatment of BMS309403 for 4 months and 6 months significantly alleviated cartilage degradation, but had no effects on the subchondral bone. Knocking out or pharmaceutical inhibition of FABP4 did not have significant effects on lean mice fed with STD. Knocking out or pharmaceutical inhibition of FABP4 alleviates OA induced by HFD in mice. Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Role of blood ribosomal protein S19 in coagulum resorption: a study using Gln137Glu-ribosomal protein S19 gene knock-in mouse.

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Chen, Jun; Fujino, Rika; Zhao, Rui; Semba, Umeko; Araki, Kimi; Yamamoto, Tetsuro

2014-11-01

Sera of human, guinea pig or mouse contain a strong monocyte chemoattractant capacity that is attributed to the ribosomal protein S19 (RP S19) oligomers generated during blood coagulation. In contrast, sera prepared from Gln137Glu-RP S19 gene knock-in mice contained negligible chemoattractant capacity. When coagula that had been pre-formed from the blood of both the wild type and knock-in mice were intraperitoneally inserted into host mice, after 3 days of recovery, the knock-in mouse coagula remained larger than the wild type mouse coagula. The wild type mouse coagula were covered by multiple macrophage layers at the surface and were infiltrated inside by macrophages. Knock-in mouse coagula exhibited less macrophage involvement. When coagula of knock-in mice and coagula of knock-in mice containing C5a/RP S19, an artificial substitute of the RP S19 oligomers, were intraperitoneally inserted as pairs, the C5a/RP S19 containing coagulum was more rapidly absorbed, concomitant with increased macrophage involvement. Finally, when the knock-in mouse and wild type mouse coagula pairs were inserted into mice in which macrophages had been depleted using clodronate liposome, the size difference of recovered coagula was reversed. These results indicate the importance of the RP S19 oligomer-induced macrophage recruitment in coagulum resorption. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH).

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Dong, Bingzi; Endo, Itsuro; Ohnishi, Yukiyo; Kondo, Takeshi; Hasegawa, Tomoka; Amizuka, Norio; Kiyonari, Hiroshi; Shioi, Go; Abe, Masahiro; Fukumoto, Seiji; Matsumoto, Toshio

2015-11-01

Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a

Motor and memory testing of long-lived pregnancy-associated plasma protein--a knock-out mice.

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Mason, Emily J; Grell, Jacquelyn A; West, Sally A; Conover, Cheryl A

2014-12-01

Mice deficient in pregnancy-associated plasma protein-A (PAPP-A), an IGF binding protein protease, have been shown to be resistant to experimentally induced atherosclerosis and diabetic nephropathy, and, in the laboratory environment, live 30-40% longer than wild-type littermates in association with delayed incidence and occurrence of age-related neoplasms and degenerative diseases. PAPP-A is highly expressed in the cerebellum and hippocampus of the mouse brain. Therefore, the studies presented here were aimed at determining motor behavior, learning and retention in PAPP-A knock-out (KO) mice compared to wild-type (WT) littermates with age. Balance and coordination were assessed using an accelerating rotarod; learning and memory were assessed in a Stone T-maze. Time on the rotarod decreased with age but there was no significant difference between PAPP-A KO and WT mice at any of the testing ages. Latency to reach the goal box and number of errors committed in the Stone T-maze did not change with age and there were no significant differences between PAPP-A KO and WT mice. Lack of PAPP-A in mice did not impact central regulation of coordination, learning or memory. Copyright © 2014 Elsevier Ltd. All rights reserved.

The validity of knock-for-knock clauses in comparative perspective

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Cavaleri, Sylvie Cécile

This article discusses the validity of so-called knock-for-knock clauses, by which parties to offshore oil and gas or maritime contracts agree that each of them will cover its own losses regardless of who caused them. The issue of validity of such clauses and of the liability exclusions they cont......This article discusses the validity of so-called knock-for-knock clauses, by which parties to offshore oil and gas or maritime contracts agree that each of them will cover its own losses regardless of who caused them. The issue of validity of such clauses and of the liability exclusions...... criteria used to promote or dismiss knock-for-knock clauses in case law and academic literature, the article reaches the conclusion that the question of whether knock-for-knock clauses should be held valid depends on whose interests are being considered, and that further research is warranted...

FAT10 knock out mice livers fail to develop Mallory-Denk bodies in the DDC mouse model.

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French, S W; French, B A; Oliva, J; Li, J; Bardag-Gorce, F; Tillman, B; Canaan, A

2012-12-01

Mallory-Denk bodies (MDBs) are aggresomes composed of undigested ubiqutinated short lived proteins which have accumulated because of a decrease in the rate of their degradation by the 26s proteasome. The decrease in the activity of the proteasome is due to a shift in the activity of the 26s proteasome to the immunoproteasome triggered by an increase in expression of the catalytic subunits of the immunoproteasome which replaces the catalytic subunits of the 26s proteasome. This switch in the type of proteasome in liver cells is triggered by the binding of IFNγ to the IFNγ sequence response element (ISRE) located on the FAT10 promoter. To determine if either FAT10 or IFNγ are essential for the formation of MDBs we fed both IFNγ and FAT10 knock out (KO) mice DDC added to the control diet for 10weeks in order to induce MDBs. Mice fed the control diet and Wild type mice fed the DDC or control diet were compared. MDBs were located by immunofluorescent double stains using antibodies to ubiquitin to stain MDBs and FAT10 to localize the increased expression of FAT10 in MDB forming hepatocytes. We found that MDB formation occurred in the IFNγ KO mice but not in the FAT10 KO mice. Western blots showed an increase in the ubiquitin smears and decreases β 5 (chymotrypsin-like 26S proteasome subunit) in the Wild type mice fed DDC but not in the FAT10 KO mice fed DDC. To conclude, we have demonstrated that FAT10 is essential to the induction of MDB formation in the DDC fed mice. Copyright © 2012 Elsevier Inc. All rights reserved.

Antibodies directed against monomorphic and evolutionary conserved self epitopes may be generated in 'knock-out' mice. Development of monoclonal antibodies directed against monomorphic MHC class I determinants

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Claesson, M H; Endel, B; Ulrik, J

1994-01-01

Beta-2 microglobulin (beta 2m) gene 'knock-out' mice (C1D) were primed with purified H-2Kb and H-2Db molecules and spleen cells from immunized mice were used to generate monoclonal antibody secreting B-cell hybridomas. Approximately 0.2% of the Ig-secreting primary microcultures contained H-2b...

Hyperfunction of muscarinic receptor maintains long-term memory in 5-HT4 receptor knock-out mice.

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Luis Segu

Full Text Available Patients suffering from dementia of Alzheimer's type express less serotonin 4 receptors (5-HTR(4, but whether an absence of these receptors modifies learning and memory is unexplored. In the spatial version of the Morris water maze, we show that 5-HTR(4 knock-out (KO and wild-type (WT mice performed similarly for spatial learning, short- and long-term retention. Since 5-HTR(4 control mnesic abilities, we tested whether cholinergic system had circumvented the absence of 5-HTR(4. Inactivating muscarinic receptor with scopolamine, at an ineffective dose (0.8 mg/kg to alter memory in WT mice, decreased long-term but not short-term memory of 5-HTR(4 KO mice. Other changes included decreases in the activity of choline acetyltransferase (ChAT, the required enzyme for acetylcholine synthesis, in the septum and the dorsal hippocampus in 5-HTR(4 KO under baseline conditions. Training- and scopolamine-induced increase and decrease, respectively in ChAT activity in the septum in WT mice were not detected in the 5-HTR(4 KO animals. Findings suggest that adaptive changes in cholinergic systems may circumvent the absence of 5-HTR(4 to maintain long-term memory under baseline conditions. In contrast, despite adaptive mechanisms, the absence of 5-HTR(4 aggravates scopolamine-induced memory impairments. The mechanisms whereby 5-HTR(4 mediate a tonic influence on ChAT activity and muscarinic receptors remain to be determined.

Synaptic function is modulated by LRRK2 and glutamate release is increased in cortical neurons of G2019S LRRK2 knock-in mice.

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Beccano-Kelly, Dayne A; Kuhlmann, Naila; Tatarnikov, Igor; Volta, Mattia; Munsie, Lise N; Chou, Patrick; Cao, Li-Ping; Han, Heather; Tapia, Lucia; Farrer, Matthew J; Milnerwood, Austen J

2014-01-01

Mutations in Leucine-Rich Repeat Kinase-2 (LRRK2) result in familial Parkinson's disease and the G2019S mutation alone accounts for up to 30% in some ethnicities. Despite this, the function of LRRK2 is largely undetermined although evidence suggests roles in phosphorylation, protein interactions, autophagy and endocytosis. Emerging reports link loss of LRRK2 to altered synaptic transmission, but the effects of the G2019S mutation upon synaptic release in mammalian neurons are unknown. To assess wild type and mutant LRRK2 in established neuronal networks, we conducted immunocytochemical, electrophysiological and biochemical characterization of >3 week old cortical cultures of LRRK2 knock-out, wild-type overexpressing and G2019S knock-in mice. Synaptic release and synapse numbers were grossly normal in LRRK2 knock-out cells, but discretely reduced glutamatergic activity and reduced synaptic protein levels were observed. Conversely, synapse density was modestly but significantly increased in wild-type LRRK2 overexpressing cultures although event frequency was not. In knock-in cultures, glutamate release was markedly elevated, in the absence of any change to synapse density, indicating that physiological levels of G2019S LRRK2 elevate probability of release. Several pre-synaptic regulatory proteins shown by others to interact with LRRK2 were expressed at normal levels in knock-in cultures; however, synapsin 1 phosphorylation was significantly reduced. Thus, perturbations to the pre-synaptic release machinery and elevated synaptic transmission are early neuronal effects of LRRK2 G2019S. Furthermore, the comparison of knock-in and overexpressing cultures suggests that one copy of the G2019S mutation has a more pronounced effect than an ~3-fold increase in LRRK2 protein. Mutant-induced increases in transmission may convey additional stressors to neuronal physiology that may eventually contribute to the pathogenesis of Parkinson's disease.

Insomnia in shift work.

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Vallières, Annie; Azaiez, Aïda; Moreau, Vincent; LeBlanc, Mélanie; Morin, Charles M

2014-12-01

Shift work disorder involves insomnia and/or excessive sleepiness associated with the work schedule. The present study examined the impact of insomnia on the perceived physical and psychological health of adults working on night and rotating shift schedules compared to day workers. A total of 418 adults (51% women, mean age 41.4 years), including 51 night workers, 158 rotating shift workers, and 209 day workers were selected from an epidemiological study. An algorithm was used to classify each participant of the two groups (working night or rotating shifts) according to the presence or absence of insomnia symptoms. Each of these individuals was paired with a day worker according to gender, age, and income. Participants completed several questionnaires measuring sleep, health, and psychological variables. Night and rotating shift workers with insomnia presented a sleep profile similar to that of day workers with insomnia. Sleep time was more strongly related to insomnia than to shift work per se. Participants with insomnia in the three groups complained of anxiety, depression, and fatigue, and reported consuming equal amounts of sleep-aid medication. Insomnia also contributed to chronic pain and otorhinolaryngology problems, especially among rotating shift workers. Work productivity and absenteeism were more strongly related to insomnia. The present study highlights insomnia as an important component of the sleep difficulties experienced by shift workers. Insomnia may exacerbate certain physical and mental health problems of shift workers, and impair their quality of life. Copyright © 2014 Elsevier B.V. All rights reserved.

Selective Attention to Visual Stimuli Using Auditory Distractors Is Altered in Alpha-9 Nicotinic Receptor Subunit Knock-Out Mice.

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Terreros, Gonzalo; Jorratt, Pascal; Aedo, Cristian; Elgoyhen, Ana Belén; Delano, Paul H

2016-07-06

During selective attention, subjects voluntarily focus their cognitive resources on a specific stimulus while ignoring others. Top-down filtering of peripheral sensory responses by higher structures of the brain has been proposed as one of the mechanisms responsible for selective attention. A prerequisite to accomplish top-down modulation of the activity of peripheral structures is the presence of corticofugal pathways. The mammalian auditory efferent system is a unique neural network that originates in the auditory cortex and projects to the cochlear receptor through the olivocochlear bundle, and it has been proposed to function as a top-down filter of peripheral auditory responses during attention to cross-modal stimuli. However, to date, there is no conclusive evidence of the involvement of olivocochlear neurons in selective attention paradigms. Here, we trained wild-type and α-9 nicotinic receptor subunit knock-out (KO) mice, which lack cholinergic transmission between medial olivocochlear neurons and outer hair cells, in a two-choice visual discrimination task and studied the behavioral consequences of adding different types of auditory distractors. In addition, we evaluated the effects of contralateral noise on auditory nerve responses as a measure of the individual strength of the olivocochlear reflex. We demonstrate that KO mice have a reduced olivocochlear reflex strength and perform poorly in a visual selective attention paradigm. These results confirm that an intact medial olivocochlear transmission aids in ignoring auditory distraction during selective attention to visual stimuli. The auditory efferent system is a neural network that originates in the auditory cortex and projects to the cochlear receptor through the olivocochlear system. It has been proposed to function as a top-down filter of peripheral auditory responses during attention to cross-modal stimuli. However, to date, there is no conclusive evidence of the involvement of olivocochlear

Insomnia in patients with COPD.

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Budhiraja, Rohit; Parthasarathy, Sairam; Budhiraja, Pooja; Habib, Michael P; Wendel, Christopher; Quan, Stuart F

2012-03-01

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality and may frequently be associated with sleep disturbances. However, the correlates of insomnia in COPD patients have not been well characterized. The aim of the current study was to describe the prevalence of insomnia disorder in COPD and to elucidate the demographic and clinical characteristics of COPD patients that are associated with insomnia. Cross-sectional study. Clinic-based sample from an academic hospital. Patients with stable COPD. An interviewer-conducted survey was administered to 183 participants with COPD. Seventy-two of these participants (30 with and 42 without insomnia) maintained a sleep diary and underwent actigraphy for 7 days. Insomnia (chronic sleep disturbance associated with impaired daytime functioning) was present in 27.3% of participants. Current tobacco users (odds ratio (OR), 2.13) and those with frequent sadness/anxiety (OR, 3.57) had higher odds, but oxygen use was associated with lower odds (OR, 0.35) of insomnia. Patients with insomnia had worse quality of life and a higher prevalence of daytime sleepiness. Actigraphy revealed shorter sleep duration and lower sleep efficiency, and a sleep diary revealed worse self-reported sleep quality in participants with insomnia. Insomnia disorder is highly prevalent in patients with COPD; current tobacco use and sadness/anxiety are associated with a higher prevalence, and oxygen use with a lower prevalence of insomnia; patients with insomnia have poorer quality of life and increased daytime sleepiness; and insomnia is associated with worse objective sleep quality.

Insomnia in Iranian Traditional Medicine

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Feyzabadi, Zohre; Jafari, Farhad; Feizabadi, Parvin Sadat; Ashayeri, Hassan; Esfahani, Mohammad Mahdi; Badiee Aval, Shapour

2014-01-01

Context: Insomnia is one of the most prevalent sleep disorders characterized by sleep difficulty that impairs daily functioning and reduces quality of life. The burden of medical, psychiatric, interpersonal, and societal consequences of insomnia expresses the importance of diagnosing and treatment of insomnia. The aim of study was to investigate causes of insomnia from the viewpoint of Iranian traditional medicine. Evidence Acquisition: In this review study, we searched insomnia in a few of t...

Insomnia in Iranian Traditional Medicine

Science.gov (United States)

Feyzabadi, Zohre; Jafari, Farhad; Feizabadi, Parvin Sadat; Ashayeri, Hassan; Esfahani, Mohammad Mahdi; Badiee Aval, Shapour

2014-01-01

Context: Insomnia is one of the most prevalent sleep disorders characterized by sleep difficulty that impairs daily functioning and reduces quality of life. The burden of medical, psychiatric, interpersonal, and societal consequences of insomnia expresses the importance of diagnosing and treatment of insomnia. The aim of study was to investigate causes of insomnia from the viewpoint of Iranian traditional medicine. Evidence Acquisition: In this review study, we searched insomnia in a few of the most famous ancient textbooks of Iranian traditional medicine from different centuries. This books includeThe Canon of Medicine by Avicenna (the first version of Beirut), Zakhire Kharazmshahi by Jurjani (the scanned version of Bonyade Farhang-e Iran), Malfaregh by Razes (the first version of Iran University of Medical Sciences), and Aqili’s cure by Aqili (the first version of Iran University of Medical Sciences). Results: This study found that in Iranian traditional medicine manuscripts, insomnia was called sahar and even though many factors induce insomnia, most of them act through causing brain dystemperament. Conclusions: The brain dystemperament is considered one of the main causes of insomnia and insomnia can be well managed with an organized line of treatment, by correcting the brain dystemperament through elimination of causes. This study helps to find new solutions to treat insomnia. PMID:24829786

Insomnia with objective short sleep duration is associated with longer duration of insomnia in the Freiburg Insomnia Cohort compared to insomnia with normal sleep duration, but not with hypertension.

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Johann, Anna F; Hertenstein, Elisabeth; Kyle, Simon D; Baglioni, Chiara; Feige, Bernd; Nissen, Christoph; McGinness, Alastair J; Riemann, Dieter; Spiegelhalder, Kai

2017-01-01

To replicate the association between insomnia with objective short sleep duration and hypertension, type 2 diabetes and duration of insomnia. Retrospective case-control study. Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg. 328 patients with primary insomnia classified according to DSM-IV criteria (125 males, 203 females, 44.3 ± 12.2 years). N/A. All participants were investigated using polysomnography, blood pressure measurements, and fasting routine laboratory. Insomnia patients with short sleep duration (insomnia compared to those with normal sleep duration (≥ 6 hours) in the first night of laboratory sleep. Insomnia patients who were categorised as short sleepers in either night were not more likely to suffer from hypertension (systolic blood pressure of ≥ 140 mm Hg, diastolic blood pressure of ≥ 90 mm Hg, or a previously established diagnosis). Data analysis showed that insomnia patients with objective short sleep duration were not more likely to suffer from type 2 diabetes (fasting plasma glucose level of ≥ 126 mg/dl, or a previously established diagnosis). However, the diabetes analysis was only based on a very small number of diabetes cases. As a new finding, insomnia patients who were categorised as short sleepers in either night presented with increases in liver enzyme levels. The finding on insomnia duration supports the concept of two distinct sub-groups of insomnia, namely insomnia with, and without, objectively determined short sleep duration. However, our data challenges previous findings that insomnia patients with short sleep duration are more likely to suffer from hypertension.

Assessing insomnia in adolescents: comparison of Insomnia Severity Index, Athens Insomnia Scale and Sleep Quality Index.

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Chung, Ka-Fai; Kan, Katherine Ka-Ki; Yeung, Wing-Fai

2011-05-01

To compare the psychometric properties of the Chinese versions of Insomnia Severity Index (ISI), Athens Insomnia Scale (AIS) and Sleep Quality Index (SQI) for assessment and screening of insomnia in adolescents. This is a school-based survey of 1516 adolescents aged 12-19 years. Sleep-wake habit questionnaire, ISI, AIS, SQI, Epworth Sleepiness Scale (ESS) and 12-item General Health Questionnaire (GHQ-12) were administered. Insomnia Interview Schedule was used to assess the severity of insomnia symptoms and DSM-IV-TR diagnosis of insomnia. The Cronbach's alpha of ISI, AIS and SQI were 0.83, 0.81 and 0.65, respectively, and the 2-week test-retest reliability were 0.79, 0.80 and 0.72. All three scales had a 2-factor structure, and their scores were significantly correlated with sleep-wake variables, ESS and GHQ-12 scores, smoking and drinking habits, and academic performance. The areas under curve of ISI, AIS and SQI for detecting clinical insomnia were 0.85, 0.80 and 0.85, respectively. The optimal cut-offs for ISI, AIS and SQI were a total score of nine (sensitivity/specificity: 0.87/0.75), seven (sensitivity/specificity: 0.78/0.74) and five (sensitivity/specificity: 0.83/0.79), respectively. The Chinese versions of ISI, AIS and SQI are reliable and valid instruments. The ISI and AIS appear to have better psychometric properties than the SQI. Copyright © 2011 Elsevier B.V. All rights reserved.

MANAJEMENT OF INSOMNIA IN GERIATRIC PATIENTS

OpenAIRE

Cokorda Istri Devi Larayanthi

2013-01-01

Sleep is an unconscious condition that is relatively more responsive to internal stimuli. Insomnia is a sleep disorder with characteristic difficulty of initiating sleep or difficulty in maintaining sleep. Insomnia is divided into 2 primary insomnia and secondary insomnia. Conection with age, the function of organs in the body decreases. So that geriatric patients are susceptible to illnesses, especially insomnia. Many of the causes of insomnia in geriatric mental disorders, psychiatric, gene...

Hawthorn (Crataegus pinnatifida Bunge) leave flavonoids attenuate atherosclerosis development in apoE knock-out mice.

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Dong, Pengzhi; Pan, Lanlan; Zhang, Xiting; Zhang, Wenwen; Wang, Xue; Jiang, Meixiu; Chen, Yuanli; Duan, Yajun; Wu, Honghua; Xu, Yantong; Zhang, Peng; Zhu, Yan

2017-02-23

Hawthorn (Crataegus pinnatifida Bunge) leave have been used to treat cardiovascular diseases in China and Europe. Hawthorn leave flavonoids (HLF) are the main part of extraction. Whether hawthorn leave flavonoids could attenuate the development of atherosclerosis and the possible mechanism remain unknown. High-fat diet (HFD) mixed with HLF at concentrations of 5mg/kg and 20mg/kg were administered to apolipoprotein E (apoE) knock out mice. 16 weeks later, mouse serum was collected to determine the lipid profile while the mouse aorta dissected was prepared to measure the lesion area. Hepatic mRNA of genes involved in lipid metabolism were determined. Peritoneal macrophages were collected to study the impact of HLF on cholesterol efflux, formation of foam cell and the expression of ATP binding cassette transporter A1 (ABCA1). Besides, in vivo reverse cholesterol transport (RCT) was conducted. HLF attenuated the development of atherosclerosis that the mean atherosclerotic lesion area in en face aortas was reduced by 23.1% (Pflavonoids can slow down the development of atherosclerosis in apoE knockout mice via induced expression of genes involved in antioxidant activities, inhibition of the foam cell formation and promotion of RCT in vivo, which implies the potential use in the prevention of atherosclerosis. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice.

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Gillis, Caitlin M; Jönsson, Friederike; Mancardi, David A; Tu, Naxin; Beutier, Héloïse; Van Rooijen, Nico; Macdonald, Lynn E; Murphy, Andrew J; Bruhns, Pierre

2017-04-01

Anaphylaxis can proceed through distinct IgE- or IgG-dependent pathways, which have been investigated in various mouse models. We developed a novel mouse strain in which the human low-affinity IgG receptor locus, comprising both activating (hFcγRIIA, hFcγRIIIA, and hFcγRIIIB) and inhibitory (hFcγRIIB) hFcγR genes, has been inserted into the equivalent murine locus, corresponding to a locus swap. We sought to determine the capabilities of hFcγRs to induce systemic anaphylaxis and identify the cell types and mediators involved. hFcγR expression on mouse and human cells was compared to validate the model. Passive systemic anaphylaxis was induced by injection of heat-aggregated human intravenous immunoglobulin and active systemic anaphylaxis after immunization and challenge. Anaphylaxis severity was evaluated based on hypothermia and mortality. The contribution of receptors, mediators, or cell types was assessed based on receptor blockade or depletion. The human-to-mouse low-affinity FcγR locus swap engendered hFcγRIIA/IIB/IIIA/IIIB expression in mice comparable with that seen in human subjects. Knock-in mice were susceptible to passive and active anaphylaxis, accompanied by downregulation of both activating and inhibitory hFcγR expression on specific myeloid cells. The contribution of hFcγRIIA was predominant. Depletion of neutrophils protected against hypothermia and mortality. Basophils contributed to a lesser extent. Anaphylaxis was inhibited by platelet-activating factor receptor or histamine receptor 1 blockade. Low-affinity FcγR locus-switched mice represent an unprecedented model of cognate hFcγR expression. Importantly, IgG-related anaphylaxis proceeds within a native context of activating and inhibitory hFcγRs, indicating that, despite robust hFcγRIIB expression, activating signals can dominate to initiate a severe anaphylactic reaction. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights

Insomnia (primary) in older people

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Alessi, Cathy; Vitiello, Michael V

2011-01-01

Up to 40% of older adults have insomnia, with difficulty getting to sleep, early waking, or feeling unrefreshed on waking. The prevalence of insomnia increases with age. Other risk factors include medical and psychiatric illnesses, psychological factors, stress, daytime napping, and hyperarousal.Primary insomnia is a chronic and relapsing condition that may increase the risks of accidents.Primary insomnia is chronic insomnia without specific underlying medical, psychiatric, or other sleep ...

The Sleep–Wake Cycle in the Nicotinic Alpha-9 Acetylcholine Receptor Subunit Knock-Out Mice

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Natalia Madrid-López

2017-10-01

Full Text Available There is a neural matrix controlling the sleep–wake cycle (SWC embedded within high ranking integrative mechanisms in the central nervous system. Nicotinic alpha-9 acetylcholine receptor subunit (alpha-9 nAChR participate in physiological processes occurring in sensory, endocrine and immune systems. There is a relationship between the SWC architecture, body homeostasis and sensory afferents so that disruption of afferent signaling is expected to affect the temporal organization of sleep and wake states. The analysis of the SWC of 9 nAChR knock-out animals may help to reveal the contribution of alpha-9 nAChR to sleep chronobiological determinants. Here we explore the polysomnogram in chronically implanted alpha-9 nAChR knock-out (KO and wild-type (WT individuals of the hybrid CBA/Sv129 mouse strain. Records were obtained in isolation chambers under a stable 12:12 light:dark cycle (LD. To unmask the 24-h modulation of the SWC a skeleton photoperiod (SP protocol was performed. Under LD the daily quota (in % of wakefulness (W, NREM sleep and REM sleep obtained in KO and WT animals were 45, 48 and 7, and 46, 46 and 8 respectively. Both groups exhibit nocturnal phase preference of W as well as diurnal and unimodal phase preference of NREM and REM sleep. The acrophase mean angles of KO vs. WT genotypes were not different (Zeitgeber Time: 6.5 vs. 14.9 for W, 4.3 vs. 2.8 for NREM sleep and 5.3 vs. 3.4 for REM sleep, respectively. Transference to SP do not affect daily state quotas, phase preferences and acrophases among genotypes. Unmasking phenomena of the SWC such as wake increment during the rest phase under SP was evident only among WT mice suggesting the involvement of retinal structures containing alpha-9 nAChR in masking processes. Furthermore, KO animals exhibit longer NREM and REM sleep episodes that is independent of illumination conditions. Consolidated diurnal NREM sleep contributed to obtain higher values of NREM sleep delta-EEG activity

Hazards of insomnia and the effects of acupuncture treatment on insomnia.

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Lin, Yu-fang; Liu, Zhi-dan; Ma, Wen; Shen, Wei-dong

2016-05-01

Insomnia is a common disease in modern society; it is made worse by increasingly fierce competition in the workplace and elsewhere, along with rapid economic and social development. Sleep disorders can result in changes in serum biomarkers and decreased immunity, and may cause maladies such as depression and cardiac diseases, as well as many other somatic symptoms. Western medications for treating insomnia can easily lead to addiction and other adverse effects. Fortunately, acupuncture can ease the symptoms of insomnia. This review summarizes the hazards associated with insomnia and the use of acupuncture in its treatment. Furthermore, the authors introduce an effective and low-cost method of treating insomnia with acupuncture. This review indicates that insomnia poses a major threat to mental health through its effects on serum components, heart function and the immune system of patients, which may lead to other physiological disorders. Anxiety and depression are the two main negative emotions affected by insomnia. Acupuncture, which has showed effectiveness against insomnia and its complications, may be an effective and complementary method for the treatment of insomnia and associated maladies.

Insomnia and paranoia.

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Freeman, Daniel; Pugh, Katherine; Vorontsova, Natasha; Southgate, Laura

2009-03-01

Insomnia is a potential cause of anxiety, depression, and anomalies of experience; separate research has shown that anxiety, depression and anomalies of experience are predictors of paranoia. Thus insomnia may contribute to the formation and maintenance of persecutory ideation. The aim was to examine for the first time the association of insomnia symptoms and paranoia in the general population and the extent of insomnia in individuals with persecutory delusions attending psychiatric services. Assessments of insomnia, persecutory ideation, anxiety, and depression were completed by 300 individuals from the general population and 30 individuals with persecutory delusions and a diagnosis of non-affective psychosis. Insomnia symptoms were clearly associated with higher levels of persecutory ideation. Consistent with the theoretical understanding of paranoia, the association was partly explained by the presence of anxiety and depression. Moderate or severe insomnia was present in more than 50% of the delusions group. The study provides the first direct evidence that insomnia is common in individuals with high levels of paranoia. It is plausible that sleep difficulties contribute to the development of persecutory ideation. The intriguing implication is that insomnia interventions for this group could have the added benefit of lessening paranoia.

The Natural History of Insomnia: Acute Insomnia and First-onset Depression

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Ellis, Jason G.; Perlis, Michael L.; Bastien, Célyne H.; Gardani, Maria; Espie, Colin A.

2014-01-01

Study Objectives: While many studies have examined the association between insomnia and depression, no studies have evaluated these associations (1) within a narrow time frame, (2) with specific reference to acute and chronic insomnia, and (3) using polysomnography. In the present study, the association between insomnia and first-onset depression was evaluated taking into account these considerations. Design: A mixed-model inception design. Setting: Academic research laboratory. Participants: Fifty-four individuals (acute insomnia [n = 33], normal sleepers [n = 21]) with no reported history of a sleep disorder, chronic medical condition, or psychiatric illness. Interventions: N/A. Measurements and Results: Participants were assessed at baseline (2 nights of polysomnography and psychometric measures of stress and mood) and insomnia and depression status were reassessed at 3 months. Individuals with acute insomnia exhibited more stress, poorer mood, worse subjective sleep continuity, increased N2 sleep, and decreased N3 sleep. Individuals who transitioned to chronic insomnia exhibited (at baseline) shorter REM latencies and reduced N3 sleep. Individuals who exhibited this pattern in the transition from acute to chronic insomnia were also more likely to develop first-onset depression (9.26%) as compared to those who remitted from insomnia (1.85%) or were normal sleepers (1.85%). Conclusion: The transition from acute to chronic insomnia is presaged by baseline differences in sleep architecture that have, in the past, been ascribed to Major Depression, either as heritable traits or as acquired traits from prior episodes of depression. The present findings suggest that the “sleep architecture stigmata” of depression may actually develop over the course transitioning from acute to chronic insomnia. Citation: Ellis JG; Perlis ML; Bastien CH; Gardani M; Espie CA. The natural history of insomnia: acute insomnia and first-onset depression. SLEEP 2014;37(1):97-106. PMID

Identification of rat Rosa26 locus enables generation of knock-in rat lines ubiquitously expressing tdTomato.

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Kobayashi, Toshihiro; Kato-Itoh, Megumi; Yamaguchi, Tomoyuki; Tamura, Chihiro; Sanbo, Makoto; Hirabayashi, Masumi; Nakauchi, Hiromitsu

2012-11-01

Recent discovery of a method for derivation and culture of germline-competent rat pluripotent stem cells (PSCs) enables generation of transgenic rats or knock-out rats via genetic modification of such PSCs. This opens the way to use rats, as is routine in mice, for analyses of gene functions or physiological features. In mouse or human, one widely used technique to express a gene of interest stably and ubiquitously is to insert that gene into the Rosa26 locus via gene targeting of PSCs. Rosa26 knock-in mice conditionally expressing a reporter or a toxin gene have contributed to tracing or ablation of specific cell lineages. We successfully identified a rat orthologue of the mouse Rosa26 locus. Insertion of tdTomato, a variant of red fluorescent protein, into the Rosa26 locus of PSCs of various rat strains allows ubiquitous expression of tdTomato. Through germline transmission of one Rosa26-tdTomato knock-in embryonic stem cell line, we also obtained tdTomato knock-in rats. These expressed tdTomato ubiquitously throughout their bodies, which indicates that the rat Rosa26 locus conserves functions of its orthologues in mouse and human. The new tools described here (targeting vectors, knock-in PSCs, and rats) should be useful for a variety of research using rats.

MANAJEMENT OF INSOMNIA IN GERIATRIC PATIENTS

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Cokorda Istri Devi Larayanthi

2013-04-01

Full Text Available Sleep is an unconscious condition that is relatively more responsive to internal stimuli. Insomnia is a sleep disorder with characteristic difficulty of initiating sleep or difficulty in maintaining sleep. Insomnia is divided into 2 primary insomnia and secondary insomnia. Conection with age, the function of organs in the body decreases. So that geriatric patients are susceptible to illnesses, especially insomnia. Many of the causes of insomnia in geriatric mental disorders, psychiatric, general medical conditions, medications, certain substances, and others. Management of insomnia in geriatric patients were divided into 3 method: 1 manage underlying cause, 2 nonpharmacological therapies such as cognitive behavior therapy (CBT, and 3 pharmacological therapies such as benzodiazepine and non-benzodiazepine that eszopiclone and Ramelteon. Pharmacological treatment in geriatrics should follow the rule "start low, go slow", starting dose of ½ of the adult dose, and its use in the short term.

Association between stress-related sleep reactivity and cognitive processes in insomnia disorder and insomnia subgroups: preliminary results.

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Palagini, Laura; Faraguna, Ugo; Mauri, Mauro; Gronchi, Alessia; Morin, Charles M; Riemann, Dieter

2016-03-01

Stress-related sleep reactivity, sleep-related cognitions, and psychological factors play an important role in insomnia. The aim was to investigate their possible association in Insomnia Disorder, insomnia subgroups, and healthy subjects. The cross-sectional study consisted of 93 subjects who met diagnostic criteria for Insomnia Disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and of 30 healthy subjects. Survey instruments included the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Ford Insomnia Response to Stress Test (FIRST), Dysfunctional Beliefs about Sleep scale (DBAS), Beck Depression Inventory (BDI), and Zung Self-Rating Anxiety Scale (SAS). Descriptive statistics, Pearson correlations, χ(2)-test, and multiple linear regression were performed. FIRST and SAS best determined the insomnia subjects vs good sleepers (FIRST χ(2) = 109.6, p insomnia, stress-related sleep reactivity, and psychological factors, such as anxiety symptoms, may distinguish insomnia subjects from good sleepers; (2) sleep reactivity and sleep-related cognitions seem interrelated, unhelpful beliefs may affect the stress reactivity; (3) psychological factors may influence sleep quality and the severity of insomnia; (4) these important sleep-related variables may have similar associations in insomnia subgroups; they may constitute the core factors for insomnia development and maintenance. Copyright © 2015 Elsevier B.V. All rights reserved.

LatY136F knock-in mouse model for human IgG4-related disease.

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Yamada, Kazunori; Zuka, Masahiko; Ito, Kiyoaki; Mizuguchi, Keishi; Kakuchi, Yasushi; Onoe, Tamehito; Suzuki, Yasunori; Yamagishi, Masakazu; Izui, Shozo; Malissen, Marie; Malissen, Bernard; Kawano, Mitsuhiro

2018-01-01

The adaptor protein Linker for activation of T cell (LAT) is a key signaling hub used by the T cell antigen receptor. Mutant mice expressing loss-of-function mutations affecting LAT and including a mutation in which tyrosine 136 is replaced by a phenylalanine (LatY136F) develop lymphoproliferative disorder involving T helper type 2 effector cells capable of triggering a massive polyclonal B cell activation that leads to hypergammaglobulinemia G1 and E and to non-resolving inflammation and autoimmunity. The purpose of this study was to evaluate whether the phenotypes of LatY136F knock-in mice resemble the immunohistopathological features of immunoglobulin G4-related disease (IgG4-RD). LatY136F knock-in mice were sacrificed at 4-20 weeks of age, and pancreas, kidney, salivary gland and lung were obtained. All organs were stained with hematoxylin-eosin and with Azan for estimation of collagen in fibrosis, and the severity scores of inflammation and fibrosis were evaluated. Immunostainings were performed to analyze the types of infiltrating cells. In addition, the effects of corticosteroid treatment on the development of tissue lesions and serum levels of IgG1 were assessed. Tissue lesions characterized by inflammatory mononuclear cell infiltration and fibrosis were detected in pancreas, kidney, and salivary gland starting from 6 weeks of age. Immunostainings showed pronounced infiltration of plasma cells, CD4-positive T cells, and macrophages. Infiltrating plasma cells predominantly expressed IgG1. The extent of inflammation in pancreas and salivary glands was markedly reduced by corticosteroid treatment. LatY136F knock-in mice displayed increased production of Th2-type IgG1 (a homologue of human IgG4) and developed multiple organ tissue lesions reminiscent of those seen in patients with IgG4-RD. Moreover, the development of these tissue lesions was highly sensitive to corticosteroid treatment like in IgG4-RD. For these reasons we consider the LatY136F knock-in mouse

The R21C Mutation in Cardiac Troponin I Imposes Differences in Contractile Force Generation between the Left and Right Ventricles of Knock-In Mice

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Jingsheng Liang

2015-01-01

Full Text Available We investigated the effect of the hypertrophic cardiomyopathy-linked R21C (arginine to cysteine mutation in human cardiac troponin I (cTnI on the contractile properties and myofilament protein phosphorylation in papillary muscle preparations from left (LV and right (RV ventricles of homozygous R21C+/+ knock-in mice. The maximal steady-state force was significantly reduced in skinned papillary muscle strips from the LV compared to RV, with the latter displaying the level of force observed in LV or RV from wild-type (WT mice. There were no differences in the Ca2+ sensitivity between the RV and LV of R21C+/+ mice; however, the Ca2+ sensitivity of force was higher in RV-R21C+/+ compared with RV-WT and lower in LV- R21C+/+ compared with LV-WT. We also observed partial loss of Ca2+ regulation at low [Ca2+]. In addition, R21C+/+-KI hearts showed no Ser23/24-cTnI phosphorylation compared to LV or RV of WT mice. However, phosphorylation of the myosin regulatory light chain (RLC was significantly higher in the RV versus LV of R21C+/+ mice and versus LV and RV of WT mice. The difference in RLC phosphorylation between the ventricles of R21C+/+ mice likely contributes to observed differences in contractile force and the lower tension monitored in the LV of HCM mice.

Effects of SIRT1 gene knock-out via activation of SREBP2 protein-mediated PI3K/AKT signaling on osteoarthritis in mice.

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Yu, Fei; Zeng, Hui; Lei, Ming; Xiao, De-Ming; Li, Wei; Yuan, Hao; Lin, Jian-Jing

2016-10-01

This study investigated the effects of SIRT1 gene knock-out on osteoarthritis in mice, and the possible roles of SREBP2 protein and the PI3K/AKT signaling pathway in the effects. Mice were randomly divided into a normal group and a SIRT1 gene knock-out group (6 mice in each group). In these groups, one side of the knee anterior cruciate ligament was traversed, and the ipsilateral medial meniscus was cut to establish an osteoarthritis model of knee joint. The countralateral synovial bursa was cut out, serving as controls. The knee joint specimens were then divided into four groups: SIRT1 +/+ control group (group A, n=6); SIRT1 +/+ osteoarthritis group (group B, n=6); SIRT1 -/- control group (group C, n=6); SIRT1 -/- osteoarthritis group (group D, n=6). HE staining, Masson staining, Safranin O-Fast Green staining and Van Gieson staining were used to observe the morphological changes in the articular cartilage of the knee. Immunohistochemical staining was employed to detect the expression of SIRT1, SREBP2, VEGF, AKT, HMGCR and type II collagen proteins. SA-β-gal staining was utilized to evaluate chondrocyte aging. The results showed clear knee joint cartilage destruction and degeneration in the SIRT1 -/- osteoarthritis group. The tidal line was twisted and displaced anteriorly. Type II collagen was destroyed and distributed unevenly. Compared with the SIRT1 +/+ osteoarthritis group and SIRT1 -/- control group, SIRT1 protein expression was not obviously changed in the SIRT1 -/- osteoarthritis group (P>0.05), while the expression levels of the SREBP2, VEGF and HMGCR proteins were significantly increased (Pknock-out may aggravate cartilage degeneration in osteoarthritis by activating the SREBP2 protein-mediated PI3K/AKT signalling pathway, suggesting that SIRT1 gene may play a protective role against osteoarthritis.

Multiple sleep alterations in mice lacking cannabinoid type 1 receptors.

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Alessandro Silvani

Full Text Available Cannabinoid type 1 (CB1 receptors are highly expressed in the brain and play a role in behavior control. Endogenous cannabinoid signaling is modulated by high-fat diet (HFD. We investigated the consequences of congenital lack of CB1 receptors on sleep in mice fed standard diet (SD and HFD. CB1 cannabinoid receptor knock-out (KO and wild-type (WT mice were fed SD or HFD for 4 months (n = 9-10 per group. Mice were instrumented with electroencephalographic (EEG and electromyographic electrodes. Recordings were performed during baseline (48 hours, sleep deprivation (gentle handling, 6 hours, sleep recovery (18 hours, and after cage switch (insomnia model paradigm, 6 hours. We found multiple significant effects of genotype on sleep. In particular, KO spent more time awake and less time in non-rapid-eye-movement sleep (NREMS and rapid-eye-movement sleep (REMS than WT during the dark (active period but not during the light (rest period, enhancing the day-night variation of wake-sleep amounts. KO had slower EEG theta rhythm during REMS. REMS homeostasis after sleep deprivation was less effective in KO than in WT. Finally, KO habituated more rapidly to the arousing effect of the cage-switch test than WT. We did not find any significant effects of diet or of diet x genotype interaction on sleep. The occurrence of multiple sleep alterations in KO indicates important roles of CB1 cannabinoid receptors in limiting arousal during the active period of the day, in sleep regulation, and in sleep EEG in mice.

Transient insomnia versus chronic insomnia: a comparison study of sleep-related psychological/behavioral characteristics.

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Yang, Chien-Ming; Lin, Shih-Chun; Cheng, Chung-Ping

2013-10-01

Vulnerability to transient insomnia is regarded as a predisposing factor for chronic insomnia. However, most individuals with transient insomnia do not develop chronic insomnia. The current study investigated the differential contributing factors for these two conditions to further the understanding of this phenomenon. Chronic insomnia patients and normal sleepers with high and low vulnerability to transient insomnia completed measures of pre-sleep arousal, dysfunctional sleep beliefs, and sleep-related safety behaviors. Both cognitive and somatic pre-sleep arousals were identified as significant predictors for transient insomnia. Dysfunctional beliefs regarding worry about insomnia and cognitive arousal were predictors for chronic insomnia. Sleep-related safety behavior, although correlated with insomnia severity, was not a significant predictor for both conditions. Dysfunctional beliefs associated with worry and losing control over sleep are the most critical factors in differentiating chronic insomnia from transient insomnia. These factors should be addressed to help prevent individuals with high sleep vulnerability from developing chronic sleep disturbance. © 2013 Wiley Periodicals, Inc.

Insomnia and paranoia

OpenAIRE

Freeman, Daniel; Pugh, Katherine; Vorontsova, Natasha; Southgate, Laura

2009-01-01

Insomnia is a potential cause of anxiety, depression, and anomalies of experience; separate research has shown that anxiety, depression and anomalies of experience are predictors of paranoia. Thus insomnia may contribute to the formation and maintenance of persecutory ideation. The aim was to examine for the first time the association of insomnia symptoms and paranoia in the general population and the extent of insomnia in individuals with persecutory delusions attending psychiatric services....

Subjective-objective sleep discrepancy among older adults: associations with insomnia diagnosis and insomnia treatment.

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Kay, Daniel B; Buysse, Daniel J; Germain, Anne; Hall, Martica; Monk, Timothy H

2015-02-01

Discrepancy between subjective and objective measures of sleep is associated with insomnia and increasing age. Cognitive behavioural therapy for insomnia improves sleep quality and decreases subjective-objective sleep discrepancy. This study describes differences between older adults with insomnia and controls in sleep discrepancy, and tests the hypothesis that reduced sleep discrepancy following cognitive behavioural therapy for insomnia correlates with the magnitude of symptom improvement reported by older adults with insomnia. Participants were 63 adults >60 years of age with insomnia, and 51 controls. At baseline, participants completed sleep diaries for 7 days while wearing wrist actigraphs. After receiving cognitive behavioural therapy for insomnia, insomnia patients repeated this sleep assessment. Sleep discrepancy variables were calculated by subtracting actigraphic sleep onset latency and wake after sleep onset from respective self-reported estimates, pre- and post-treatment. Mean level and night-to-night variability in sleep discrepancy were investigated. Baseline sleep discrepancies were compared between groups. Pre-post-treatment changes in Insomnia Severity Index score and sleep discrepancy variables were investigated within older adults with insomnia. Sleep discrepancy was significantly greater and more variable across nights in older adults with insomnia than controls, P ≤ 0.001 for all. Treatment with cognitive behavioural therapy for insomnia was associated with significant reduction in the Insomnia Severity Index score that correlated with changes in mean level and night-to-night variability in wake after sleep onset discrepancy, P insomnia. © 2014 European Sleep Research Society.

Nighttime Insomnia Symptoms and Perceived Health in the America Insomnia Survey (AIS)

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Walsh, James K.; Coulouvrat, Catherine; Hajak, Goeran; Lakoma, Matthew D.; Petukhova, Maria; Roth, Thomas; Sampson, Nancy A.; Shahly, Victoria; Shillington, Alicia; Stephenson, Judith J.; Kessler, Ronald C.

2011-01-01

Study Objectives: To explore the distribution of the 4 cardinal nighttime symptoms of insomnia—difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), and nonrestorative sleep (NRS)—in a national sample of health plan members and the associations of these nighttime symptoms with sociodemographics, comorbidity, and perceived health. Design/Setting/Participants: Cross-sectional telephone survey of 6,791 adult respondents. Intervention: None. Measurements/Results: Current insomnia was assessed using the Brief Insomnia Questionnaire (BIQ)—a fully structured validated scale generating diagnoses of insomnia using DSM-IV-TR, ICD-10, and RDC/ICSD-2 inclusion criteria. DMS (61.0%) and EMA (52.2%) were more prevalent than DIS (37.7%) and NRS (25.2%) among respondents with insomnia. Sociodemographic correlates varied significantly across the 4 symptoms. All 4 nighttime symptoms were significantly related to a wide range of comorbid physical and mental conditions. All 4 also significantly predicted decrements in perceived health both in the total sample and among respondents with insomnia after adjusting for comorbid physical and mental conditions. Joint associations of the 4 symptoms predicting perceived health were additive and related to daytime distress/impairment. Individual-level associations were strongest for NRS. At the societal level, though, where both prevalence and strength of individual-level associations were taken into consideration, DMS had the strongest associations. Conclusions: The extent to which nighttime insomnia symptoms are stable over time requires future long-term longitudinal study. Within the context of this limitation, the results suggest that core nighttime symptoms are associated with different patterns of risk and perceived health and that symptom-based subtyping might have value. Citation: Walsh JK; Coulouvrat C; Hajak G; Lakoma MD; Petukhova M; Roth T; Sampson NA; Shahly V; Shillington A

Reduction in open field activity in the absence of memory deficits in the AppNL-G-F knock-in mouse model of Alzheimer's disease.

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Whyte, Lauren S; Hemsley, Kim M; Lau, Adeline A; Hassiotis, Sofia; Saito, Takashi; Saido, Takaomi C; Hopwood, John J; Sargeant, Timothy J

2018-01-15

The recent development of knock-in mouse models of Alzheimer's disease provides distinct advantages over traditional transgenic mouse models that rely on over-expression of amyloid precursor protein. Two such knock-in models that have recently been widely adopted by Alzheimer's researchers are the App NL-F and App NL-G-F mice. This study aimed to further characterise the behavioural phenotype and amyloid plaque distribution of App NL-G-F/NL-G-F (C57BL/6J background) mice at six-months of age. An attempt to replicate a previous study that observed deficits in working memory in the Y-maze, showed no difference between App NL-G-F/NL-G-F and wild-type mice. Further assessment of these mice using the novel object recognition test and Morris water maze also revealed no differences between App NL-G-F/NL-G-F and wild-type mice. Despite a lack of demonstrated cognitive deficits, we report a reduction in locomotor/exploratory activity in an open field. Histological examination of App NL-G-F/NL-G-F mice showed widespread distribution of amyloid plaques at this age. We conclude that whilst at six-months of age, memory deficits are not sufficiently robust to be replicated in varying environments, amyloid plaque burden is significant in App NL-G-F/NL-G-F knock-in brain. Copyright © 2017 Elsevier B.V. All rights reserved.

The generation of knock-in mice expressing fluorescently tagged galanin receptors 1 and 2

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Kerr, Niall; Holmes, Fiona E.; Hobson, Sally-Ann; Vanderplank, Penny; Leard, Alan; Balthasar, Nina; Wynick, David

2015-01-01

The neuropeptide galanin has diverse roles in the central and peripheral nervous systems, by activating the G protein-coupled receptors Gal1, Gal2 and the less studied Gal3 (GalR1–3 gene products). There is a wealth of data on expression of Gal1–3 at the mRNA level, but not at the protein level due to the lack of specificity of currently available antibodies. Here we report the generation of knock-in mice expressing Gal1 or Gal2 receptor fluorescently tagged at the C-terminus with, respectively, mCherry or hrGFP (humanized Renilla green fluorescent protein). In dorsal root ganglia (DRG) neurons expressing the highest levels of Gal1-mCherry, localization to the somatic cell membrane was detected by live-cell fluorescence and immunohistochemistry, and that fluorescence decreased upon addition of galanin. In spinal cord, abundant Gal1-mCherry immunoreactive processes were detected in the superficial layers of the dorsal horn, and highly expressing intrinsic neurons of the lamina III/IV border showed both somatic cell membrane localization and outward transport of receptor from the cell body, detected as puncta within cell processes. In brain, high levels of Gal1-mCherry immunofluorescence were detected within thalamus, hypothalamus and amygdala, with a high density of nerve endings in the external zone of the median eminence, and regions with lesser immunoreactivity included the dorsal raphe nucleus. Gal2-hrGFP mRNA was detected in DRG, but live-cell fluorescence was at the limits of detection, drawing attention to both the much lower mRNA expression than to Gal1 in mice and the previously unrecognized potential for translational control by upstream open reading frames (uORFs). PMID:26292267

Insomnia in people with epilepsy: A review of insomnia prevalence, risk factors and associations with epilepsy-related factors.

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Macêdo, Philippe Joaquim Oliveira Menezes; Oliveira, Pedro Sudbrack de; Foldvary-Schaefer, Nancy; Gomes, Marleide da Mota

2017-09-01

Insomnia is a common sleep complaint in the general population, and sleep loss may be a trigger for epileptic seizures. To conduct a comprehensive review of the literature of insomnia symptoms and insomnia disorder, their prevalence and epilepsy-related risk factors in people with epilepsy (PWE). A PUBMED search was performed for articles indexed to June 2016 involving human subjects, excluding papers in languages other than English, Spanish and Portuguese and case reports. Eligible studies were those using a clear definition of insomnia and reporting quantitative data on prevalence rates and risk factors. The search included the following terms: insomnia, sleep disorder(s), sleep disturbance(s) and sleep-wake in the title and abstract; and epilep* in the title. 425 papers were reviewed and 31 were selected for the final analysis (21 adult and 10 paediatric). Twenty-one studies used a control group. Two reviewer authors independently extracted all data and a third author resolved disagreements. Most studies were hospital-based, cross-sectional and evaluated convenience samples representing highly select populations. Various insomnia inventories were used. Fourteen assessed insomnia (10 in adults, four, children), but only five as primary outcome (none in children). Four evaluated insomnia disorder based on international classification criteria (International Classification of Sleep Disorders - ICSD-2-in 3, and DSM-IV-TR, in 1). In adults, insomnia prevalence was 28.9-51% based on the Insomnia Severity Index ≥15 and 36-74.4% based on DSM-IV-TR or ICSD-2. The prevalence of insomnia in children was 13.1-31.5% using the Sleep Disturbance Scale for Children and 11% based on ICSD-2 diagnostic criteria. Compared to control groups, PWE usually had higher frequencies of insomnia symptoms and disorder. Insomnia was associated with greater impairment in quality of life and higher degree of depressive symptoms in several studies, and was inconsistently related to female

Familial Aggregation of Insomnia.

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Jarrin, Denise C; Morin, Charles M; Rochefort, Amélie; Ivers, Hans; Dauvilliers, Yves A; Savard, Josée; LeBlanc, Mélanie; Merette, Chantal

2017-02-01

There is little information about familial aggregation of insomnia; however, this type of information is important to (1) improve our understanding of insomnia risk factors and (2) to design more effective treatment and prevention programs. This study aimed to investigate evidence of familial aggregation of insomnia among first-degree relatives of probands with and without insomnia. Cases (n = 134) and controls (n = 145) enrolled in a larger epidemiological study were solicited to invite their first-degree relatives and spouses to complete a standardized sleep/insomnia survey. In total, 371 first-degree relatives (Mage = 51.9 years, SD = 18.0; 34.3% male) and 138 spouses (Mage = 55.5 years, SD = 12.2; 68.1% male) completed the survey assessing the nature, severity, and frequency of sleep disturbances. The dependent variable was insomnia in first-degree relatives and spouses. Familial aggregation was claimed if the risk of insomnia was significantly higher in the exposed (relatives of cases) compared to the unexposed cohort (relatives of controls). The risk of insomnia was also compared between spouses in the exposed (spouses of cases) and unexposed cohort (spouses of controls). The risk of insomnia in exposed and unexposed biological relatives was 18.6% and 10.4%, respectively, yielding a relative risk (RR) of 1.80 (p = .04) after controlling for age and sex. The risk of insomnia in exposed and unexposed spouses was 9.1% and 4.2%, respectively; however, corresponding RR of 2.13 (p = .28) did not differ significantly. Results demonstrate evidence of strong familial aggregation of insomnia. Additional research is warranted to further clarify and disentangle the relative contribution of genetic and environmental factors in insomnia. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2.

Science.gov (United States)

Chen, Ying; Hu, Lingxiang; Wang, Xueling; Sun, Changling; Lin, Xin; Li, Lei; Mei, Ling; Huang, Zhiwu; Yang, Tao; Wu, Hao

2016-09-13

The homozygous p.V37I variant in GJB2 is prevalent in East and Southeast Asians and may lead to mild-to-moderate hearing loss with reduced penetrance. To investigate the pathogenic mechanism underlying this variant, we generated a knock-in mouse model of homozygous p.V37I by an embryonic stem cell gene targeting method. Auditory brainstem response test showed that the knock-in mice developed progressive, mild-to-moderate hearing loss over the first 4-9 months. Overall no significant developmental and morphological abnormality was observed in the knock-in mouse cochlea, while confocal immunostaining and electron microscopic scanning revealed minor loss of the outer hair cells. Gene expression microarray analysis identified 105 up-regulated and 43 down-regulated genes in P5 knock-in mouse cochleae (P knock-in mouse modeled the hearing phenotype of the human patients and can serve as a useful animal model for further studies. The differentially expressed genes identified in this study may shed new insights into the understanding of the pathogenic mechanism and the phenotypic modification of homozygous p.V37I.

Efficient generation of Rosa26 knock-in mice using CRISPR/Cas9 in C57BL/6 zygotes.

Science.gov (United States)

Chu, Van Trung; Weber, Timm; Graf, Robin; Sommermann, Thomas; Petsch, Kerstin; Sack, Ulrike; Volchkov, Pavel; Rajewsky, Klaus; Kühn, Ralf

2016-01-16

The CRISPR/Cas9 system is increasingly used for gene inactivation in mouse zygotes, but homology-directed mutagenesis and use of inbred embryos are less established. In particular, Rosa26 knock-in alleles for the insertion of transgenes in a genomic 'safe harbor' site, have not been produced. Here we applied CRISPR/Cas9 for the knock-in of 8-11 kb inserts into Rosa26 of C57BL/6 zygotes. We found that 10-20 % of live pups derived from microinjected zygotes were founder mutants, without apparent off-target effects, and up to 50 % knock-in embryos were recovered upon coinjection of Cas9 mRNA and protein. Using this approach, we established a new mouse line for the Cre/loxP-dependent expression of Cas9. Altogether, our protocols and resources support the fast and direct generation of new Rosa26 knock-in alleles and of Cas9-mediated in vivo gene editing in the widely used C57BL/6 inbred strain.

A RANS knock model to predict the statistical occurrence of engine knock

International Nuclear Information System (INIS)

D'Adamo, Alessandro; Breda, Sebastiano; Fontanesi, Stefano; Irimescu, Adrian; Merola, Simona Silvia; Tornatore, Cinzia

2017-01-01

Highlights: • Development of a new RANS model for SI engine knock probability. • Turbulence-derived transport equations for variances of mixture fraction and enthalpy. • Gasoline autoignition delay times calculated from detailed chemical kinetics. • Knock probability validated against experiments on optically accessible GDI unit. • PDF-based knock model accounting for the random nature of SI engine knock in RANS simulations. - Abstract: In the recent past engine knock emerged as one of the main limiting aspects for the achievement of higher efficiency targets in modern spark-ignition (SI) engines. To attain these requirements, engine operating points must be moved as close as possible to the onset of abnormal combustions, although the turbulent nature of flow field and SI combustion leads to possibly ample fluctuations between consecutive engine cycles. This forces engine designers to distance the target condition from its theoretical optimum in order to prevent abnormal combustion, which can potentially damage engine components because of few individual heavy-knocking cycles. A statistically based RANS knock model is presented in this study, whose aim is the prediction not only of the ensemble average knock occurrence, poorly meaningful in such a stochastic event, but also of a knock probability. The model is based on look-up tables of autoignition times from detailed chemistry, coupled with transport equations for the variance of mixture fraction and enthalpy. The transported perturbations around the ensemble average value are based on variable gradients and on a local turbulent time scale. A multi-variate cell-based Gaussian-PDF model is proposed for the unburnt mixture, resulting in a statistical distribution for the in-cell reaction rate. An average knock precursor and its variance are independently calculated and transported; this results in the prediction of an earliest knock probability preceding the ensemble average knock onset, as confirmed by

Identifying At-Risk Individuals for Insomnia Using the Ford Insomnia Response to Stress Test

Science.gov (United States)

Kalmbach, David A.; Pillai, Vivek; Arnedt, J. Todd; Drake, Christopher L.

2016-01-01

Study Objectives: A primary focus of the National Institute of Mental Health's current strategic plan is “predicting” who is at risk for disease. As such, the current investigation examined the utility of premorbid sleep reactivity in identifying a specific and manageable population at elevated risk for future insomnia. Methods: A community-based sample of adults (n = 2,892; 59.3% female; 47.9 ± 13.3 y old) with no lifetime history of insomnia or depression completed web-based surveys across three annual assessments. Participants reported parental history of insomnia, demographic characteristics, sleep reactivity on the Ford Insomnia in Response to Stress Test (FIRST), and insomnia symptoms. DSM-IV diagnostic criteria were used to determine insomnia classification. Results: Baseline FIRST scores were used to predict incident insomnia at 1-y follow-up. Two clinically meaningful FIRST cutoff values were identified: FIRST ≥ 16 (sensitivity 77%; specificity 50%; odds ratio [OR] = 2.88, P insomnia onset, even after controlling for stress exposure and demographic characteristics. Of the incident cases, insomniacs with highly reactive sleep systems reported longer sleep onset latencies (FIRST ≥ 16: 65 min; FIRST ≥ 18: 68 min) than participants with nonreactive insomnia (FIRST insomnia based on trait sleep reactivity. The FIRST accurately identifies a focused target population in which the psychobiological processes complicit in insomnia onset and progression can be better investigated, thus improving future preventive efforts. Citation: Kalmbach DA, Pillai V, Arnedt JT, Drake CL. Identifying at-risk individuals for insomnia using the ford insomnia response to stress test. SLEEP 2016;39(2):449–456. PMID:26446111

Autophagy and UPR in alpha-crystallin mutant knock-in mouse models of hereditary cataracts.

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Andley, Usha P; Goldman, Joshua W

2016-01-01

Knock-in mice provide useful models of congenital and age-related cataracts caused by α-crystallin mutations. R49C αA-crystallin and R120G αB-crystallin mutations are linked with hereditary cataracts. Knock-in αA-R49C+/- heterozygotes develop cataracts by 1-2months, whereas homozygote mice have cataracts at birth. The R49C mutation drastically reduces lens protein water solubility and causes cell death in knock-in mouse lenses. Mutant crystallin cannot function as a chaperone, which leads to protein aggregation and lens opacity. Protein aggregation disrupts the lens fiber cell structure and normal development and causes cell death in epithelial and fiber cells. We determined what aspects of the wild-type phenotype are age-dependently altered in the mutant lens. Wild-type, heterozygote (αA-R49C+/-), and homozygote (αA-R49C+/+) mouse lenses were assessed pre- and postnatally for lens morphology (electron microscopy, immunohistochemistry), and autophagy or unfolded protein response markers (immunoblotting). Morphology was altered by embryonic day 17 in R49C+/+ lenses; R49C+/- lens morphology was unaffected at this stage. Active autophagy in the lens epithelium of mutant lenses was indicated by the presence of autophagosomes using electron microscopy. Protein p62 levels, which are degraded specifically by autophagy, increased in αA-R49C mutant versus wild-type lenses, suggesting autophagy inhibition in the mutant lenses. The unfolded protein response marker XBP-1 was upregulated in adult lenses of αB-R120G+/+ mice, suggesting its role in lens opacification. Mutated crystallins alter lens morphology, autophagy, and stress responses. Therapeutic modulation of autophagic pathways may improve protein degradation in cataractous lenses and reduce lens opacity. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Study of insomnia in rotating shift-workers

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Kaushik Chatterjee

2017-01-01

Full Text Available Background: Shift-workers commonly suffer from insomnia. This study evaluates different domains of insomnia. Aim: This study was aimed to study sleep and insomnia in rotating shift-workers and compare with day-workers. Materials and Methods: This was case–control study. The sleep of rotating shift-workers is compared with day workers using Athens Insomnia Scale. Results: Rotating shift-workers had significantly higher scores on Athens insomnia scale on domains of initial, intermediate and terminal insomnia than day workers. Duration and quality of sleep and sense of well-being are lower in rotating shift-workers. Rotating shift-workers also experienced more day-time sleepiness than day workers. However, there was no difference in perceived physical and mental functioning between the two groups. Conclusion: Individuals working in rotating shifts for more than 15 days have significantly higher prevalence of insomnia than day-workers.

Insomnia

Science.gov (United States)

... or chronic (ongoing). Acute insomnia is common. Common causes include stress at work, family pressures, or a traumatic event. It usually ... it is not caused by something else. Its cause is not well understood, but ... travel and shift work can be factors. Primary insomnia usually lasts more ...

A Novel Mgp-Cre Knock-In Mouse Reveals an Anticalcification/Antistiffness Candidate Gene in the Trabecular Meshwork and Peripapillary Scleral Region.

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Borrás, Teresa; Smith, Matthew H; Buie, LaKisha K

2015-04-01

Soft tissue calcification is a pathological condition. Matrix Gla (MGP) is a potent mineralization inhibitor secreted by cartilage chondrocytes and arteries' vascular smooth muscle cells. Mgp knock-out mice die at 6 weeks due to massive arterial calcification. Arterial calcification results in arterial stiffness and higher systolic blood pressure. Intriguingly, MGP was highly abundant in trabecular meshwork (TM). Because tissue stiffness is relevant to glaucoma, we investigated which additional eye tissues use Mgp's function using knock-in mice. An Mgp-Cre-recombinase coding sequence (Cre) knock-in mouse, containing Mgp DNA plus an internal ribosomal entry site (IRES)-Cre-cassette was generated by homologous recombination. Founders were crossed with Cre-mediated reporter mouse R26R-lacZ. Their offspring expresses lacZ where Mgp is transcribed. Eyes from MgpCre/+;R26RlacZ/+ (Mgp-lacZ knock-in) and controls, 1 to 8 months were assayed for β-gal enzyme histochemistry. As expected, Mgp-lacZ knock-in's TM was intensely blue. In addition, this mouse revealed high specific expression in the sclera, particularly in the peripapillary scleral region (ppSC). Ciliary muscle and sclera above the TM were also positive. Scleral staining was located immediately underneath the choroid (chondrocyte layer), began midsclera and was remarkably high in the ppSC. Cornea, iris, lens, ciliary body, and retina were negative. All mice exhibited similar staining patterns. All controls were negative. Matrix Gla's restricted expression to glaucoma-associated tissues from anterior and posterior segments suggests its involvement in the development of the disease. Matrix Gla's anticalcification/antistiffness properties in the vascular tissue, together with its high TM and ppCS expression, place this gene as a strong candidate for TM's softness and sclera's stiffness regulation in glaucoma.

Expression of wild-type Rp1 protein in Rp1 knock-in mice rescues the retinal degeneration phenotype.

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Qin Liu

Full Text Available Mutations in the retinitis pigmentosa 1 (RP1 gene are a common cause of autosomal dominant retinitis pigmentosa (adRP, and have also been found to cause autosomal recessive RP (arRP in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39 are located in the 4(th and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3(rd exon of RP1 (c.686delC; p.P229QfsX35 found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated Rp1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as Rp1 transgenic mice carrying a wild-type BAC Rp1 transgene. The Rp1-Q662X allele produces a truncated Rp1 protein, and homozygous Rp1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC Rp1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled.

Sleep Disorders: Insomnia.

Science.gov (United States)

Burman, Deepa

2017-09-01

Insomnia is the most common type of sleep disorder in the family medicine population. It is defined as a persistent difficulty initiating or maintaining sleep, or a report of nonrestorative sleep, accompanied by related daytime impairment. Insomnia is a significant public health problem because of its high prevalence and management challenges. There is increasing evidence of a strong association between insomnia and various medical and psychiatric comorbidities. Diagnosis of insomnia and treatment planning rely on a thorough sleep history to address contributing and precipitating factors as well as maladaptive behaviors resulting in poor sleep. Using a sleep diary or sleep log is more accurate than patient recall to determine sleep patterns. A sleep study is not routinely indicated for evaluation of insomnia. Cognitive behavioral therapy for insomnia (CBT-I) is the mainstay of treatment and is a safe and effective approach. The key challenge of CBT-I is the lack of clinicians to implement it. The newer generation nonbenzodiazepines (eg, zolpidem, zaleplon) are used as first-line pharmacotherapy for chronic insomnia. Newer drugs active on targets other than the gamma-aminobutyric acid receptor are now available, but clear treatment guidelines are needed. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Effects of ascorbic acid on carcinogenicity and acute toxicity of nickel subsulfide, and on tumor transplants growth in gulonolactone oxidase knock-out mice and wild-type C57BL mice

Energy Technology Data Exchange (ETDEWEB)

Kasprzak, Kazimierz S. [Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 21702 (United States); Diwan, Bhalchandra A. [Basic Research Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD 21702 (United States); Kaczmarek, Monika Z. [Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 21702 (United States); Logsdon, Daniel L. [Laboratory Animal Sciences Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD 21702 (United States); Fivash, Mathew J. [Data Management Services, National Cancer Institute at Frederick, Frederick, MD 21702 (United States); Salnikow, Konstantin, E-mail: salnikok@mail.nih.gov [Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 21702 (United States)

2011-11-15

The aim of this study was to test a hypothesis that ascorbate depletion could enhance carcinogenicity and acute toxicity of nickel. Homozygous L-gulono- < gamma > -lactone oxidase gene knock-out mice (Gulo-/- mice) unable to produce ascorbate and wild-type C57BL mice (WT mice) were injected intramuscularly with carcinogenic nickel subsulfide (Ni{sub 3}S{sub 2}), and observed for the development of injection site tumors for 57 weeks. Small pieces of one of the induced tumors were transplanted subcutaneously into separate groups of Gulo-/- and WT mice and the growth of these tumors was measured for up to 3 months. The two strains of mice differed significantly with regard to (1) Ni{sub 3}S{sub 2} carcinogenesis: Gulo-/- mice were 40% more susceptible than WT mice; and (2) transplanted tumors development: Gulo-/- mice were more receptive to tumor growth than WT mice, but only in terms of a much shorter tumor latency; later in the exponential phase of growth, the growth rates were the same. And, with adequate ascorbate supplementation, the two strains were equally susceptible to acute toxicity of Ni{sub 3}S{sub 2}. Statistically significant effects of dietary ascorbate dosing levels were the following: (1) reduction in ascorbate supplementation increased acute toxicity of Ni{sub 3}S{sub 2} in Gulo-/- mice; (2) ascorbate supplementation extended the latency of transplanted tumors in WT mice. In conclusion, the lack of endogenous ascorbate synthesis makes Gulo-/- mice more susceptible to Ni{sub 3}S{sub 2} carcinogenesis. Dietary ascorbate tends to attenuate acute toxicity of Ni{sub 3}S{sub 2} and to extend the latency of transplanted tumors. The latter effects may be of practical importance to humans and thus deserve further studies. -- Highlights: Black-Right-Pointing-Pointer Ascorbate depletion enhances carcinogenicity and acute toxicity of nickel. Black-Right-Pointing-Pointer Gulo-/- mice unable to synthesize ascorbate were used in this study. Black

Effects of ascorbic acid on carcinogenicity and acute toxicity of nickel subsulfide, and on tumor transplants growth in gulonolactone oxidase knock-out mice and wild-type C57BL mice

International Nuclear Information System (INIS)

Kasprzak, Kazimierz S.; Diwan, Bhalchandra A.; Kaczmarek, Monika Z.; Logsdon, Daniel L.; Fivash, Mathew J.; Salnikow, Konstantin

2011-01-01

The aim of this study was to test a hypothesis that ascorbate depletion could enhance carcinogenicity and acute toxicity of nickel. Homozygous L-gulono- -lactone oxidase gene knock-out mice (Gulo−/− mice) unable to produce ascorbate and wild-type C57BL mice (WT mice) were injected intramuscularly with carcinogenic nickel subsulfide (Ni 3 S 2 ), and observed for the development of injection site tumors for 57 weeks. Small pieces of one of the induced tumors were transplanted subcutaneously into separate groups of Gulo−/− and WT mice and the growth of these tumors was measured for up to 3 months. The two strains of mice differed significantly with regard to (1) Ni 3 S 2 carcinogenesis: Gulo−/− mice were 40% more susceptible than WT mice; and (2) transplanted tumors development: Gulo−/− mice were more receptive to tumor growth than WT mice, but only in terms of a much shorter tumor latency; later in the exponential phase of growth, the growth rates were the same. And, with adequate ascorbate supplementation, the two strains were equally susceptible to acute toxicity of Ni 3 S 2 . Statistically significant effects of dietary ascorbate dosing levels were the following: (1) reduction in ascorbate supplementation increased acute toxicity of Ni 3 S 2 in Gulo−/− mice; (2) ascorbate supplementation extended the latency of transplanted tumors in WT mice. In conclusion, the lack of endogenous ascorbate synthesis makes Gulo−/− mice more susceptible to Ni 3 S 2 carcinogenesis. Dietary ascorbate tends to attenuate acute toxicity of Ni 3 S 2 and to extend the latency of transplanted tumors. The latter effects may be of practical importance to humans and thus deserve further studies. -- Highlights: ► Ascorbate depletion enhances carcinogenicity and acute toxicity of nickel. ► Gulo−/− mice unable to synthesize ascorbate were used in this study. ► The reduction in ascorbate levels in Gulo−/− mice increased acute toxicity induced by Ni 3 S 2 . �

Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.

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Ihssane Bouybayoune

2015-04-01

Full Text Available Fatal familial insomnia (FFI and a genetic form of Creutzfeldt-Jakob disease (CJD178 are clinically different prion disorders linked to the D178N prion protein (PrP mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD mice modeling CJD178. No prion infectivity was detectable in Tg(FFI and Tg(CJD brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI and Tg(CJD neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

Three-Year Follow-Up of Insomnia and Hypnotics after Controlled Internet Treatment for Insomnia.

Science.gov (United States)

Blom, Kerstin; Jernelöv, Susanna; Rück, Christian; Lindefors, Nils; Kaldo, Viktor

2016-06-01

To investigate the long-term effects of therapist-guided Internet-based insomnia treatment on insomnia severity and sleep medication use, compared with active control. This study was an 8 week randomized controlled trial with follow-up posttreatment and at 6, 12, and 36 months, set at the Internet Psychiatry Clinic, Stockholm, Sweden. Participants were 148 media-recruited nondepressed adults with insomnia. Interventions were Guided Internet-based cognitive behavioral therapy for insomnia (ICBT-i) or active control treatment (ICBT-ctrl). Primary outcome was insomnia severity, measured with the Insomnia Severity Index. Secondary outcomes were sleep medication use and use of other treatments. The large pretreatment to posttreatment improvements in insomnia severity of the ICBT-i group were maintained during follow-up. ICBT-ctrl exhibited significantly less improvement posttreatment (between-Cohen d = 0.85), but after 12 and 36 months, there was no longer a significant difference. The within-group effect sizes from pretreatment to the 36-months follow-up were 1.6 (ICBT-i) and 1.7 (ICBT-ctrl), and 74% of the interviewed participants no longer had insomnia diagnosis after 36 mo. ICBT-ctrl used significantly more sleep medication (P = 0.017) and underwent significantly more other insomnia treatments (P insomnia has long-term effects. After 36 months, the groups did not differ in insomnia severity, but ICBT-ctrl had used more sleep medication and undergone more other additional insomnia treatments during the follow-up period. The trial was registered, together with a parallel trial, at Clinicaltrials.gov as "Internet-CBT for Insomnia" registration ID: NCT01256099. © 2016 Associated Professional Sleep Societies, LLC.

WHAT IS INSOMNIA

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Nurzakiah binti Zaini

2013-12-01

Full Text Available Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 Insomnia is a sleep disorder with recurrent difficulty to sleep or maintaining sleep with symptoms tired all day. There are several types of insomnia, transient insomnia which is temporary insomnia, short-term insomnia that can last for several weeks, and chronic insomnia that can last for more than four weeks. Insomnia is caused by several factors, including physical factors such as suffering from certain diseases, environmental factors, psychological factors and psychiatric problems. To overcome this disorder we can use relaxation techniques, subconscious programming, and drug therapy. /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

The Pathophysiology of Insomnia

Science.gov (United States)

Levenson, Jessica C.; Kay, Daniel B.

2015-01-01

Insomnia disorder is characterized by chronic dissatisfaction with sleep quantity or quality that is associated with difficulty falling asleep, frequent nighttime awakenings with difficulty returning to sleep, and/or awakening earlier in the morning than desired. Although progress has been made in our understanding of the nature, etiology, and pathophysiology of insomnia, there is still no universally accepted model. Greater understanding of the pathophysiology of insomnia may provide important information regarding how, and under what conditions, the disorder develops and is maintained as well as potential targets for prevention and treatment. The aims of this report are (1) to summarize current knowledge on the pathophysiology of insomnia and (2) to present a model of the pathophysiology of insomnia that considers evidence from various domains of research. Working within several models of insomnia, evidence for the pathophysiology of the disorder is presented across levels of analysis, from genetic to molecular and cellular mechanisms, neural circuitry, physiologic mechanisms, sleep behavior, and self-report. We discuss the role of hyperarousal as an overarching theme that guides our conceptualization of insomnia. Finally, we propose a model of the pathophysiology of insomnia that integrates the various types of evidence presented. PMID:25846534

Identifying At-Risk Individuals for Insomnia Using the Ford Insomnia Response to Stress Test.

Science.gov (United States)

Kalmbach, David A; Pillai, Vivek; Arnedt, J Todd; Drake, Christopher L

2016-02-01

A primary focus of the National Institute of Mental Health's current strategic plan is "predicting" who is at risk for disease. As such, the current investigation examined the utility of premorbid sleep reactivity in identifying a specific and manageable population at elevated risk for future insomnia. A community-based sample of adults (n = 2,892; 59.3% female; 47.9 ± 13.3 y old) with no lifetime history of insomnia or depression completed web-based surveys across three annual assessments. Participants reported parental history of insomnia, demographic characteristics, sleep reactivity on the Ford Insomnia in Response to Stress Test (FIRST), and insomnia symptoms. DSM-IV diagnostic criteria were used to determine insomnia classification. Baseline FIRST scores were used to predict incident insomnia at 1-y follow-up. Two clinically meaningful FIRST cutoff values were identified: FIRST ≥ 16 (sensitivity 77%; specificity 50%; odds ratio [OR] = 2.88, P insomnia onset, even after controlling for stress exposure and demographic characteristics. Of the incident cases, insomniacs with highly reactive sleep systems reported longer sleep onset latencies (FIRST ≥ 16: 65 min; FIRST ≥ 18: 68 min) than participants with nonreactive insomnia (FIRST insomnia based on trait sleep reactivity. The FIRST accurately identifies a focused target population in which the psychobiological processes complicit in insomnia onset and progression can be better investigated, thus improving future preventive efforts. © 2016 Associated Professional Sleep Societies, LLC.

Difference in Perseverative Errors during a Visual Attention Task with Auditory Distractors in Alpha-9 Nicotinic Receptor Subunit Wild Type and Knock-Out Mice.

Science.gov (United States)

Jorratt, Pascal; Delano, Paul H; Delgado, Carolina; Dagnino-Subiabre, Alexies; Terreros, Gonzalo

2017-01-01

The auditory efferent system is a neural network that originates in the auditory cortex and projects to the cochlear receptor through olivocochlear (OC) neurons. Medial OC neurons make cholinergic synapses with outer hair cells (OHCs) through nicotinic receptors constituted by α9 and α10 subunits. One of the physiological functions of the α9 nicotinic receptor subunit (α9-nAChR) is the suppression of auditory distractors during selective attention to visual stimuli. In a recent study we demonstrated that the behavioral performance of alpha-9 nicotinic receptor knock-out (KO) mice is altered during selective attention to visual stimuli with auditory distractors since they made less correct responses and more omissions than wild type (WT) mice. As the inhibition of the behavioral responses to irrelevant stimuli is an important mechanism of the selective attention processes, behavioral errors are relevant measures that can reflect altered inhibitory control. Errors produced during a cued attention task can be classified as premature, target and perseverative errors. Perseverative responses can be considered as an inability to inhibit the repetition of an action already planned, while premature responses can be considered as an index of the ability to wait or retain an action. Here, we studied premature, target and perseverative errors during a visual attention task with auditory distractors in WT and KO mice. We found that α9-KO mice make fewer perseverative errors with longer latencies than WT mice in the presence of auditory distractors. In addition, although we found no significant difference in the number of target error between genotypes, KO mice made more short-latency target errors than WT mice during the presentation of auditory distractors. The fewer perseverative error made by α9-KO mice could be explained by a reduced motivation for reward and an increased impulsivity during decision making with auditory distraction in KO mice.

The Experience of Chronic Insomnia in Chinese Adults: A Study Using Focus Groups and Insomnia Experience Diaries.

Science.gov (United States)

Yung, Kam-Ping; Chung, Ka-Fai; Ho, Fiona Yan-Yee; Yeung, Wing-Fai; Ng, Tommy Ho-Yee

2016-01-01

The subjective experience in 43 Chinese adults with chronic primary insomnia was assessed using focus groups and insomnia experience diaries. Participants recruited from the community and a sleep clinic were diagnosed with DSM-IV-TR insomnia disorder and had sleep difficulties on 3 or more nights per week for at least 6 months. Six focus groups, of 6-8 participants each, were conducted; it was stopped as thematic saturation emerged in the last 2 groups. Using grounded theory approach, we identified 4 themes and 16 subthemes, covering beliefs about the nature and treatment of insomnia, behavioral responses to insomnia, cognitive-emotional and physiological arousal, and emotional experiences associated with insomnia. The findings are in general compatible with qualitative studies in the West, but some subthemes are influenced by Chinese cultural beliefs and values, in particular, use of the traditional Chinese medicine concept, being modest in sleep expectation, and a letting go attitude. Strategies for cultural adaptation of cognitive-behavioral therapy for insomnia in a Chinese society using patients' subjective experience are discussed.

MANAGEMENT OF INSOMNIA

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Liya Rosdiana Sholehah

2013-04-01

Full Text Available Sleep is an essential component of health and well-being. The effects of insomnia, Whether as a primary or secondary symptoms, is a major health concern and should be closely studied and Examined across all age groups. There is growing evidence that the effects of insomnia on Adolescent's functioning is comparable to that of other major psychiatric disorders (eg, mood disorders, anxiety disorders, etc... Insomnia is associated with significant negative Consequences, impairing functioning across a number of emotional, social, cognitive, and physical domains (Carskadon, 1999; Johnson, Roth, Schultz, & Breslau, 2006; Roberts, Roberts, & Duong, 2008b; Wolfson & Carskadon, 1998. Based on the academic literature to date, it is hypothesized that insomnia will be Significantly more prevalent   among   Adolescents   of   the   female   sex   and   among   those   reporting psychological and / or physical health concerns. The analyzes conducted included basic descriptive statistics (frequencies / percentages, bivariate analyzes (Chi-square tests, and a multiple logistic regression. The prevalence rate of insomnia in adolescents was 9.5%, with no significant association found between sex and insomnia. The multivariate analysis Showed Significantly insomnia to be associated with the presence of a chronic condition, selected mood disorders (12 months, in adolescents  who  are  experiencing  "quite  a  bit"  to  "extreme"  life  stress,  and  in adolescents who were living in than other households with both parents. Insomnia was not found to be associated Significantly with sex, selected anxiety disorder (12 months, heavy drinking, heavy cannabis use, and in Adolescents who were only experiencing "some life stress".  heavy cannabis  use  and  having  a selected  anxiety Significantly disorder was associated with insomnia. More informed knowledge can be used to create prevention and treatment strategies to address �

Childhood adversity and insomnia in adolescence.

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Wang, Yan; Raffeld, Miriam R; Slopen, Natalie; Hale, Lauren; Dunn, Erin C

2016-05-01

The study aims to evaluate the association between exposure to childhood adversity and insomnia, with an emphasis on the role of adversity type, timing, and accumulation (i.e., the number of specific types of adversities the child reported being exposed to). Our analytic sample comprised 9582 adolescents from the National Comorbidity Survey Replication Adolescent Supplement (NCS-A), a nationally representative population-based sample. We examined the association between 18 different types of retrospectively reported adversities (capturing interpersonal violence, accidents and injuries, social network or witnessing events, and other adverse events) and risk of self-reported past-year insomnia. We also examined whether the age at first exposure to adversity was associated with the risk of insomnia, and whether exposure to a greater number of different types of adversities (ie, accumulation) conferred an elevated risk of insomnia. In addition, we performed a sensitivity analysis excluding adolescents with a past-year diagnosis of major depression, dysthymia, post-traumatic stress disorder (PTSD), or generalized anxiety disorder. Almost one-third of adolescents reported insomnia, with a higher prevalence among girls and those from racial/ethnic minority groups. Adolescents exposed to at least one childhood adversity of any type (59.41%) were more likely than their nonexposed peers to experience insomnia (across adversities, prevalence ratios (PRs) ranged from 1.31 to 1.89). Risk of insomnia differed based on the age at first exposure to adversity as well as the type of adversity. Adolescents exposed to a greater number of different types of adversities had a higher risk of insomnia compared to those experiencing fewer adversities. These results were similar, by and large, to those obtained after excluding adolescents with at least one of the four past-year psychiatric disorders. Exposure to adversity confers an elevated risk of insomnia. This association varied by type

[Etiology of adult insomnia].

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Dollander, M

2002-01-01

In the article, the author develops an analysis of external and intrapsychic factors related to adults' insomnia. First she undertakes a literature review to describe semiological, evolutive and etiological levels of insomnia. From a semiological point of view, it is usual to differenciate initial insomnia (associated to the first phase of sleeping), intermittent insomnia (related to frequent awakenings) and final insomnia (related to early morning awakenings). From an evolutive point of view, we can identify transitory insomnia (characterized by frequent awakenings) and chronic insomnia. On the other hand, we are allowed to distinguish organic insomnia (disorder where an organic cerebral injury is demonstrated or suspected) from insomnias related to psychiatric or somatic disease or idiopathic one. Then, the author makes a literary review to identify various insomnia causes and points out. Social factors: insomnia rates are higher by divorced, separated or widowed people. Percentages are higher when scholastic level is weak, domestic income is less then 915 O a month, or by unemployed people. Besides, sleep quality is deteriorated by ageing. Sleeping and waking rhythm is able to loose its synchronization. Complaints about insomnia occur far frequently from women than men. Environmental factors: working constraints increase sleep disorders. It is possible to make the same conclusion when we have to face overcharge of external events, deep intrapsychic conflicts (related to grief, unemployment, damage or hospitalization) or interpersonal conflicts' situations where we are confronted to stress related to socio-affective environment, lack of social support or conjugal difficulties. Medical and physiologic causes: legs impatience syndrome, recurrent limbs shakings syndrome, breathe stop during sleep, narcolepsy, excessive medicine or hypnotic drugs use, some central nervous system injuries, every nocturnal awakening (related to aches.), surgical operation

Pain-related insomnia versus primary insomnia: a comparison study of sleep pattern, psychological characteristics, and cognitive-behavioral processes.

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Tang, Nicole K Y; Goodchild, Claire E; Hester, Joan; Salkovskis, Paul M

2012-06-01

Recent applications of cognitive-behavior therapy for primary insomnia in the management of pain-related insomnia are based on the implicit assumption that the 2 types of insomnia share the same presentation and maintaining mechanisms. The objectives of this study were to compare the characteristics of patients who have pain-related insomnia with those reporting primary insomnia and to identify psychological factors that predict pain-related insomnia. Chronic pain patients with concomitant insomnia (n=137; Pain-related Insomnia Group) completed a selection of questionnaires that measure sleep patterns, psychological attributes, and cognitive-behavioral processes associated with the persistence of insomnia. Their responses were compared with those of primary insomnia patients (n=33; Primary Insomnia Group), using 3 sets of multivariate analyses of covariance that took account of demographic differences. Hierarchical regression analyses were performed to identify predictors of insomnia severity among the chronic pain patients. The Pain-related Insomnia Group did not differ from the Primary Insomnia Group in their pattern and severity of sleep disturbance. The 2 groups were largely comparable in terms of their psychological characteristics, except that the Primary Insomnia Group was distinguishable from the Pain-related Insomnia Group by their greater tendency to worry. Patients in the Pain-related Insomnia Group reported levels of sleep-related anxiety and presleep somatic arousal that matched with those reported by patients in the Primary Insomnia Group. However, relative to patients in the Pain-related Insomnia Group, those in the Primary Insomnia Group reported more dysfunctional sleep beliefs and presleep cognitive arousal. In addition to pain intensity, depression, and presleep cognitive arousal were significant predictors of insomnia severity within the Pain-related Insomnia Group. There are more similarities than differences between the 2 types of insomnia

Optimizing Sleep in Older Adults: Treating Insomnia

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Wennberg, Alexandra M.; Canham, Sarah L.; Smith, Michael T.; Spira, Adam P.

2013-01-01

As the world’s population ages, the elevated prevalence of insomnia in older adults is a growing concern. Insomnia is characterized by difficulty falling or remaining asleep, or by non-restorative sleep, and resultant daytime dysfunction. In addition to being at elevated risk for primary insomnia, older adults are at greater risk for comorbid insomnia, which results from, or occurs in conjunction with another medical or psychiatric condition. In this review, we discuss normal changes in sleep...

Fibulin-4 E57K Knock-in Mice Recapitulate Cutaneous, Vascular and Skeletal Defects of Recessive Cutis Laxa 1B with both Elastic Fiber and Collagen Fibril Abnormalities.

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Igoucheva, Olga; Alexeev, Vitali; Halabi, Carmen M; Adams, Sheila M; Stoilov, Ivan; Sasaki, Takako; Arita, Machiko; Donahue, Adele; Mecham, Robert P; Birk, David E; Chu, Mon-Li

2015-08-28

Fibulin-4 is an extracellular matrix protein essential for elastic fiber formation. Frameshift and missense mutations in the fibulin-4 gene (EFEMP2/FBLN4) cause autosomal recessive cutis laxa (ARCL) 1B, characterized by loose skin, aortic aneurysm, arterial tortuosity, lung emphysema, and skeletal abnormalities. Homozygous missense mutations in FBLN4 are a prevalent cause of ARCL 1B. Here we generated a knock-in mouse strain bearing a recurrent fibulin-4 E57K homozygous missense mutation. The mutant mice survived into adulthood and displayed abnormalities in multiple organ systems, including loose skin, bent forelimb, aortic aneurysm, tortuous artery, and pulmonary emphysema. Biochemical studies of dermal fibroblasts showed that fibulin-4 E57K mutant protein was produced but was prone to dimer formation and inefficiently secreted, thereby triggering an endoplasmic reticulum stress response. Immunohistochemistry detected a low level of fibulin-4 E57K protein in the knock-in skin along with altered expression of selected elastic fiber components. Processing of a precursor to mature lysyl oxidase, an enzyme involved in cross-linking of elastin and collagen, was compromised. The knock-in skin had a reduced level of desmosine, an elastin-specific cross-link compound, and ultrastructurally abnormal elastic fibers. Surprisingly, structurally aberrant collagen fibrils and altered organization into fibers were characteristics of the knock-in dermis and forelimb tendons. Type I collagen extracted from the knock-in skin had decreased amounts of covalent intermolecular cross-links, which could contribute to the collagen fibril abnormalities. Our studies provide the first evidence that fibulin-4 plays a role in regulating collagen fibril assembly and offer a preclinical platform for developing treatments for ARCL 1B. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Case Studies of Chronic Insomnia Patients Participating in Group Cognitive Behavioral Therapy for Insomnia

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Mi Jin Yi

2012-10-01

Full Text Available Background and Objective Pharmacotherapy currently widely used in the treatment of insomnia can be helpful in transient insomnia, but research regarding its effectiveness and safety of long-term use is not enough. Therefore, to complement the limitations of pharmacotherapy in the treatment of patients with insomnia, non-pharmacologic treatment methods (cognitive behavioral therapy, CBT are used. But CBT for insomnia appear to be costly and time-consuming compared to pharmacotherapy, clinical practice in the field can be difficult to be applied. We took the format of group therapy rather than individual therapy to complement the disadvantages of CBT and now we would like to have a thought into its meaning by reporting the effectiveness of group CBT for insomnia. Methods Patients were recruited at Sleep Center of St. Vincent’s Hospital, 2 men and 3 women led to a group of five patients. CBT is a treatment for correction factors that cause and maintain insomnia, it includes a variety of techniques such as sleep hygiene education, stimulus control, sleep restriction, relaxation and cognitive therapy. A series of treatment were performed five sessions once a week with a frequency from February to March 2012 and were proceeded for about 1 hour and 30 minutes per session. Results Results indicated that the subjective quality of sleep and sleep efficiency of all patients improved and Pittsburgh Sleep Quality Index and Beck Depression Inventory were decreased in spite of reducing dose of medication. Conclusions Like these cases, we can contribute to reduce the time and economic burden by performing group CBT for insomnia rather than individual therapy.

Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice.

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Marina Kovalenko

Full Text Available The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111 with mice carrying a conditional (floxed Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of Msh2 in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of Msh2 was sufficient to eliminate the vast majority of striatal HTT CAG expansions in HdhQ111 mice. Furthermore, MSN-specific deletion of Msh2 modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore, Msh2 acts within MSNs as a genetic enhancer both of somatic HTT CAG expansions and of HTT CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.

Insomnia and the Performance of US Workers: Results from the America Insomnia Survey

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Kessler, Ronald C.; Berglund, Patricia A.; Coulouvrat, Catherine; Hajak, Goeran; Roth, Thomas; Shahly, Victoria; Shillington, Alicia C.; Stephenson, Judith J.; Walsh, James K.

2011-01-01

Study Objectives: To estimate the prevalence and associations of broadly defined (i.e., meeting full ICD-10, DSM-IV, or RDC/ICSD-2 inclusion criteria) insomnia with work performance net of comorbid conditions in the America Insomnia Survey (AIS). Design/Setting: Cross-sectional telephone survey. Participants: National sample of 7,428 employed health plan subscribers (ages 18+). Interventions: None. Measurements and Results: Broadly defined insomnia was assessed with the Brief Insomnia Questionnaire (BIQ). Work absenteeism and presenteeism (low on-the-job work performance defined in the metric of lost workday equivalents) were assessed with the WHO Health and Work Performance Questionnaire (HPQ). Regression analysis examined associations between insomnia and HPQ scores controlling 26 comorbid conditions based on self-report and medical/pharmacy claims records. The estimated prevalence of insomnia was 23.2%. Insomnia was significantly associated with lost work performance due to presenteeism (χ21 = 39.5, P absenteeism (χ21 = 3.2, P = 0.07), with an annualized individual-level association of insomnia with presenteeism equivalent to 11.3 days of lost work performance. This estimate decreased to 7.8 days when controls were introduced for comorbid conditions. The individual-level human capital value of this net estimate was $2,280. If we provisionally assume these estimates generalize to the total US workforce, they are equivalent to annualized population-level estimates of 252.7 days and $63.2 billion. Conclusions: Insomnia is associated with substantial workplace costs. Although experimental studies suggest some of these costs could be recovered with insomnia disease management programs, effectiveness trials are needed to obtain precise estimates of return-on-investment of such interventions from the employer perspective. Citation: Kessler RC; Berglund PA; Coulouvrat C; Hajak G; Roth T; Shahly V; Shillington AC; Stephenson JJ; Walsh JK. Insomnia and the performance

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

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Kelsey Moore

2016-11-01

Full Text Available Blood oxygen level dependent (BOLD imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ opioid receptor knock-outs (MuKO in response to oxycodone (OXY. Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high µ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala and hypothalamus, and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex and prelimbic cortex. Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala and preoptic areas. This result indicates that most effects of OXY on positive BOLD are mediated by the µ opioid receptor (on-target effects. OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122 and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum, and in some case intensified (hippocampus. Negative BOLD analysis therefore shows activation and deactivation events in the absence of the µ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects. Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY

Drugs for insomnia.

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Zisapel, Nava

2012-09-01

Sleep is a vital neurochemical process involving sleep-promoting and arousal centers in the brain. Insomnia is a pervasive disorder characterized by difficulties in initiating or maintaining or non-refreshing (poor quality) sleep and clinically significant daytime distress. Insomnia is more prevalent in women and old age and puts sufferers at significant physical and mental health risks. This review summarizes published data on the current and emerging insomnia drug classes, rationale for development and associated risks/benefits. (Summary of Product Characteristics and Medline search on "hypnotic" or specific drug names and "Insomnia"). GABA(A) receptor modulators facilitate sleep onset and some improve maintenance but increase risk of dependence, memory, cognitive and psychomotor impairments, falls, accidents and mortality. Melatonin receptor agonists improve quality of sleep and/or sleep onset but response may develop over several days. They have more benign safety profiles and are indicated for milder insomnia, longer usage and (prolonged release melatonin) older patients. Histamine H-1 receptor antagonists improve sleep maintenance but their effects on cognition, memory and falls remain to be demonstrated. Late-stage pipeline orexin OX1/OX2 and serotonin 5HT2A receptor antagonists may hold the potential to address several unmet needs in insomnia pharmacotherapy but safety issues cast some doubts over their future. Current and new insomnia drugs in the pipeline target different sleep regulating mechanisms and symptoms and have different tolerability profiles. Drug selection would ideally be based on improvement in the quality of patients' sleep, overall quality of life and functional status weighed against risk to the individual and public health.

Insomnia of childhood.

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Lipton, Jonathan; Becker, Ronald E; Kothare, Sanjeev V

2008-12-01

Insomnia is a major public health problem and is the most common sleep disturbance in both adults and children. The causes of sleeplessness are age-dependent and have potentially enormous effects on cognitive development, behavior, family dynamics, and the metabolic health of children. Here we review the epidemiology, cause, pathophysiology, and clinical approach to pediatric insomnia. Normal sleep is crucial for brain function, behavior, and normal metabolism. Consistently, sleep loss has been linked to behavioral and attention problems, impaired learning and memory, obesity, and psychiatric disorders. The neurological mechanisms that govern sleep initiation and maintenance are poorly understood. The types of insomnia are age-dependent and can occur as primary disorders, or in the context of another primary sleep disorder such as restless legs syndrome, or secondary to another underlying medical condition. Children with chronic diseases and especially children with neurodevelopmental disorders are at particular risk of insomnia. Pediatric insomnia is common and is a source of potential psychophysiological stress to both children and their caregivers. The causes of insomnia are various. Pediatricians should have a working knowledge of the causes of sleeplessness in order to promptly curtail the chronic effects of sleep loss and effectively screen for underlying, potentially treatable disorders.

Insomnia and the performance of US workers: results from the America insomnia survey.

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Kessler, Ronald C; Berglund, Patricia A; Coulouvrat, Catherine; Hajak, Goeran; Roth, Thomas; Shahly, Victoria; Shillington, Alicia C; Stephenson, Judith J; Walsh, James K

2011-09-01

To estimate the prevalence and associations of broadly defined (i.e., meeting full ICD-10, DSM-IV, or RDC/ICSD-2 inclusion criteria) insomnia with work performance net of comorbid conditions in the America Insomnia Survey (AIS). Cross-sectional telephone survey. National sample of 7,428 employed health plan subscribers (ages 18+). None. Broadly defined insomnia was assessed with the Brief Insomnia Questionnaire (BIQ). Work absenteeism and presenteeism (low on-the-job work performance defined in the metric of lost workday equivalents) were assessed with the WHO Health and Work Performance Questionnaire (HPQ). Regression analysis examined associations between insomnia and HPQ scores controlling 26 comorbid conditions based on self-report and medical/pharmacy claims records. The estimated prevalence of insomnia was 23.2%. Insomnia was significantly associated with lost work performance due to presenteeism (χ² (1) = 39.5, P absenteeism (χ² (1) = 3.2, P = 0.07), with an annualized individual-level association of insomnia with presenteeism equivalent to 11.3 days of lost work performance. This estimate decreased to 7.8 days when controls were introduced for comorbid conditions. The individual-level human capital value of this net estimate was $2,280. If we provisionally assume these estimates generalize to the total US workforce, they are equivalent to annualized population-level estimates of 252.7 days and $63.2 billion. Insomnia is associated with substantial workplace costs. Although experimental studies suggest some of these costs could be recovered with insomnia disease management programs, effectiveness trials are needed to obtain precise estimates of return-on-investment of such interventions from the employer perspective.

Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides

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Shaobin Yang

2018-01-01

Full Text Available The Akt kinase has been widely assumed for years as a key downstream effector of the PI3K signaling pathway in promoting neuronal survival. This notion was however challenged by the finding that neuronal survival responses were still preserved in mice with reduced Akt activity. Moreover, here we show that the Akt signaling is elevated in the aged brain of two different mice models of Alzheimer Disease. We manipulate the rate of Akt stimulation by employing knock-in mice expressing a mutant form of PDK1 (phosphoinositide-dependent protein kinase 1 with reduced, but not abolished, ability to activate Akt. We found increased membrane localization and activity of the TACE/ADAM17 α-secretase in the brain of the PDK1 mutant mice with concomitant TNFR1 processing, which provided neurons with resistance against TNFα-induced neurotoxicity. Opposite to the Alzheimer Disease transgenic mice, the PDK1 knock-in mice exhibited an age-dependent attenuation of the unfolding protein response, which protected the mutant neurons against endoplasmic reticulum stressors. Moreover, these two mechanisms cooperatively provide the mutant neurons with resistance against amyloid-beta oligomers, and might singularly also contribute to protect these mice against amyloid-beta pathology.

Insomnia in the elderly: cause, approach, and treatment.

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Kamel, Nabil S; Gammack, Julie K

2006-06-01

Insomnia is a prevalent problem in late life. Sleep problems in the elderly are often mistakenly considered a normal part of aging. Insomnia, the most common sleep disorder, is a subjective report of insufficient or nonrestorative sleep despite adequate opportunity to sleep. Despite the fact that more than 50% of elderly people have insomnia, it is typically undertreated, and nonpharmacologic interventions are underused by health care practitioners. This article will review the causes of insomnia in the elderly, the approach to patient evaluation, and the nonpharmacologic and pharmacologic treatment of insomnia.

Insomnia among community dwelling elderly in Alexandria, Egypt.

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Ayoub, Abla I; Attia, Medhat; El Kady, Heba M; Ashour, Ayat

2014-12-01

Insomnia is a common problem in the elderly population. Poor sleep quality is associated with decreased memory and concentration, increased risk of falls, cognitive decline, and higher rate of mortality. Inadequate sleep hygiene such as irregular sleep schedules, use of stimulants, and daytime naps may predispose to insomnia. The aim of this study was to determine the prevalence of insomnia among community dwelling elderly in Alexandria and to assess some of the risk factors and comorbid conditions related to insomnia. This is a cross-sectional study conducted among 380 elderly people taken from different clubs in Alexandria using a predesigned structured interview questionnaire. Data on sociodemographic characteristics, medical history, and personal and sleeping habits were collected. The Insomnia Severity Index was used to assess insomnia and the Depression Anxiety Stress Scale was used to measure depression, anxiety, and stress. One-third (33.4%) of the elderly suffered from insomnia. On logistic regression, the most independent factors that were significantly associated with insomnia were number of chronic diseases [odds ratio (OR)=7.25 for having ≥5 diseases], being female (OR=2.37), anxiety (OR=1.91), watching television in bed before sleeping (OR=1.90), depression (OR=1.74), nocturia (OR=1.13), and daily sunlight exposure (OR=0.57). Insomnia is a common problem among the elderly in Alexandria. Female sex, chronic diseases, mental health problems, and bad sleep hygiene practice increase the risk for insomnia. Improving knowledge among the elderly about the prevalence and risk factors of insomnia could help the development of effective public health prevention and intervention programs for better sleep quality.

The societal costs of insomnia

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Alan G Wade

2010-12-01

Full Text Available Alan G WadeCPS Research, Glasgow, ScotlandObjective: Insomnia can be broadly defined as difficulty initiating or maintaining sleep, or sleep that is not refreshing or of poor quality with negative effect on daytime function. Insomnia can be a primary condition or comorbid to an underlying disorder. Subjective measures of insomnia used in population studies, usually based on complaints of unsatisfactory sleep, put the prevalence at about 10%. Insomnia is more common in the elderly and in women, and is often associated with medical and psychiatric disorders. This review examines the measures used to assess quality of sleep (QOS and daytime functioning and the impact of insomnia on society using these measures.Methods: Literature searches were performed to identify all studies of insomnia (primary and comorbid in adults (aged 18–64 years and the elderly (aged ≥ 65 years with baseline and/or outcomes relating to QOS or daytime functioning. The impact of poor QOS on quality of life (QOL, psychomotor and cognitive skills, health care resource utilization, and other societal effects was examined.Results: Although definitions and measurement scales used to assess sleep quality vary widely, it is clear that the societal consequences of insomnia are substantial and include impaired QOL and increased health care utilization. The impact of poor QOS and impaired daytime functioning common in insomnia can lead to indirect effects such as lower work productivity, increased sick leave, and a higher rate of motor vehicle crashes.Conclusions: Insomnia is associated with substantial direct and indirect costs to society. It is almost impossible to separate the costs associated with primary and comorbid insomnia. More studies are required which control for the severity of any primary disorder to accurately evaluate the costs of comorbid insomnia. Development of standardized diagnostic and assessment scales will enable more accurate quantification of the true

Subjective-objective sleep discrepancy among older adults: Associations with insomnia diagnosis and insomnia treatment

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Kay, Daniel B.; Buysse, Daniel J.; Germain, Anne; Hall, Martica; Monk, Timothy H.

2014-01-01

Discrepancy between subjective and objective measures of sleep is associated with insomnia and increasing age. Cognitive behavioral therapy for insomnia improves sleep quality and decreases subjective-objective sleep discrepancy. This study describes differences between older adults with insomnia and controls in sleep discrepancy, and tests the hypothesis that reduced sleep discrepancy following cognitive behavioral therapy for insomnia correlates with the magnitude of symptom improvement rep...

Significance of perfectionism in understanding different forms of insomnia

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Totić-Poznanović Sanja

2012-01-01

Full Text Available Introduction. Studies consistently show a connection between perfectionism as a multidimensional construct with various psychological and psychopathological states and characteristics. However, studies that analyze the connection between this concept and sleep disturbances, especially modalities of insomnia, are rare. Objective. The aim of this study was to examine whether dimensions of perfectionism can explain different forms of insomnia; difficulties initiating sleep (insomnia early, difficulties during the sleep (insomnia middle, waking in early hours of the morning (insomnia late and dissatisfaction with sleep quality (subjective insomnia. Methods. The sample consisted of 254 students of the School of Medicine in Belgrade. Predictive significance of nine perfectionism dimensions, measured by Frost’s and Hewitt’s and Flett’s scales of multi-dimensional perfectionism, related to four modalities of insomnia, measured by a structured questionnaire, was analyzed by multiple linear regression method. Results. Perfectionism dimensions are significant predictors of each of the tested forms of insomnia. Doubt about actions significantly predicts initial insomnia; to other-oriented perfectionism in the negative pole and socially prescribed perfectionism underlie the difficulties during the sleep, while organization and parental criticism underlie late insomnia. Significant predictors of subjective insomnia are personal standards and organization and to other-oriented perfectionism on the negative pole. Three of nine analyzed dimensions were not confirmed as significant; concern over mistakes, parental expectations and self-oriented perfectionism. Conclusion. Various aspects of perfectionism can be considered as a vulnerability factor for understanding some forms of insomnia. Out of all forms of insomnia tested, perfectionism as the personality trait proved to be the most significant for understanding subjective insomnia.

[Insomnia associated with psychiatric disorders].

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Suzuki, Masahiro; Konno, Chisato; Furihata, Ryuji; Osaki, Koichi; Uchiyama, Makoto

2009-08-01

Most psychiatric disorders, such as schizophrenia, mood disorders, or neurotic disorders are associated with sleep disorders of various kinds, among which insomnia is most prevalent and important in psychiatric practice. Almost all patients suffering from major depression complain of insomnia. Pharmacological treatment of insomnia associated with major depression shortens the duration to achieve remission of depression. Insomnia has been recently reported to be a risk factor for depression. In patients with schizophrenia, insomnia is often an early indicator of the aggravation of psychotic symptoms. Electroencephalographic sleep studies have also revealed sleep abnormalities characteristic to mood disorders, schizophrenia and anxiety disorders. A shortened REM sleep latency has been regarded as a biological marker of depression. Reduced amount of deep non-REM sleep has been reported to be correlated with negative symptoms of schizophrenia. Recently, REM sleep abnormalities were found in teenagers having post-traumatic stress disorder after a boat accident. Although these facts indicate that insomnia plays an important role in the development of psychiatric disorders, there are few hypotheses explaining the cause and effect of insomnia in these disorders. Here, we reviewed recent articles on insomnia associated with psychiatric disorders together with their clinical managements.

Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice.

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Cathy Joanna Jensen

Full Text Available In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by crossing homozygous β2-adrenergic receptor floxed mice (Adrb2flox and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2. Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that β2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function.

Difference in Perseverative Errors during a Visual Attention Task with Auditory Distractors in Alpha-9 Nicotinic Receptor Subunit Wild Type and Knock-Out Mice

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Pascal Jorratt

2017-11-01

Full Text Available The auditory efferent system is a neural network that originates in the auditory cortex and projects to the cochlear receptor through olivocochlear (OC neurons. Medial OC neurons make cholinergic synapses with outer hair cells (OHCs through nicotinic receptors constituted by α9 and α10 subunits. One of the physiological functions of the α9 nicotinic receptor subunit (α9-nAChR is the suppression of auditory distractors during selective attention to visual stimuli. In a recent study we demonstrated that the behavioral performance of alpha-9 nicotinic receptor knock-out (KO mice is altered during selective attention to visual stimuli with auditory distractors since they made less correct responses and more omissions than wild type (WT mice. As the inhibition of the behavioral responses to irrelevant stimuli is an important mechanism of the selective attention processes, behavioral errors are relevant measures that can reflect altered inhibitory control. Errors produced during a cued attention task can be classified as premature, target and perseverative errors. Perseverative responses can be considered as an inability to inhibit the repetition of an action already planned, while premature responses can be considered as an index of the ability to wait or retain an action. Here, we studied premature, target and perseverative errors during a visual attention task with auditory distractors in WT and KO mice. We found that α9-KO mice make fewer perseverative errors with longer latencies than WT mice in the presence of auditory distractors. In addition, although we found no significant difference in the number of target error between genotypes, KO mice made more short-latency target errors than WT mice during the presentation of auditory distractors. The fewer perseverative error made by α9-KO mice could be explained by a reduced motivation for reward and an increased impulsivity during decision making with auditory distraction in KO mice.

Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload.

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Elena Montes-Cobos

Full Text Available Mineralocorticoid receptor (MR inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox. Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes.

The validity of knock-for-knock clauses in comparative perspective / Sylvie Cėcile Cavaleri

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Cavaleri, Sylvie Cėcile

2018-01-01

Seoses Põhjamere nafta- ja gaasitootmisega sõlmitavatest lepingutest, kus kasutatakse nn "knock-for-knock" klausleid. Nende kohaselt katab iga lepingu osaline ise oma kahjud, sõltumata kahjude põhjustajast

PLAG1 deficiency impairs spermatogenesis and sperm motility in mice.

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Juma, Almas R; Grommen, Sylvia V H; O'Bryan, Moira K; O'Connor, Anne E; Merriner, D Jo; Hall, Nathan E; Doyle, Stephen R; Damdimopoulou, Pauliina E; Barriga, Daniel; Hart, Adam H; Van de Ven, Wim J M; De Groef, Bert

2017-07-13

Deficiency in pleomorphic adenoma gene 1 (PLAG1) leads to reduced fertility in male mice, but the mechanism by which PLAG1 contributes to reproduction is unknown. To investigate the involvement of PLAG1 in testicular function, we determined (i) the spatial distribution of PLAG1 in the testis using X-gal staining; (ii) transcriptomic consequences of PLAG1 deficiency in knock-out and heterozygous mice compared to wild-type mice using RNA-seq; and (iii) morphological and functional consequences of PLAG1 deficiency by determining testicular histology, daily sperm production and sperm motility in knock-out and wild-type mice. PLAG1 was sparsely expressed in germ cells and in Sertoli cells. Genes known to be involved in spermatogenesis were downregulated in the testes of knock-out mice, as well as Hsd17b3, which encodes a key enzyme in androgen biosynthesis. In the absence of Plag1, a number of genes involved in immune processes and epididymis-specific genes were upregulated in the testes. Finally, loss of PLAG1 resulted in significantly lowered daily sperm production, in reduced sperm motility, and in several animals, in sloughing of the germinal epithelium. Our results demonstrate that the subfertility seen in male PLAG1-deficient mice is, at least in part, the result of significantly reduced sperm output and sperm motility.

Insomnia in Sweden: A Population-Based Survey

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Mallon, Lena; Broman, Jan-Erik; Åkerstedt, Torbjörn; Hetta, Jerker

2014-01-01

Aims. Estimate the prevalence of insomnia and examine effects of sex, age, health problems, sleep duration, need for treatment, and usage of sleep medication. Methods. A sample of 1,550 subjects aged 18–84 years was selected for a telephone interview. The interview was completed by 1,128 subjects (72.8%). Results. 24.6% reported insomnia symptoms. Insomnia disorder, that is, insomnia symptoms and daytime consequences, was reported by 10.5%. The prevalence was similar among all age groups, wit...

Altered learning, memory, and social behavior in type 1 taste receptor subunit 3 knock-out mice are associated with neuronal dysfunction.

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Martin, Bronwen; Wang, Rui; Cong, Wei-Na; Daimon, Caitlin M; Wu, Wells W; Ni, Bin; Becker, Kevin G; Lehrmann, Elin; Wood, William H; Zhang, Yongqing; Etienne, Harmonie; van Gastel, Jaana; Azmi, Abdelkrim; Janssens, Jonathan; Maudsley, Stuart

2017-07-07

The type 1 taste receptor member 3 (T1R3) is a G protein-coupled receptor involved in sweet-taste perception. Besides the tongue, the T1R3 receptor is highly expressed in brain areas implicated in cognition, including the hippocampus and cortex. As cognitive decline is often preceded by significant metabolic or endocrinological dysfunctions regulated by the sweet-taste perception system, we hypothesized that a disruption of the sweet-taste perception in the brain could have a key role in the development of cognitive dysfunction. To assess the importance of the sweet-taste receptors in the brain, we conducted transcriptomic and proteomic analyses of cortical and hippocampal tissues isolated from T1R3 knock-out (T1R3KO) mice. The effect of an impaired sweet-taste perception system on cognition functions were examined by analyzing synaptic integrity and performing animal behavior on T1R3KO mice. Although T1R3KO mice did not present a metabolically disrupted phenotype, bioinformatic interpretation of the high-dimensionality data indicated a strong neurodegenerative signature associated with significant alterations in pathways involved in neuritogenesis, dendritic growth, and synaptogenesis. Furthermore, a significantly reduced dendritic spine density was observed in T1R3KO mice together with alterations in learning and memory functions as well as sociability deficits. Taken together our data suggest that the sweet-taste receptor system plays an important neurotrophic role in the extralingual central nervous tissue that underpins synaptic function, memory acquisition, and social behavior. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Insomnia Patients With Objective Short Sleep Duration Have a Blunted Response to Cognitive Behavioral Therapy for Insomnia.

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Bathgate, Christina J; Edinger, Jack D; Krystal, Andrew D

2017-01-01

This study examined whether individuals with insomnia and objective short sleep duration insomnia (CBT-I) when compared to individuals with insomnia and normal sleep duration ≥6 h. Secondary analyses of a randomized, clinical trial with 60 adult participants (n = 31 women) from a single academic medical center. Outpatient treatment lasted 8 weeks, with a final follow-up conducted at 6 months. Mixed-effects models controlling for age, sex, CBT-I treatment group assignment, and treatment provider examined sleep parameters gathered via actigraphy, sleep diaries, and an Insomnia Symptom Questionnaire (ISQ) across the treatment and follow-up period. Six months post-CBT-I treatment, individuals with insomnia and normal sleep duration ≥6 h fared significantly better on clinical improvement milestones than did those with insomnia and short sleep duration insomnia and normal sleep duration had significantly higher insomnia remission (ISQ 80%; χ2[1, N = 60] = 21, p 50% decline in MWASO (χ2[1, N = 60] = 60, p insomnia and short sleep duration. Additionally, those with insomnia and normal sleep duration had more success decreasing their total wake time (TWT) at the 6-month follow-up compared to those with insomnia and short sleep duration (χ2[2, N = 60] = 44.1, p insomnia remission, with the area under the curve = 0.986. Findings suggest that individuals with insomnia and objective short sleep duration insomnia and normal sleep duration ≥6 h. Using an actigraphy TST cutoff of 6 hours to classify sleep duration groups was highly accurate and provided good discriminant value for determining insomnia remission. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Generation and characterization of PDGFRα-GFPCreERT2 knock-In mouse line.

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Miwa, Hiroyuki; Era, Takumi

2015-05-01

Platelet-derived growth factor (PDGF) and its receptor play an important role in embryogenesis. PDGF receptor α (PDGFRα) is expressed specifically in the embryonic day 7.5 (E7.5) mesoderm and in the E9.5 neural crest among other tissues. PDGFRα-expressing cells and their descendants are involved in the formation of various tissues. To trace PDGFRα-expressing cells in vivo, we generated a knock-in mouse line that expressed a fusion protein of green fluorescent protein (GFP), Cre recombinase (Cre), and mutated estrogen receptor ligand-binding domain (ERT2) under the control of the PDGFRα promoter. In these mice, Cre activity in PDGFRα-expressing cells could be induced by tamoxifen treatment. Taken together, our results suggest that the knock-in mouse line generated here could be useful for studying PDGFRα-expressing cells and their descendants in vivo at various stages of development. © 2015 Wiley Periodicals, Inc.

Insomnia and Well-Being

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Hamilton, Nancy A.; Gallagher, Matthew W.; Preacher, Kristopher J.; Stevens, Natalie; Nelson, Christy A.; Karlson, Cynthia; McCurdy, Danyale

2007-01-01

Most Americans have occasional problems with insomnia. The relationship of insomnia to illness is well known. However, insomnia may also relate to lower levels of well-being. Although there are various definitions of well-being, one of the most clearly articulated and comprehensive models identifies 2 overarching constructs, psychological…

Eszopiclone for late-life insomnia

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Christina S McCrae

2007-10-01

Full Text Available Christina S McCrae1, Amanda Ross1, Ashley Stripling2, Natalie D Dautovich21Department of Clinical and Health Psychology, 2Department of Psychology, University of Florida, Gainesville, Florida, USAAbstract: Insomnia, the most common sleep disturbance in later life, affects 20%–50% of older adults. Eszopiclone, a short-acting nonbenzodiazepine hypnotic agent developed for the treatment of insomnia, has been available in Europe since 1992 and in the US since 2005. Although not yet evaluated for transient insomnia in older adults, eszopiclone has been shown to be safe and efficacious for short-term treatment (2 weeks of chronic, primary insomnia in older adults (64–91 years. Clinical studies in younger adults (mean = 44 years have shown eszopiclone can be used for 6–12 months without evidence of problems. Because the oldest participant in these longer-term trials was 69, it not known whether eszopiclone is effective for older adults [particularly the old old (75–84 years and oldest old (85+] when used over longer periods. This is unfortunate, because older individuals frequently suffer from chronic insomnia. Cognitive-behavioral therapy for insomnia, which effectively targets the behavioral factors that maintain chronic insomnia, represents an attractive treatment alternative or adjuvant to eszopiclone for older adults. To date, no studies have compared eszopiclone to other hypnotic medications or to nonpharmacological interventions, such as cognitive-behavioral therapy for insomnia, in older adults. All of the clinical trials reported herein were funded by Sepracor. This paper provides an overview of the literature on eszopiclone with special emphasis on its use for the treatment of late-life insomnia. Specific topics covered include pharmacology, pharmacodynamics, pharmacokinetics, clinical trial data, adverse events, drug interactions, tolerance/dependence, and economics/cost considerations for older adults. Keywords: aging, eszopiclone

The burden of insomnia in Japan

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Mishima K

2015-01-01

Full Text Available Kazuo Mishima,1 Marco daCosta DiBonaventura,2 Hillary Gross2 1Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 2Kantar Health, New York, NY, USA Objectives: Several studies have suggested that patients who experience insomnia report a number of significant impairments. However, despite this literature, fewer studies have focused on the burden of insomnia among patients in Japan. The objective of the current study is to extend this work in Japan to further understand the effect of insomnia on health-related quality of life (hrQOL. Further, another objective is to understand general predictors of hrQOL among patients with insomnia. Methods: Data from the 2012 Japan National Health and Wellness Survey, an annual, cross-sectional study of adults aged 18 years or older, were used (N=30,000. All National Health and Wellness Survey respondents were categorized based on the incidence of self-reported insomnia diagnosis and prescription medication usage (clinical insomniacs under treatment versus [vs] good sleepers without insomnia or insomnia symptoms. Comparisons among different groups were made using multiple regression models controlling for demographics and health history. Results: Clinical insomniacs (n=1,018; 3.4% reported significantly worse hrQOL compared with good sleepers (n=20,542 (mental component summary: 34.2 vs 48.0; physical component summary: 48.0 vs 52.8; health utilities: 0.61 vs 0.76; all P<0.05. Health behaviors (smoking, exercise, alcohol use and comorbidities were the strongest predictors of health utilities for clinical insomniacs. For all three clinical insomniac subgroups of interest, those with a physical comorbidity but not a psychiatric one, those with a psychiatric comorbidity but not a physical one, and those without either a physical or psychiatric comorbidity, large decrements in health utilities were observed for respondents who did

Monthly fluctuations of insomnia symptoms in a population-based sample.

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Morin, Charles M; Leblanc, M; Ivers, H; Bélanger, L; Mérette, Chantal; Savard, Josée; Jarrin, Denise C

2014-02-01

To document the monthly changes in sleep/insomnia status over a 12-month period; to determine the optimal time intervals to reliably capture new incident cases and recurrent episodes of insomnia and the likelihood of its persistence over time. Participants were 100 adults (mean age = 49.9 years; 66% women) randomly selected from a larger population-based sample enrolled in a longitudinal study of the natural history of insomnia. They completed 12 monthly telephone interviews assessing insomnia, use of sleep aids, stressful life events, and physical and mental health problems in the previous month. A total of 1,125 interviews of a potential 1,200 were completed. Based on data collected at each assessment, participants were classified into one of three subgroups: good sleepers, insomnia symptoms, and insomnia syndrome. At baseline, 42 participants were classified as good sleepers, 34 met criteria for insomnia symptoms, and 24 for an insomnia syndrome. There were significant fluctuations of insomnia over time, with 66% of the participants changing sleep status at least once over the 12 monthly assessments (51.5% for good sleepers, 59.5% for insomnia syndrome, and 93.4% for insomnia symptoms). Changes of status were more frequent among individuals with insomnia symptoms at baseline (mean = 3.46, SD = 2.36) than among those initially classified as good sleepers (mean = 2.12, SD = 2.70). Among the subgroup with insomnia symptoms at baseline, 88.3% reported improved sleep (i.e., became good sleepers) at least once over the 12 monthly assessments compared to 27.7% whose sleep worsened (i.e., met criteria for an insomnia syndrome) during the same period. Among individuals classified as good sleepers at baseline, risks of developing insomnia symptoms and syndrome over the subsequent months were, respectively, 48.6% and 14.5%. Monthly assessment over an interval of 6 months was found most reliable to estimate incidence rates, while an interval of 3 months proved the most

Changes in insomnia subtypes in early Parkinson disease.

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Tholfsen, Lena K; Larsen, Jan P; Schulz, Jörn; Tysnes, Ole-Bjørn; Gjerstad, Michaela D

2017-01-24

To examine the development of factors associated with insomnia in a cohort of originally drug-naive patients with incident Parkinson disease (PD) during the first 5 years after diagnosis. One hundred eighty-two drug-naive patients with PD derived from a population-based incident cohort and 202 control participants were assessed for insomnia before treatment initiation and were repeatedly examined after 1, 3, and 5 years. Insomnia was diagnosed according to the Stavanger Sleepiness Questionnaire. The Parkinson's Disease Sleep Scale was used to differentiate sleep initiation problems from problems of sleep maintenance. Generalized estimating equation models were applied for statistical measures. The prevalence of insomnia in general was not higher in patients with PD compared to controls at the 5-year follow-up. There were changes in the prevalence of the different insomnia subtypes over the 5-year follow-up. The prevalence of solitary problems in sleep maintenance increased from 31% (n = 18) in the drug-naive patients at baseline to 49% (n = 29) after 1 year and were associated with the use of dopamine agonists and higher Montgomery-Åsberg Depression Rating Scale scores. The prevalence of solitary sleep initiation problems decreased continuously from 21% (n = 12) at baseline to 7.4% (n = 4) after 5 years; these were associated with less daytime sleepiness. The prevalence rates of the different insomnia subtypes changed notably in patients with early PD. The frequency of sleep maintenance problems increased, and these problems were associated with dopamine agonist use and depressive symptoms, while the total number of patients with insomnia remained stable. Our findings reflect the need for early individual assessments of insomnia subtypes and raise the possibility of intervention to reduce these symptoms in patients with early PD. © 2016 American Academy of Neurology.

Cognitive Behavioral Therapy for Insomnia in Older Adults

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Belanger, Lynda; LeBlanc, Melanie; Morin, Charles M.

2012-01-01

Insomnia is associated with significant morbidity and is often a persistent problem, particularly in older adults. It is important to attend to this complaint and not assume that it will remit spontaneously. In many cases, unfortunately, insomnia remains unrecognized and untreated, often because it is presumed that insomnia is an inevitable…

Insomnia, dreams, and suicide: Connecting links

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Sagar B Karia

2016-01-01

Full Text Available Introduction: A growing empirical literature has examined insomnia symptoms as a possible risk factor for a range of suicidal behavior. Not much literature is available in normal adolescent population. Aims: The aim is to find insomnia prevalence, studying various dream factors, and suicidality prevalence among students of various courses. To check if there is a relation between insomnia and suicidal behavior and dreams, particularly nightmares and suicide. Materials and Methods: A total of 400 students of various courses were assessed using Insomnia Severity Index and The Mannheim Dream Questionnaire and Suicide Behaviour Questionnaire. Results: Insomnia was present in 11%, 23%, 19%, and 19% and suicide behavior in 16%, 17%, 12%, and 22%, respectively, in medical, commerce, engineering, and arts students. Statistically significant correlation was found between suicide and insomnia severity and various dream factors. Conclusions: Insomnia and dreams had relation with suicidality in normal adolescent population.

Cocaine self-administration in mice with forebrain knock-down of trpc5 ion channels [v1; ref status: indexed, http://f1000r.es/pb

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Matthew B Pomrenze

2013-02-01

Full Text Available Canonical transient receptor potential (TRPC channels are a family of non-selective cation channels that play a crucial role in modulating neuronal excitability due to their involvement in intracellular Ca2+ regulation and dendritic growth. TRPC5 channels a are one of the two most prevalent TRPC channels in the adult rodent brain; b are densely expressed in deep layer pyramidal neurons of the prefrontal cortex (PFC; and c modulate neuronal persistent activity necessary for working memory and attention. In order to evaluate the causal role of TRPC5 in motivation/reward-related behaviors, conditional forebrain TRPC5 knock-down (trpc5-KD mice were generated and trained to nose-poke for intravenous cocaine. Here we present a data set containing the first 6 days of saline or cocaine self-administration in wild type (WT and trpc5-KD mice. In addition, we also present a data set showing the dose-response to cocaine after both groups had achieved similar levels of cocaine self-administration. Compared to WT mice, trpc5-KD mice exhibited an apparent increase in self-administration on the first day of cocaine testing without prior operant training. There were no apparent differences between WT and trpc5-KD mice for saline responding on the first day of training. Both groups showed similar dose-response sensitivity to cocaine after several days of achieving similar levels of cocaine intake.

Clinical Experience in TCM Treatment of Insomnia

Institute of Scientific and Technical Information of China (English)

无

2007-01-01

@@ Insomnia is a sleeping disorder that affects 1 in 10 Americans and around 50% of the seniors. It is often more prevalent in women. Since September 11, 2005 these estimations have increased. Insomnia can affect not only your energy level and mood, but your health as well because sleep helps bolster your immune system. Insomnia is characterized by: 1) difficulty in falling asleep; 2) waking up frequently during the night with difficulty of returning to sleep; 3) waking up too early in the morning; and 4) with unrefreshing sleep, the patient has a low spirit, palpation, poor memory, viscera function disorder. All these seriously affect the patient's life and work. The following is an account of the authors' clinical TCM experience in treating insomnia.

Human physiological models of insomnia.

Science.gov (United States)

Richardson, Gary S

2007-12-01

Despite the wide prevalence and important consequences of insomnia, remarkably little is known about its pathophysiology. Available models exist primarily in the psychological domain and derive from the demonstrated efficacy of behavioral treatment approaches to insomnia management. However, these models offer little specific prediction about the anatomic or physiological foundation of chronic primary insomnia. On the other hand, a growing body of data on the physiology of sleep supports a reasonably circumscribed overview of possible pathophysiological mechanisms, as well as the development of physiological models of insomnia to guide future research. As a pragmatic step, these models focus on primary insomnia, as opposed to comorbid insomnias, because the latter is by its nature a much more heterogeneous presentation, reflecting the effects of the distinct comorbid condition. Current understanding of the regulation of sleep and wakefulness in mammalian brain supports four broad candidate areas: 1) disruption of the sleep homeostat; 2) disruption of the circadian clock; 3) disruption of intrinsic systems responsible for the expression of sleep states; or 4) disruption (hyperactivity) of extrinsic systems capable of over-riding normal sleep-wake regulation. This review examines each of the four candidate pathophysiological mechanisms and the available data in support of each. While studies that directly test the viability of each model are not yet available, descriptive data on primary insomnia favor the involvement of dysfunctional extrinsic stress-response systems in the pathology of primary chronic insomnia.

Monthly Fluctuations of Insomnia Symptoms in a Population-Based Sample

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Morin, Charles M.; LeBlanc, M.; Ivers, H.; Bélanger, L.; Mérette, Chantal; Savard, Josée; Jarrin, Denise C.

2014-01-01

Study Objectives: To document the monthly changes in sleep/insomnia status over a 12-month period; to determine the optimal time intervals to reliably capture new incident cases and recurrent episodes of insomnia and the likelihood of its persistence over time. Design: Participants were 100 adults (mean age = 49.9 years; 66% women) randomly selected from a larger population-based sample enrolled in a longitudinal study of the natural history of insomnia. They completed 12 monthly telephone interviews assessing insomnia, use of sleep aids, stressful life events, and physical and mental health problems in the previous month. A total of 1,125 interviews of a potential 1,200 were completed. Based on data collected at each assessment, participants were classified into one of three subgroups: good sleepers, insomnia symptoms, and insomnia syndrome. Results: At baseline, 42 participants were classified as good sleepers, 34 met criteria for insomnia symptoms, and 24 for an insomnia syndrome. There were significant fluctuations of insomnia over time, with 66% of the participants changing sleep status at least once over the 12 monthly assessments (51.5% for good sleepers, 59.5% for insomnia syndrome, and 93.4% for insomnia symptoms). Changes of status were more frequent among individuals with insomnia symptoms at baseline (mean = 3.46, SD = 2.36) than among those initially classified as good sleepers (mean = 2.12, SD = 2.70). Among the subgroup with insomnia symptoms at baseline, 88.3% reported improved sleep (i.e., became good sleepers) at least once over the 12 monthly assessments compared to 27.7% whose sleep worsened (i.e., met criteria for an insomnia syndrome) during the same period. Among individuals classified as good sleepers at baseline, risks of developing insomnia symptoms and syndrome over the subsequent months were, respectively, 48.6% and 14.5%. Monthly assessment over an interval of 6 months was found most reliable to estimate incidence rates, while an

Treating Acute Insomnia: A Randomized Controlled Trial of a "Single-Shot" of Cognitive Behavioral Therapy for Insomnia.

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Ellis, Jason G; Cushing, Toby; Germain, Anne

2015-06-01

Despite considerable evidence supporting cognitive behavioral therapy for insomnia (CBT-I) for chronic insomnia, it remains untested within the context of acute insomnia. This study examined the efficacy of a single session of CBT-I, with an accompanying self-help pamphlet, for individuals with acute insomnia. A pragmatic parallel group randomized controlled trial. Community. Forty adults (mean age 32.9 ± 13.72 y) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined insomnia disorder, except a self-reported duration of less than 3 mo (i.e., acute insomnia), who reported no previous exposure to CBT-I and were not currently taking medication for sleep. A single 60- to 70-min session of CBT-I (n = 20), with an accompanying self-help pamphlet, or wait list control group (n = 20). All subjects were offered a full individual course of CBT-I on completion of the study, regardless of group allocation. Subjects completed sleep diaries and the Insomnia Severity Index (ISI) pretreatment and 1 mo following treatment. There were no between-group differences on baseline ISI scores or subjective sleep continuity. The intervention group reported significantly lower ISI scores than controls (t(38) 2.24, P insomnia caseness (i.e., ≥ 10), 60% of those in the CBT-I group had remitted by 1 mo compared to 15% of those in the control group. This single session of cognitive behavioral therapy for insomnia (CBT-I) is sufficiently efficacious for a significant proportion of those with acute insomnia. The results are discussed in terms of integrating this brief form of CBT-I into the "stepped care" model of insomnia. Testing the efficacy of an early intervention for acute insomnia (SRCTN05891695) http://www.controlled-trials.com/ISRCTN05891695. © 2015 Associated Professional Sleep Societies, LLC.

Cognitive behavioral program in treating insomnia among elderly patients

OpenAIRE

Richter, Kneginja; Miloseva, Lence; Niklewski, Günter; Piehl, Anja

2015-01-01

Introduction: Insomnia is a most common in elderly patients. World wide experience showed that Cognitive behavioral program in treating insomnia is one of the best effective model. Objectives: The present study aim to present clinical experience from University Clinic Nuremberg, Centre for Sleeping Medicine with application of Cognitive behavioral program in treating insomnia among elderly. Material and Methods: The sample consists of 22 patients with chronic insomnia (10 primary insom...

Insomnia disorder and endogenous neurophysiological dynamics

NARCIS (Netherlands)

Colombo, M.

2018-01-01

Insomnia symptoms are the most common medical complaints, affecting up to a third of the general population. Insomnia symptoms include sleep problems (initiating or maintaining sleep) as well their repercussions on wake-time functioning. Insomnia Disorder can be diagnosed when insomnia symptoms are

[Chronic insomnia: not always psychophysiological].

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Neerings-Verberkmoes, Nicole E; Vlak, Monique H M; de Lau, Lonneke M L; Hamburger, Hans L

2014-01-01

To determine the sensitivity, specificity and the positive and negative predictive value of taking a detailed sleep history for making the diagnosis of psychophysiological insomnia. Retrospective case file study. We examined 767 patients referred to the Amsterdam Centre for Sleep and Wake Disorders, and who underwent polysomnography for the first time between 1 January and 31 December 2010. We compared the probable diagnosis made following history-taking with the final diagnosis made after polysomnography. In this we differentiated between organic and non-organic insomnia. The sensitivity, specificity, positive and negative predictive values of the sleep history were calculated. In 24.8% of the 303 patients whose histories did not indicate organic insomnia, polysomnography showed there to be an organic cause. Primary causes were obstructive sleep apnoea (13.2%), upper airway resistance syndrome (5.4%), and periodic limb movement disorder (4.0%) or a combination of these. In the histories of 464 patients there were indications that the insomnia had an organic cause and in 325 of them this was confirmed by polysomnography. The sensitivity of detailed history taking to psychophysiological insomnia was 62.1%, the specificity 81.3%, the positive predictive value was 75.2% and the negative predictive value was 70.0%. In patients under the age of 40 with a score on the Epworth sleepiness scale insomnia, organic insomnia could not be demonstrated, with the exception of one parasomnia. History-taking only meant that the organic cause was missed in a substantial percentage of patients with insomnia, in particular in older patients with hypersomnolence and a high BMI.

Insomnia patients' help-seeking experiences.

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Cheung, Janet M Y; Bartlett, Delwyn J; Armour, Carol L; Glozier, Nicholas; Saini, Bandana

2014-03-04

Timely access to appropriate treatment is important for optimizing insomnia management. To date, little is known about insomnia patients' treatment experiences or how they access and engage with the available health care resources. This study sought to capture the help-seeking experiences and behavioral patterns of patients with insomnia who are seeking or receiving specialist care. A purposive sample of 26 insomnia patients from specialist sleep and mental health clinics located in metropolitan New South Wales, Australia was recruited. Participants completed a brief questionnaire, followed by an in-depth, semi-structured interview. Interviews were digitally recorded, transcribed verbatim, and analyzed using framework analysis. Three key themes emerged from the data: patients' sleep beliefs, treatment beliefs, and accessing specialized care. The findings show that daytime symptoms arising from insomnia serve as important illness cues for patients to seek medical help. In addition, participants' treatment pathways highlight factors that prevent the widespread use of cognitive behavioral therapy for insomnia (CBT-I), including limited awareness about CBT-I, tentative referral mechanisms, limited service providers, and the high cost of CBT-I.

Insomnia in chronic renal patients on dialysis in Saudi Arabia

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Al-Hejaili Fayez F

2010-06-01

Full Text Available Abstract Background Studies have shown that insomnia is a common sleep disorder among patients with end-stage renal disease (ESRD. This study aimed to assess the prevalence of insomnia in Saudi patients with ESRD who are on maintenance dialysis. Methods This was an observational cross-sectional study carried out over a period of five months in two hemodialysis centers in Saudi Arabia. To assess the prevalence of insomnia, we used the ICSD-2 definition. We also examined the association between insomnia and other sleep disorders, the underlying causes of renal failure, dialysis duration, dialysis shift, and other demographic data. Results Out of 227 enrolled patients, insomnia was reported by 60.8%. The mean patient age was 55.7 ± 17.2 years; 53.7% were male and 46.3% were female. Insomnia was significantly associated with female gender, afternoon hemodialysis, Restless Legs Syndrome, high risk for obstructive Sleep Apnea Syndrome and excessive daytime sleepiness (P-values: 0.05, 0.01, Conclusion Insomnia is common in dialysis patients and was significantly associated with other sleep disorders. Greater attention needs to be given to the care of dialysis patients with regard to the diagnosis and management of insomnia and associated sleep disorders.

Behavioral interventions for insomnia: Theory and practice

OpenAIRE

Sharma, Mahendra P.; Andrade, Chittaranjan

2012-01-01

Insomnia is a general clinical term that refers to a difficulty in initiating or maintaining sleep. Insomnia is widely prevalent in the general population, especially in the elderly and in those with medical and psychiatric disorders. Hypnotic drug treatments of insomnia are effective but are associated with potential disadvantages. This article presents an overview of behavioral interventions for insomnia. Behavioral interventions for insomnia include relaxation training, stimulus control th...

Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency.

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Korner, Germaine; Noain, Daniela; Ying, Ming; Hole, Magnus; Flydal, Marte I; Scherer, Tanja; Allegri, Gabriella; Rassi, Anahita; Fingerhut, Ralph; Becu-Villalobos, Damasia; Pillai, Samyuktha; Wueest, Stephan; Konrad, Daniel; Lauber-Biason, Anna; Baumann, Christian R; Bindoff, Laurence A; Martinez, Aurora; Thöny, Beat

2015-10-01

Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH-p.R233H), often unresponsive to l-DOPA treatment. The Th knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated with a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard l-DOPA treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Behavioral interventions for insomnia: Theory and practice.

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Sharma, Mahendra P; Andrade, Chittaranjan

2012-10-01

Insomnia is a general clinical term that refers to a difficulty in initiating or maintaining sleep. Insomnia is widely prevalent in the general population, especially in the elderly and in those with medical and psychiatric disorders. Hypnotic drug treatments of insomnia are effective but are associated with potential disadvantages. This article presents an overview of behavioral interventions for insomnia. Behavioral interventions for insomnia include relaxation training, stimulus control therapy, sleep restriction therapy, sleep hygiene, paradoxical intention therapy, cognitive restructuring, and other approaches. These are briefly explained. Research indicates that behavioral interventions are efficacious, effective, and likely cost-effective treatments for insomnia that yield reliable, robust, and long-term benefits in adults of all ages. Detailed guidance is provided for the practical management of patients with insomnia.

Treating Acute Insomnia: A Randomized Controlled Trial of a “Single-Shot” of Cognitive Behavioral Therapy for Insomnia

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Ellis, Jason G.; Cushing, Toby; Germain, Anne

2015-01-01

Study Objectives: Despite considerable evidence supporting cognitive behavioral therapy for insomnia (CBT-I) for chronic insomnia, it remains untested within the context of acute insomnia. This study examined the efficacy of a single session of CBT-I, with an accompanying self-help pamphlet, for individuals with acute insomnia. Design: A pragmatic parallel group randomized controlled trial. Setting: Community. Participants: Forty adults (mean age 32.9 ± 13.72 y) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined insomnia disorder, except a self-reported duration of less than 3 mo (i.e., acute insomnia), who reported no previous exposure to CBT-I and were not currently taking medication for sleep. Interventions: A single 60- to 70-min session of CBT-I (n = 20), with an accompanying self-help pamphlet, or wait list control group (n = 20). All subjects were offered a full individual course of CBT-I on completion of the study, regardless of group allocation. Measurements and Results: Subjects completed sleep diaries and the Insomnia Severity Index (ISI) pretreatment and 1 mo following treatment. There were no between-group differences on baseline ISI scores or subjective sleep continuity. The intervention group reported significantly lower ISI scores than controls (t(38) 2.24, P insomnia caseness (i.e., ≥ 10), 60% of those in the CBT-I group had remitted by 1 mo compared to 15% of those in the control group. Conclusions: This single session of cognitive behavioral therapy for insomnia (CBT-I) is sufficiently efficacious for a significant proportion of those with acute insomnia. The results are discussed in terms of integrating this brief form of CBT-I into the “stepped care” model of insomnia. Trial Registration: Testing the efficacy of an early intervention for acute insomnia (SRCTN05891695) http://www.controlled-trials.com/ISRCTN05891695. Citation: Ellis JG, Cushing T, Germain A. Treating acute insomnia: a randomized

Insomnia in hemodialysis patients: A multicenter study from morocco

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Mohamed Amine Hamzi

2017-01-01

Full Text Available Previous studies have shown that insomnia is a common sleep disorder in patients with end-stage renal disease. This study aims to determine the prevalence and risk factors of insomnia in our chronic hemodialysis (HD patients. This is a cross-sectional study conducted in three HD units in Morocco. To assess the prevalence of insomnia, we used a specific questionnaire. Patients complaining of difficulty in falling asleep and/or nocturnal awakenings occurring seven nights a week during the last month were included in the group “insomnia;” the other patients were used as controls. Clinical, biological, and dialysis data were recorded for each patient. Sleep disorders and their subjective causes were also identified. Eighty-nine percent of questioned patients admitted to having sleep disturbances of different degrees. Insomnia was significantly associated with female gender and time of dialysis. Age, body mass index, inter-dialytic weight gain, and blood pressure were similar between the two groups, as well as dialytic parameters and drug use. There was no significant difference in the values of plasma creatinine, urea, hemoglobin, parathyroid hormone, calcium, phosphorus, C-reactive protein, and albumin between the groups. Disorders most frequently encountered in patients with insomnia were waking up at night (90%, difficulty falling asleep (60%, and daytime sleepiness (60%. The restless legs syndrome was seen in half of these patients. The main reported causes of insomnia were anxiety and/or depression (70% and bone pain (67%. Insomnia is common in HD patients and is frequently associated with other disorders of sleep. Female sex and duration on dialysis are the two risk factors found in our study. Insomnia does not appear related to any biochemical or dialysis parameters. Increased attention should be given to the management of dialysis patients regarding the diagnosis and management of insomnia and associated sleep disorders.

Subjective daytime functioning assessment in people with insomnia.

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Grabowski, Karol; Nowicka-Sauer, Katarzyna; Zdrojewski, Tomasz; Rutkowski, Marcin; Bandosz, Piotr; Nowicki, Zbigniew

2017-10-29

The aim of this study was to assess the prevalence and severity of subjective daytime functioning impairment among people with insomnia complaints. Another goal was to establish its relationships with age, gender, type and duration of subjective insomnia. Study group consisted of NATPOL study participants - 2,413 people (1,245 women and 1,168 men) aged 18-79. We extracted group with declared insomnia complaints, consisting of 1,221 people (736 women and 485 men) aged 18-79. Data on insomnia symptoms characteristics, their duration and subjective functioning impairment were further analyzed. Functioning impairment was declared by 825 people (67.7% of those who declared subjective insomnia) and it was more common in women. It was most common among people with insomnia complaints lasting over two weeks - 72.4%. In people with symptoms lasting less than two weeks or for a few days it was 70.7% and 64.9% respectively. People with insomnia symptoms lasting over two weeks accounted for 20% of group with severe functioning impairment. For shorter duration of symptoms it was 8.6% and 6.9% respectively. Among people with mild functioning impairment, persons with symptoms lasting for a few days and less than two weeks were predominant - 32.5% and 35.3% respectively. In people aged 18-24 years mild functioning impairment was predominant (66.66%). Subjective daytime functioning impairment is common in people declaring insomnia symptoms. It is more common in women and its prevalence and intensity are greater in people with longer duration of sleep problems. Its prevalence is not correlated with age and it is the mildest in people aged 18-24.

Persistent insomnia is associated with mortality risk.

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Parthasarathy, Sairam; Vasquez, Monica M; Halonen, Marilyn; Bootzin, Richard; Quan, Stuart F; Martinez, Fernando D; Guerra, Stefano

2015-03-01

Insomnia has been associated with mortality risk, but whether this association is different in subjects with persistent vs intermittent insomnia is unclear. Additionally, the role of systemic inflammation in such an association is unknown. We used data from a community-based cohort to determine whether persistent or intermittent insomnia, defined based on persistence of symptoms over a 6-year period, was associated with death during the following 20 years of follow-up. We also determined whether changes in serum C-reactive protein (CRP) levels measured over 2 decades between study initiation and insomnia determination were different for the persistent, intermittent, and never insomnia groups. The results were adjusted for confounders such as age, sex, body mass index, smoking, physical activity, alcohol, and sedatives. Of the 1409 adult participants, 249 (18%) had intermittent and 128 (9%) had persistent insomnia. During a 20-year follow-up period, 318 participants died (118 due to cardiopulmonary disease). In adjusted Cox proportional-hazards models, participants with persistent insomnia (adjusted hazards ratio [HR] 1.58; 95% confidence interval [CI], 1.02-2.45) but not intermittent insomnia (HR 1.22; 95% CI, 0.86-1.74) were more likely to die than participants without insomnia. Serum CRP levels were higher and increased at a steeper rate in subjects with persistent insomnia as compared with intermittent (P = .04) or never (P = .004) insomnia. Although CRP levels were themselves associated with increased mortality (adjusted HR 1.36; 95% CI, 1.01-1.82; P = .04), adjustment for CRP levels did not notably change the association between persistent insomnia and mortality. In a population-based cohort, persistent, and not intermittent, insomnia was associated with increased risk for all-cause and cardiopulmonary mortality and was associated with a steeper increase in inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

The nature of stable insomnia phenotypes.

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Pillai, Vivek; Roth, Thomas; Drake, Christopher L

2015-01-01

We examined the 1-y stability of four insomnia symptom profiles: sleep onset insomnia; sleep maintenance insomnia; combined onset and maintenance insomnia; and neither criterion (i.e., insomnia cases that do not meet quantitative thresholds for onset or maintenance problems). Insomnia cases that exhibited the same symptom profile over a 1-y period were considered to be phenotypes, and were compared in terms of clinical and demographic characteristics. Longitudinal. Urban, community-based. Nine hundred fifty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based current insomnia (46.6 ± 12.6 y; 69.4% female). None. At baseline, participants were divided into four symptom profile groups based on quantitative criteria. Follow-up assessment 1 y later revealed that approximately 60% of participants retained the same symptom profile, and were hence judged to be phenotypes. Stability varied significantly by phenotype, such that sleep onset insomnia (SOI) was the least stable (42%), whereas combined insomnia (CI) was the most stable (69%). Baseline symptom groups (cross-sectionally defined) differed significantly across various clinical indices, including daytime impairment, depression, and anxiety. Importantly, however, a comparison of stable phenotypes (longitudinally defined) did not reveal any differences in impairment or comorbid psychopathology. Another interesting finding was that whereas all other insomnia phenotypes showed evidence of an elevated wake drive both at night and during the day, the 'neither criterion' phenotype did not; this latter phenotype exhibited significantly higher daytime sleepiness despite subthreshold onset and maintenance difficulties. By adopting a stringent, stability-based definition, this study offers timely and important data on the longitudinal trajectory of specific insomnia phenotypes. With the exception of daytime sleepiness, few clinical differences are apparent across stable phenotypes. �

Nonpharmacologic Management of Chronic Insomnia.

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Maness, David L; Khan, Muneeza

2015-12-15

Insomnia affects 10% to 30% of the population with a total cost of $92.5 to $107.5 billion annually. Short-term, chronic, and other types of insomnia are the three major categories according to the International Classification of Sleep Disorders, 3rd ed. The criteria for diagnosis are difficulty falling asleep, difficulty staying asleep, or early awakening despite the opportunity for sleep; symptoms must be associated with impaired daytime functioning and occur at least three times per week for at least one month. Factors associated with the onset of insomnia include a personal or family history of insomnia, easy arousability, poor self-reported health, and chronic pain. Insomnia is more common in women, especially following menopause and during late pregnancy, and in older adults. A comprehensive sleep history can confirm the diagnosis. Psychiatric and medical problems, medication use, and substance abuse should be ruled out as contributing factors. Treatment of comorbid conditions alone may not resolve insomnia. Patients with movement disorders (e.g., restless legs syndrome, periodic limb movement disorder), circadian rhythm disorders, or breathing disorders (e.g., obstructive sleep apnea) must be identified and treated appropriately. Chronic insomnia is associated with cognitive difficulties, anxiety and depression, poor work performance, decreased quality of life, and increased risk of cardiovascular disease and all-cause mortality. Insomnia can be treated with nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapies include sleep hygiene, cognitive behavior therapy, relaxation therapy, multicomponent therapy, and paradoxical intention. Referral to a sleep specialist may be considered for refractory cases.

The Nature of Stable Insomnia Phenotypes

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Pillai, Vivek; Roth, Thomas; Drake, Christopher L.

2015-01-01

Study Objectives: We examined the 1-y stability of four insomnia symptom profiles: sleep onset insomnia; sleep maintenance insomnia; combined onset and maintenance insomnia; and neither criterion (i.e., insomnia cases that do not meet quantitative thresholds for onset or maintenance problems). Insomnia cases that exhibited the same symptom profile over a 1-y period were considered to be phenotypes, and were compared in terms of clinical and demographic characteristics. Design: Longitudinal. Setting: Urban, community-based. Participants: Nine hundred fifty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based current insomnia (46.6 ± 12.6 y; 69.4% female). Interventions: None. Measurements and results: At baseline, participants were divided into four symptom profile groups based on quantitative criteria. Follow-up assessment 1 y later revealed that approximately 60% of participants retained the same symptom profile, and were hence judged to be phenotypes. Stability varied significantly by phenotype, such that sleep onset insomnia (SOI) was the least stable (42%), whereas combined insomnia (CI) was the most stable (69%). Baseline symptom groups (cross-sectionally defined) differed significantly across various clinical indices, including daytime impairment, depression, and anxiety. Importantly, however, a comparison of stable phenotypes (longitudinally defined) did not reveal any differences in impairment or comorbid psychopathology. Another interesting finding was that whereas all other insomnia phenotypes showed evidence of an elevated wake drive both at night and during the day, the “neither criterion” phenotype did not; this latter phenotype exhibited significantly higher daytime sleepiness despite subthreshold onset and maintenance difficulties. Conclusions: By adopting a stringent, stability-based definition, this study offers timely and important data on the longitudinal trajectory of specific insomnia phenotypes. With

The value of mindfulness meditation in the treatment of insomnia.

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Martires, Joanne; Zeidler, Michelle

2015-11-01

Insomnia is the most common reported sleep disorder with limited treatment options including pharmacotherapy and cognitive behavioral therapy for insomnia. Pharmacotherapy can be complicated by tolerance and significant side-effects and cognitive behavioral therapy for insomnia providers are limited in number. This article reviews mindfulness meditation as an additional therapy for insomnia. Both mindfulness-based stress reduction (MBSR) and mindfulness-based therapy for insomnia (MBTI) have been studied in the treatment of insomnia. Randomized controlled studies of MBSR and MBTI have shown overall reduction in sleep latency and total wake time and increase in total sleep time after mindfulness therapy using both patient reported outcome and quantitative measures of sleep. Mindfulness techniques have been shown to be well accepted by patients with long-lasting effects. A three-arm randomized study with MBSR, MBTI, and self-monitoring showed similar improvement in insomnia between the MBSR and MBTI groups, with possibly longer duration of efficacy in the MBTI group. Recent data show that MBTI is also an effective and accepted treatment for insomnia in older patients. Increasing evidence shows that mindfulness meditation, delivered either via MBSR or MBTI, can be successfully used for the treatment of insomnia with good patient acceptance and durable results.

VE-cadherin Y685F knock-in mouse is sensitive to vascular permeability in recurrent angiogenic organs.

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Sidibé, Adama; Polena, Helena; Pernet-Gallay, Karin; Razanajatovo, Jeremy; Mannic, Tiphaine; Chaumontel, Nicolas; Bama, Soumalamaya; Maréchal, Irène; Huber, Philippe; Gulino-Debrac, Danielle; Bouillet, Laurence; Vilgrain, Isabelle

2014-08-01

Covalent modifications such as tyrosine phosphorylation are associated with the breakdown of endothelial cell junctions and increased vascular permeability. We previously showed that vascular endothelial (VE)-cadherin was tyrosine phosphorylated in vivo in the mouse reproductive tract and that Y685 was a target site for Src in response to vascular endothelial growth factor in vitro. In the present study, we aimed to understand the implication of VE-cadherin phosphorylation at site Y685 in cyclic angiogenic organs. To achieve this aim, we generated a knock-in mouse carrying a tyrosine-to-phenylalanine point mutation of VE-cadherin Y685 (VE-Y685F). Although homozygous VE-Y685F mice were viable and fertile, the nulliparous knock-in female mice exhibited enlarged uteri with edema. This phenotype was observed in 30% of females between 4 to 14 mo old. Histological examination of longitudinal sections of the VE-Y685F uterus showed an extensive disorganization of myometrium and endometrium with highly edematous uterine glands, numerous areas with sparse cells, and increased accumulation of collagen fibers around blood vessels, indicating a fibrotic state. Analysis of cross section of ovaries showed the appearance of spontaneous cysts, which suggested increased vascular hyperpermeability. Electron microscopy analysis of capillaries in the ovary showed a slight but significant increase in the gap size between two adjacent endothelial cell membranes in the junctions of VE-Y685F mice (wild-type, 11.5 ± 0.3, n = 78; and VE-Y685F, 12.48 ± 0.3, n = 65; P = 0.045), as well as collagen fiber accumulation around capillaries. Miles assay revealed that either basal or vascular endothelial growth factor-stimulated permeability in the skin was increased in VE-Y685F mice. Since edema and fibrotic appearance have been identified as hallmarks of initial increased vascular permeability, we conclude that the site Y685 in VE-cadherin is involved in the physiological regulation of capillary

'Knock, and it shall be opened': knocking out and knocking in to reveal mechanisms of disease and novel therapies.

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Hacking, Douglas F

2008-12-01

Recent significant advances in molecular biology have generated genetically modified bacteria, yeast, nematodes, fruit flies, and fish. However, it is the genetic modification of mammalian model organisms, particularly the mouse, that has the greatest potential to shed light on human development, physiology and pathology in ways that have significant implications for neonatal and paediatric clinical practice. Here, we review some of the techniques for knocking out (inactivating), mutating and knocking in (inserting) selected genes that are important to neonatology and show how this research will lead both to a better understanding of disease and to novel therapies for infants and children.

Genetic Pathways to Insomnia

OpenAIRE

Mackenzie J. Lind; Philip R. Gehrman

2016-01-01

This review summarizes current research on the genetics of insomnia, as genetic contributions are thought to be important for insomnia etiology. We begin by providing an overview of genetic methods (both quantitative and measured gene), followed by a discussion of the insomnia genetics literature with regard to each of the following common methodologies: twin and family studies, candidate gene studies, and genome-wide association studies (GWAS). Next, we summarize the most recent gene identif...

Insomnia in central neurologic diseases--occurrence and management.

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Mayer, Geert; Jennum, Poul; Riemann, Dieter; Dauvilliers, Yves

2011-12-01

The objective of this review is to highlight the impact of insomnia in central neurological disorders by providing information on its prevalence and give recommendations for diagnosis and treatment. Insomnia in neurological disorders is a frequent, but underestimated symptom. Its occurrence may be a direct consequence of the disease itself or may be secondary to pain, depression, other sleep disorders or the effects of medications. Insomnia can have a significant impact on the patient's cognitive and physical function and may be associated with psychological distress and depression. Diagnosis of insomnia is primarily based on medical history and validated questionnaires. Actigraphy is a helpful diagnostic tool for assessing the circadian sleep-wake rhythm. For differential diagnosis and to measure the duration of sleep full polysomnography may be recommended. Prior to initiating treatment the cause of insomnia must be clearly identified. First line treatment aims at the underlying neurologic disease. The few high quality treatment studies show that short term treatment with hypnotics may be recommended in most disorders after having ruled out high risk for adverse effects. Sedating antidepressants may be an effective treatment for insomnia in stroke and Parkinson's disease (PD) patients. Melatonin and light treatment can stabilize the sleep-wake circadian rhythm and shorten sleep latency in dementias and PD. Cognitive behavioral therapy (CBT) can be effective in treating insomnia symptoms associated with most of the central neurological diseases. The prevalence and treatment of insomnia in neurological diseases still need to be studied in larger patient groups with randomized clinical trials to a) better understand their impact and causal relationship and b) to develop and improve specific evidence-based treatment strategies. Copyright © 2011 Elsevier Ltd. All rights reserved.

Analysis of insomnia in those over 60 year of age

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Weronika Wolińska

2016-12-01

Full Text Available Background . Insomnia means an absolute lack of sleep; however, in reality, it is a more complex phenomenon. Insomnia is characterized by an insufficient quantity or quality of sleep. For diagnosis of insomnia, it is crucial to find out about the patient’s subjective feelings. Loneliness is a phenomenon that people experience in an individual way – subjectively. The problems with sleep intensify with age, which can consequently cause depression. Depression is conducive to loneliness, both as a temporary feeling as well as a continual feeling of loneliness and exclusion. Objectives. The aim of this research was to the evaluation of frequency of insomnia among individuals over 60 years of age - students of the University of the Third Age in Stargard. Material and methods . The research was conducted among 131 individuals aged 60 years and over, including 72.51% (n = 95 females and 27.48% (n = 36 males. The mean age was 68.12 ± 6.63. The survey was used with elements of the Athens Insomnia Scale (AIS , Insomnia Severity Index (ISI , Beck Depression Inventory and the author’s proprietary questionnaire with socio-economic data. Results . Insomnia was observed among 27.48% (n = 36 of the respondents surveyed with AIS . More than 25% (n = 33 of respondents scored on the borderline for diagnosis of insomnia. The results obtained by combining the Beck Depression Inventory with Athens Insomnia Scale show a statistically significant relationship between insomnia and depression (p = 0.0001. Conclusions . Insomnia is present in more than a quarter of respondents among persons above 60 years of age, being students of the University of the Third Age in Stargard.

Social Support, Insomnia, and Adherence to Cognitive Behavioral Therapy for Insomnia After Cancer Treatment.

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Kamen, Charles; Garland, Sheila N; Heckler, Charles E; Peoples, Anita R; Kleckner, Ian R; Cole, Calvin L; Perlis, Michael L; Morrow, Gary R; Mustian, Karen M; Roscoe, Joseph A

2017-01-27

While cognitive-behavioral therapy for insomnia (CBT-I) has been shown to be efficacious in treating cancer survivors' insomnia, 30-60% of individuals have difficulty adhering to intervention components. Psychosocial predictors of adherence and response to CBT-I, such as social support, have not been examined in intervention studies for cancer survivors. Data from a randomized placebo-controlled 2 x 2 trial of CBT-I and armodafinil (a wakefulness promoting agent) were used to assess adherence. Ninety-six cancer survivors participated in the trial (mean age 56, 86% female, 68% breast cancer). CBT-I and armodafinil were administered over the course of seven weeks, and participants were assessed at baseline, during intervention, postintervention, and at a three-month follow-up. Social support was assessed using a Functional Assessment of Chronic Illness Therapy subscale, insomnia severity was assessed using the Insomnia Severity Index, and adherence was measured based on CBT-I sleep prescriptions. At baseline, social support was negatively correlated with insomnia severity (r = -0.30, p = 0.002) and associations between social support, CBT-I, and insomnia were maintained through the three-month follow-up. Social support was positively associated with adherence to CBT-I during intervention weeks 3, 4, and 5, and with overall intervention adherence. At postintervention, both social support and treatment with CBT-I independently predicted decreased insomnia severity (p adherence and improved sleep independent of CBT-I. Additional research is needed to determine whether social support can be leveraged to improve adherence and response to CBT-I.

Utilizing Cognitive-Behavioral Therapy for Insomnia to Facilitate Discontinuation of Sleep Medication in Chronic Insomnia Patients

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Jason Ong

2012-04-01

Full Text Available Many chronic insomnia patients use sleep medication well beyond the recommended duration, and patients who are hypnotic-dependent encounter several challenges when attempting to discontinue. The current article presents these challenges and reviews studies that have added cognitive-behavioral therapy for insomnia (CBTI to a gradual tapering program to facilitate discontinuation of hypnotic medication in chronic insomnia patients. The current literature provides substantial support for using CBTI to facilitate discontinuation of hypnotic medication in chronic insomnia patients. Across several randomized clinical trials, the majority of the findings indicate that using CBTI, delivered by a therapist or self-help, along with a supervised or gradual tapering program is superior to tapering only or CBTI only in terms of medication discontinuation. Although these results are promising, it should be noted that the long-term evidence is more equivocal, as over 40% of patients relapse in the need for sleep medication within 2 years, which may highlight the importance of adding follow-up booster sessions in hypnotic-dependent insomniacs. These findings indicate that rather than choosing between CBT and hypnotic medication, clinicians might be better served using both treatment modalities to optimize the relative strengths of each treatment. Such an approach represents a more modern view of treating chronic insomnia patients by using both pharmacological and non-pharmacological tools.

[Management of adult secondary insomnia in primary health care].

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Cavadas, Luís Filipe; Ribeiro, Lúcia

2011-01-01

Insomnia is the most common sleep disorder in adults, with secondary insomnia being the most prevalent. This sleep disorder is associated with important medical and social consequences. The General Practitioner (GP) plays a key role in the diagnosis of insomnia, which may affect about 69% of their patients in the PHC (Primary Health Care). Recognize the differential diagnosis of secondary insomnia in adults, evaluate and manage these patients in the PHC, appropriately use the treatments available and meet the criteria for referral. Bibliographic search in MEDLINE databases, and evidence based review databases, using the MeSH terms: Primary Health Care, Sleep Disorders, Insomnia, for articles published since January 2000 until July 2009, in English, Portuguese, French and Spanish. Index de Revistas Médicas Portuguesas and scientific societies dedicated to sleep disorders were searched. Mood and anxiety disorders are the main co-morbidities associated with secondary insomnia, being present in 30% to 50% of patients with insomnia. The medical pathology and substance abuse are present respectively in 10% of patients. It is essential a proper clinical history, with a history of sleep, sleep diary and the partner information. There is evidence that the combination of specific pharmacological treatments (benzodiazepines and the benzodiazepine receptor agonists) with the nonpharmacological (cognitive-behavioral therapy) may be useful in secondary insomnia, as co-adjuvant treatment of the underlying disease. There are several treatment options with their indications and adverse effects. The criteria for referral should be defined according to the availability of human resources. Due to the high prevalence and the serious consequences of secondary insomnia in adults, it must be systematically managed by the GP. It is important to know and to use non-pharmacological therapy in GP consultation, because this therapy was shown to be important in treating this type of insomnia

Insomnia and Personality-A Network Approach

NARCIS (Netherlands)

Dekker, Kim; Blanken, Tessa F; Van Someren, Eus J W

2017-01-01

Studies on personality traits and insomnia have remained inconclusive about which traits show the most direct associations with insomnia severity. It has moreover hardly been explored how traits relate to specific characteristics of insomnia. We here used network analysis in a large sample (N= 2089)

Insomnia and Personality-A Network Approach

NARCIS (Netherlands)

Dekker, Kim; Blanken, Tessa F; Van Someren, Eus J W

2017-01-01

Studies on personality traits and insomnia have remained inconclusive about which traits show the most direct associations with insomnia severity. It has moreover hardly been explored how traits relate to specific characteristics of insomnia. We here used network analysis in a large sample (N =

Psychometric properties of the Sleep Condition Indicator and Insomnia Severity Index in the evaluation of insomnia disorder.

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Wong, Mark Lawrence; Lau, Kristy Nga Ting; Espie, Colin A; Luik, Annemarie I; Kyle, Simon D; Lau, Esther Yuet Ying

2017-05-01

The Sleep Condition Indicator (SCI) and Insomnia Severity Index (ISI) are commonly used instruments to assess insomnia. We evaluated their psychometric properties, particularly their discriminant validity against structured clinical interview (according to DSM-5 and ICSD-3), and their concurrent validity with measures of sleep and daytime functioning. A total of 158 young adults, 16% of whom were diagnosed with DSM-5 insomnia disorder and 13% with ICSD-3 Chronic Insomnia by structured interview, completed the ISI and SCI twice in 7-14 days, in addition to measures of sleep and daytime function. The Chinese version of the SCI was validated with good psychometric properties (ICC = 0.882). A cutoff of ≥8 on the ISI, ≤5 on the SCI short form, and ≤21 on the SCI achieved high discriminant validity (AUC > 0.85) in identifying individuals with insomnia based on both DSM-5 and ICSD-3 criteria. The SCI and ISI had comparable associations with subjective (0.18 sleep (0.31 disorder. Moreover, they showed good concordance with measures of daytime dysfunction, as well as subjective and objective sleep. The SCI and ISI are recommended for use in clinical and research settings. Copyright © 2016 Elsevier B.V. All rights reserved.

Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

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Williams, Michael R; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T; Luikart, Bryan W

2015-01-21

Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate" or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. Copyright © 2015 the authors 0270-6474/15/350943-17$15.00/0.

Oleylphosphocholine (OlPC) arrests Cryptosporidium parvum growth in vitro and prevents lethal infection in interferon gamma receptor knock-out mice.

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Sonzogni-Desautels, Karine; Renteria, Axel E; Camargo, Fabio V; Di Lenardo, Thomas Z; Mikhail, Alexandre; Arrowood, Michael J; Fortin, Anny; Ndao, Momar

2015-01-01

Cryptosporidium parvum is a species of protozoa that causes cryptosporidiosis, an intestinal disease affecting many mammals including humans. Typically, in healthy individuals, cryptosporidiosis is a self-limiting disease. However, C. parvum can cause a severe and persistent infection that can be life-threatening for immunocompromised individuals, such as AIDS patients. As there are no available treatments for these patients that can cure the disease, there is an urgent need to identify treatment options. We tested the anti-parasitic activity of the alkylphosphocholine oleylphosphocholine (OlPC), an analog of miltefosine, against C. parvum in in vitro and in vivo studies. In vitro experiments using C. parvum infected human ileocecal adenocarcinoma cells (HCT-8 cells) showed that OlPC has an EC50 of 18.84 nM. Moreover, no cell toxicity has been seen at concentrations ≤50 μM. C57BL/6 interferon gamma receptor knock-out mice, were infected by gavage with 4000 C. parvum oocysts on Day 0. Oral treatments, with OlPC, miltefosine, paromomycin or PBS, began on Day 3 post-infection for 10 days. Treatment with OlPC, at 40 mg/kg/day resulted in 100% survival, complete clearance of parasite in stools and a 99.9% parasite burden reduction in the intestines at Day 30. Doses of 30 and 20 mg/kg/day also demonstrated an increased survival rate and a dose-dependent parasite burden reduction. Mice treated with 10 mg/kg/day of miltefosine resulted in 50% survival at Day 30. In contrast, control mice, treated with PBS or 100 mg/kg/day of paromomycin, died or had to be euthanized between Days 6 and 13 due to severe illness. Results of parasite burden were obtained by qPCR and cross-validated by both flow cytometry of stool oocysts and histological sections of the ileum. Together, our results strongly support that OlPC represents a potential candidate for the treatment of C. parvum infections in immunocompromised patients.

Oleylphosphocholine (OlPC arrests Cryptosporidium parvum growth in vitro and prevents lethal infection in interferon gamma receptor knock-out mice

Directory of Open Access Journals (Sweden)

Karine eSonzogni-Desautels

2015-09-01

Full Text Available Cryptosporidium parvum is a species of protozoa that causes cryptosporidiosis, an intestinal disease affecting many mammals including humans. Typically, in healthy individuals, cryptosporidiosis is a self-limiting disease. However, C. parvum can cause a severe and persistent infection that can be life-threatening for immunocompromised individuals, such as AIDS patients. As there are no available treatments for these patients that can cure the disease, there is an urgent need to identify treatment options. We tested the anti-parasitic activity of the alkylphosphocholine oleylphosphocholine (OlPC, an analog of miltefosine, against C. parvum in in vitro and in vivo studies. In vitro experiments using C. parvum infected human ileocecal adenocarcinoma cells (HCT-8 cells showed that OlPC has an EC50 of 18.84 nM. Moreover, no cell toxicity has been seen at concentrations ≤50 µM. C57BL/6 interferon gamma receptor knock-out mice, were infected by gavage with 4000 C. parvum oocysts on Day 0. Oral treatments, with OlPC, miltefosine, paromomycin or PBS, began on Day 3 post-infection for 10 days. Treatment with OlPC, at 40 mg/kg/day resulted in 100% survival, complete clearance of parasite in stools and a 99.9% parasite burden reduction in the intestines at Day 30. Doses of 30 mg/kg/day and 20 mg/kg/day also demonstrated an increased survival rate and a dose-dependent parasite burden reduction. Mice treated with 10 mg/kg/day of miltefosine resulted in 50% survival at Day 30. In contrast, control mice, treated with PBS or 100 mg/kg/day of paromomycin, died or had to be euthanized between Days 6 and 13 due to severe illness. Results of parasite burden were obtained by qPCR and cross-validated by both flow cytometry of stool oocysts and histological sections of the ileum. Together, our results strongly support that OlPC represents a potential candidate for the treatment of C. parvum infections in immunocompromised patients.

Mice lacking Brinp2 or Brinp3, or both, exhibit behaviours consistent with neurodevelopmental disorders

Directory of Open Access Journals (Sweden)

Susie Ruth Berkowicz

2016-10-01

Full Text Available Background: Brinps 1 – 3, and Astrotactins (Astn 1 and 2, are members of the Membrane Attack Complex / Perforin (MACPF superfamily that are predominantly expressed in the mammalian brain during development. Genetic variation at the human BRINP2/ASTN1 and BRINP1/ASTN2 loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown that Brinp1-/- mice exhibit behaviour reminiscent of autism spectrum disorder (ASD and attention deficit hyperactivity disorder (ADHD.Method: We created Brinp2-/- mice and Brinp3-/- mice via the Cre-mediated LoxP system to investigate the effect of gene deletion on anatomy and behaviour. Additionally, Brinp2-/-Brinp3-/- double knock-out mice were generated by interbreeding Brinp2-/- and Brinp3-/- mice. Genomic validation was carried out for each knock-out line, followed by histological, weight and behavioural examination. Brinp1-/-Brinp2-/-Brinp3-/- triple knock-out mice were also generated by crossing Brinp2/3 double knock-out mice with previously generated Brinp1-/- mice, and examined by weight and histological analysis.Results: Brinp2-/- and Brinp3-/- mice differ in their behaviour: Brinp2-/- mice are hyperactive, whereas Brinp3-/- mice exhibit marked changes in anxiety-response on the elevated plus maze. Brinp3-/- mice also show evidence of altered sociability. Both Brinp2-/- and Brinp3-/- mice have normal short-term memory, olfactory responses, pre-pulse inhibition and motor learning. The double knock-out mice show behaviours of Brinp2-/- and Brinp3-/- mice, without evidence of new or exacerbated phenotypes. Conclusion: Brinp3 is important in moderation of anxiety, with potential relevance to anxiety disorders. Brinp2 dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2. Brinp2-/- and Brinp3-/- genes do not compensate in the mammalian brain and likely have distinct molecular or cell-type specific functions.

New Developments in Insomnia Medications of Relevance to Mental Health Disorders.

Science.gov (United States)

Krystal, Andrew D

2015-12-01

Many insomnia medications with high specificity have become available recently. They provide a window into the clinical effects of modulating specific brain systems and establish a new guiding principal for conceptualizing insomnia medications: "mechanism matters." A new paradigm for insomnia therapy in which specific drugs are selected to target the specific type of sleep difficulty for each patient includes administering specific treatments for patients with insomnia comorbid with particular psychiatric disorders. This article reviews insomnia medications and discusses the implications for optimizing the treatment of insomnia occurring comorbid with psychiatric conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Hubungan Derajat Insomnia Dengan Konsentrasi Belajar Mahasiswa Program Studi Ilmu Keperawatan Di YOGYAKARTA (Correlation Between Insomnia with Learning Concentration Among Nursing Students in YOGYAKARTA)

OpenAIRE

Waliyanti, Ema; Pratiwi, Wisni

2017-01-01

Intisari Insomnia merupakan salah satu gangguan tidur yang dapat disebabkan oleh stres, masalah sekolah maupun pekerjaan, kesehatan, merokok, ataupun efek samping dari pengobatan. Insomnia berdampak pada kualitas hidup seseorang seperti penurunan konsentrasi. Berdasarkan Statistic by Country for Insomnia terdapat 10% kejadian insomnia yang ada di Indonesia. Penelitian ini bertujuan untuk mengetahui hubungan antara derajat insomnia dengan konsentrasi belajar pada mahasiswa keperawatan di Yogya...

INSOMNIA AND CORRELATION WITH PSYCHOSOCIAL FACTORS IN PRIMARY HEALTH CARE

OpenAIRE

Made Gede Cahyadi Permana

2013-01-01

Insomnia is regarded as sleep disorder that most often affects people in the world, both in primary and in the presence of comorbid conditions. Based on those facts, insomnia could be a serious problem at the level of primary health care. General Practitioner should be able to diagnose insomnia and able to perform the appropriate treatment for the patient. Psychosocial factors may related to the degree of severity of insomnia, among others are health status, depression, dysfunctional beliefs ...

A virtual sleepcoach for people suffering from insomnia

NARCIS (Netherlands)

Horsch, C.H.G.

2016-01-01

People suffering from insomnia have problems falling asleep or staying asleep. Insomnia impairs people’s daily life and their quality of life decreases. Approximately 10% of the population suffers from insomnia. The common treatment for insomnia is cognitive behavioural therapy for insomnia (CBT-I),

Efficient gene knock-out and knock-in with transgenic Cas9 in Drosophila.

Science.gov (United States)

Xue, Zhaoyu; Ren, Mengda; Wu, Menghua; Dai, Junbiao; Rong, Yikang S; Gao, Guanjun

2014-03-21

Bacterial Cas9 nuclease induces site-specific DNA breaks using small gRNA as guides. Cas9 has been successfully introduced into Drosophila for genome editing. Here, we improve the versatility of this method by developing a transgenic system that expresses Cas9 in the Drosophila germline. Using this system, we induced inheritable knock-out mutations by injecting only the gRNA into embryos, achieved highly efficient mutagenesis by expressing gRNA from the promoter of a novel non-coding RNA gene, and recovered homologous recombination-based knock-in of a fluorescent marker at a rate of 4.5% by co-injecting gRNA with a circular DNA donor. Copyright © 2014 Xue et al.

Insomnia: prevalence and associated factors

OpenAIRE

Lopes, Cátia; Lopes, Daniela; Ferreira, Sofia; Correia, Teresa; Pinto, Isabel C.

2014-01-01

Nowadays sleep disorders are very common and affect most of the population, the most common may be insomnia. Insomnia is defined as the difficulty of initiating or maintaining sleep it, may also be reflected in an early wake up and by the presence of a non-restful sleep and it is associated with impairment in social and occupational functioning of the individual. Knowing the prevalence and the associated factors of insomnia. This is a cross-sectional epidemiological study. The pop...

Nocturnal Regrets and Insomnia in Elderly People

Science.gov (United States)

Schmidt, Ralph E.; Renaud, Olivier; Van Der Linden, Martial

2011-01-01

Despite their importance for general health, emotion-related factors have rarely been considered in the etiology of late-life insomnia. This study explored the relations between impulsivity, regret experiences, use of different thought-control strategies, and insomnia severity in a sample of older adults whose age ranged from 51 to 98 years.…

Insomnia in central neurologic diseases--occurrence and management

DEFF Research Database (Denmark)

Mayer, Geert; Jennum, Poul; Riemann, Dieter

2011-01-01

The objective of this review is to highlight the impact of insomnia in central neurological disorders by providing information on its prevalence and give recommendations for diagnosis and treatment. Insomnia in neurological disorders is a frequent, but underestimated symptom. Its occurrence may...... be a direct consequence of the disease itself or may be secondary to pain, depression, other sleep disorders or the effects of medications. Insomnia can have a significant impact on the patient's cognitive and physical function and may be associated with psychological distress and depression. Diagnosis...... of insomnia is primarily based on medical history and validated questionnaires. Actigraphy is a helpful diagnostic tool for assessing the circadian sleep-wake rhythm. For differential diagnosis and to measure the duration of sleep full polysomnography may be recommended. Prior to initiating treatment...

Bowlegs and Knock-Knees

Science.gov (United States)

... Español Text Size Email Print Share Bowlegs and Knock-Knees Page Content Article Body Toddlers’ legs often ... about two years old, then they’ll look knock-kneed until they are about six years of ...

Can Insomnia in Pregnancy Predict Postpartum Depression? A Longitudinal, Population-Based Study

Science.gov (United States)

Dørheim, Signe K.; Bjorvatn, Bjørn; Eberhard-Gran, Malin

2014-01-01

Background Insomnia and depression are strongly interrelated. This study aimed to describe changes in sleep across childbirth, and to evaluate whether insomnia in pregnancy is a predictor of postpartum depression. Methods A longitudinal, population-based study was conducted among perinatal women giving birth at Akershus University Hospital, Norway. Women received questionnaires in weeks 17 and 32 of pregnancy and eight weeks postpartum. This paper presents data from 2,088 of 4,662 women with complete data for insomnia and depression in week 32 of pregnancy and eight weeks postpartum. Sleep times, wake-up times and average sleep durations were self-reported. The Bergen Insomnia Scale (BIS) was used to measure insomnia. The Edinburgh Postnatal Depression Scale (EPDS) was used to measure depressive symptoms. Results After delivery, sleep duration was reduced by 49 minutes (to 6.5 hours), and mean sleep efficiency was reduced from 84% to 75%. However, self-reported insomnia scores (BIS) improved from 17.2 to 15.4, and the reported prevalence of insomnia decreased from 61.6% to 53.8%. High EPDS scores and anxiety in pregnancy, fear of delivery, previous depression, primiparity, and higher educational level were risk factors for both postpartum insomnia and depression. Insomnia did not predict postpartum depression in women with no prior history of depression, whereas women who recovered from depression had residual insomnia. Limitations Depression and insomnia were not verified by clinical interviews. Women with depressive symptoms were less likely to remain in the study. Conclusions Although women slept fewer hours at night after delivery compared to during late pregnancy, and reported more nights with nighttime awakenings, their self-reported insomnia scores improved, and the prevalence of insomnia according to the DSM-IV criteria decreased. Insomnia in pregnancy may be a marker for postpartum recurrence of depression among women with previous depression. PMID

Computational singular perturbation analysis of super-knock in SI engines

KAUST Repository

Jaasim, Mohammed

2018-04-02

Pre-ignition engine cycles leading to super-knock were simulated with a 48 species skeletal iso-octane mechanism to identify the dominant reaction pathways that are present in super-knock. To mimic pre-ignition, a deflagration front was generated via a hot spot that is placed over the piston at close proximity to the end-wall. Computational singular perturbation (CSP) was used to analyze the chemical dynamics at various in-cylinder locations: a point at the center of the cylinder where the deflagration front consumes the air/fuel mixture and two points located at 3 mm from the end-wall where super-knock and mild knock occur. The CSP analysis of the point at the center of the cylinder reveals weak two-stage ignition-like dynamics with a short second stage. At the other points, a pronounced two-stage ignition is displayed with a long second stage. A distinct contribution of formaldehyde (CHO) at the second stage of ignition that adds to fast explosive modes in the super-knock points is not observed in the point at the center. A comparison between knock and super-knock analysis indicates that a similar set of reactions is responsible for the abnormal behavior but the fast explosive time scales are comparatively slower for knock, indicating lower reactivity, which results in the reduced intensity of knock. The analyzed results decoded important reactions responsible for the occurrence of super-knock.

Prevalence of insomnia in the adult Norwegian population.

Science.gov (United States)

Pallesen, S; Nordhus, I H; Nielsen, G H; Havik, O E; Kvale, G; Johnsen, B H; Skjøtskift, S

2001-11-01

A representative adult sample (18 years and above) of the Norwegian population, comprising 2001 subjects, participated in telephone interviews, focusing on the one-month point prevalence of insomnia and use of prescribed hypnotics. Employment of DSM-IV inclusion criteria of insomnia yielded a prevalence rate of 11.7%. Logistic regression analysis performed on the different insomnia symptoms revealed that somatic and psychiatric health were the strongest predictors of insomnia, whereas gender, age, and socioeconomic status showed a more inconsistent relationship. Use of prescribed hypnotic drugs was reported by 6.9% and was related to being female, elderly, and having somatic and emotional problems. Sleep onset problems and daytime impairment were more common during winter compared to summer. Use of hypnotics was more common in the southern (rather than the northern) regions of Norway. For sleep onset problems a Season x Region interaction was found, indicating that the prevalence of sleep onset problems increased in southern Norway from summer to winter, while the opposite pattern was found in the northern regions. The importance of clinically adequate criteria and seasonal variation in the evaluation of insomnia is briefly discussed.

Knock-out reactions

International Nuclear Information System (INIS)

de Forest, T. Jr.

1977-01-01

It is pointed out that the primary motivation for performing high energy single nucleon knock-out reactions is based on the concept of quasi-elastic scattering. The validity of and corrections to the partial wave impulse approximation and kinematical invariance of knock-out reactions and tests of the reaction mechanism are treated. The effect of distortions on the momentum distribution in the effective momentum approximation for given parameters are plotted. 12 references

Statistical Engine Knock Control

DEFF Research Database (Denmark)

Stotsky, Alexander A.

2008-01-01

A new statistical concept of the knock control of a spark ignition automotive engine is proposed . The control aim is associated with the statistical hy pothesis test which compares the threshold value to the average value of the max imal amplitud e of the knock sensor signal at a given freq uency....... C ontrol algorithm which is used for minimization of the regulation error realizes a simple count-up-count-d own logic. A new ad aptation algorithm for the knock d etection threshold is also d eveloped . C onfi d ence interval method is used as the b asis for ad aptation. A simple statistical mod el...... which includ es generation of the amplitud e signals, a threshold value d etermination and a knock sound mod el is d eveloped for evaluation of the control concept....

A kinase-dead knock-in mutation in mTOR leads to early embryonic lethality and is dispensable for the immune system in heterozygous mice

Directory of Open Access Journals (Sweden)

Cavender Druie

2009-05-01

Full Text Available Abstract Background The mammalian target of rapamycin protein (mTOR is an evolutionarily conserved kinase that regulates protein synthesis, cell cycle progression and proliferation in response to various environmental cues. As a critical downstream mediator of PI3K signaling, mTOR is important for lymphocyte development and function of mature T and B-cells. Most studies of mTOR in immune responses have relied on the use of pharmacological inhibitors, such as rapamycin. Rapamycin-FKBP12 complex exerts its immunosuppressive and anti-proliferative effect by binding outside the kinase domain of mTOR, and subsequently inhibiting downstream mTOR signaling. Results To determine the requirement for mTOR kinase activity in the immune system function, we generated knock-in mice carrying a mutation (D2338 in the catalytic domain of mTOR. While homozygous mTOR kd/kd embryos died before embryonic day 6.5, heterozygous mTOR+/kd mice appeared entirely normal and are fertile. mTOR +/kd mice exhibited normal T and B cell development and unaltered proliferative responses of splenocytes to IL-2 and TCR/CD28. In addition, heterozygousity for the mTOR kinase-dead allele did not sensitize T cells to rapamycin in a CD3-mediated proliferation assay. Unexpectedly, mTOR kinase activity towards its substrate 4E-BP1 was not decreased in hearts and livers from heterozygous animals. Conclusion Altogether, our findings indicate that mTOR kinase activity is indispensable for the early development of mouse embryos. Moreover, a single wild type mTOR allele is sufficient to maintain normal postnatal growth and lymphocyte development and proliferation.

Determinan Insomnia pada Lanjut Usia

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Andi Zulkifli Abdullah

2012-11-01

Full Text Available Insomnia merupakan gangguan tidur yang paling sering ditemukan pada lanjut usia (lansia dengan prevalensi sekitar 67%. Penelitian ini bertujuan untuk menilai hubungan antara kecemasan, depresi, dukungan keluarga, dan kondisi lingkungan dengan kejadian insomnia pada lansia di Panti Sosial Tresna Werdha Gau Mabaji Kabupaten Gowa. Penelitian ini menggunakan desain studi observasional dengan rancangan cross sectional dan metode exhausive sampling. Data dianalisis dengan uji chi square, koefisien phi (f dengan a = 0,05. Sebanyak 96 lansia penghuni panti memenuhi kriteria penelitian. Uji chi square menunjukkan bahwa terdapat hubungan antara kecemasan (nilai p = 0,014; f = 0,251, depresi (nilai p = 0,019; f = 0,238, dukungan keluarga (nilai p = 0,000; f = 0,797, dan kondisi lingkungan panti (nilai p < 0,05; f = 0,238 dengan kejadian insomnia. Pemberian penyuluhan kepada keluarga lansia adalah salah satu kegiatan yang penting dilakukan untuk meningkatkan pengetahuan keluarga lansia bahwa lansia tidak hanya sekadar diperhatikan kebutuhan fisiknya tetapi juga kebutuhan psikologisnya. Kata kunci: Depresi, insomnia, kecemasan Abstract Insomnia is sleep disorder, most often found on elderly with high prevalence about 67%. The aim of this research is to prove the relation between anxiousness, depression, family support, and environmental condition with the occurence of insomnia at old ages in social institution Tresna Werdha Gau Mabaji Gowa Regency. This research used an observasional study with cross sectional design, using the exhausive sampling method. Data were analysed by chi square test, phi coefficient with a = 0,05. About 96 elderly in social institution met the research criteria, chi square test indicates that there are relation between anxiousness (p value = 0,014; f = 0,251, depression (p value = 0,019; f = 0,238, family support (p value = 0,000; f = 0,797, and environmental condition of social institution (p value = 0,019; f = 0,238 with the

The interactions between IC engine thermodynamics and knock

International Nuclear Information System (INIS)

Caton, Jerald A.

2017-01-01

Highlights: • Importance of engine thermodynamics regarding knock was quantified. • Effects of compression ratio, engine speed and EGR on knock was reported. • Retarding combustion to avoid knock resulted in decreases of efficiency. - Abstract: The development of high efficiency spark-ignition internal combustion engines is often constrained by the occurrence of knock. Knock may result in engine damage, lower performance, and lower efficiency. The options for preventing knock often involve lower compression ratios, lower boost, retarded spark timing, and other design choices that are detrimental to engine performance and efficiency. Since knock is largely a function of the thermodynamic state of the unburned zone, the occurrence of knock is expected to be a strong function of the engine thermodynamics. The purpose of the current work is to couple a simple knock model with a comprehensive engine cycle simulation to determine the interactions between the engine thermodynamics and knock. This work has explored the effects of engine parameters such as compression ratio (4–12), engine speed (500–2500 rpm), inlet pressure (50–100 kPa), exhaust gas recirculation (0–25%), combustion duration and heat transfer on knock. In each case, the occurrence of knock is connected to the cylinder pressures and the gas temperatures of the unburned zone. For example for a compression ratio of 12, to avoid knock the brake thermal efficiency decreased from 36.5% to 34% due to retarding the combustion.

Sleep system sensitization: evidence for changing roles of etiological factors in insomnia.

Science.gov (United States)

Kalmbach, David A; Pillai, Vivek; Arnedt, J Todd; Anderson, Jason R; Drake, Christopher L

2016-05-01

To test for sensitization of the sleep system in response to insomnia development and major life stress. In addition, to evaluate the impact on depression and anxiety associated with sleep system sensitization. A longitudinal study with three annual assessments. The community-based sample included 262 adults with no history of insomnia or depression who developed insomnia one year after baseline (67.6% female; 44.0 ± 13.4 yr). Measures included the Ford Insomnia Response to Stress Test to assess sleep reactivity, Quick Inventory of Depressive Symptomatology, and Beck Anxiety Inventory. Insomnia classification was based on DSM-IV criteria. Sleep system sensitization was operationally defined as significant increases in sleep reactivity. Sensitization of the sleep system was observed from baseline to insomnia onset at 1-yr follow-up among insomniacs with low premorbid vulnerability (p insomnia remission (p insomnia onset. The impact of sensitization on depression was stable at 2-yr follow-up (p = 0.01). Evidence supports sensitization of the sleep system as a consequence of insomnia development and major life stress among individuals with low premorbid sleep reactivity. Sleep system sensitization may serve as a mechanism by which insomnia is perpetuated. Harmful effects of the sensitization process may increase risk for insomnia-related depression and anxiety. Copyright © 2016 Elsevier B.V. All rights reserved.

Generation of Oxtr cDNA(HA)-Ires-Cre Mice for Gene Expression in an Oxytocin Receptor Specific Manner.

Science.gov (United States)

Hidema, Shizu; Fukuda, Tomokazu; Hiraoka, Yuichi; Mizukami, Hiroaki; Hayashi, Ryotaro; Otsuka, Ayano; Suzuki, Shingo; Miyazaki, Shinji; Nishimori, Katsuhiko

2016-05-01

The neurohypophysial hormone oxytocin (OXT) and its receptor (OXTR) have critical roles in the regulation of pro-social behaviors, including social recognition, pair bonding, parental behavior, and stress-related responses. Supporting this hypothesis, a portion of patients suffering from autism spectrum disorder have mutations, such as single nucleotide polymorphisms, or epigenetic modifications in their OXTR gene. We previously reported that OXTR-deficient mice exhibit pervasive social deficits, indicating the critical role of OXTR in social behaviors. In the present study, we generated Oxtr cDNA(HA)-Ires-Cre knock-in mice, expressing both OXTR and Cre recombinase under the control of the endogenous Oxtr promoter. Knock-in cassette of Oxtr cDNA(HA)-Ires-Cre consisted of Oxtr cDNA tagged with the hemagglutinin epitope at the 3' end (Oxtr cDNA(HA)), internal ribosomal entry site (Ires), and Cre. Cre was expressed in the uterus, mammary gland, kidney, and brain of Oxtr cDNA(HA)-Ires-Cre knock-in mice. Furthermore, the distribution of Cre in the brain was similar to that observed in Oxtr-Venus fluorescent protein expressing mice (Oxtr-Venus), another animal model previously generated by our group. Social behavior of Oxtr cDNA(HA)-Ires-Cre knock-in mice was similar to that of wild-type animals. We demonstrated that this construct is expressed in OXTR-expressing neurons specifically after an infection with the recombinant adeno-associated virus carrying the flip-excision switch vector. Using this system, we showed the transport of the wheat-germ agglutinin tracing molecule from the OXTR-expressing neurons to the innervated neurons in knock-in mice. This study might contribute to the monosynaptic analysis of neuronal circuits and to the optogenetic analysis of neurons expressing OXTR. © 2015 Wiley Periodicals, Inc.

Insomnia management in prisons in England and Wales: a mixed-methods study.

Science.gov (United States)

Dewa, Lindsay H; Hassan, Lamiece; Shaw, Jenny J; Senior, Jane

2017-06-01

Insomnia in prison is common; however, research is limited regarding the management strategies that prison establishments employ. To address this knowledge gap, we conducted a survey to identify how insomnia is detected, diagnosed and treated in adult prisons in England and Wales. Telephone interviews with a purposive sample of health-care managers were then conducted. The survey was sent to all establishments holding adult prisoners, covering screening and assessment methods to detect insomnia; treatment options, both pharmacological and non-pharmacological; the importance of insomnia as a treatable condition; and staff training available. Eighty-four (73%) prisons completed the survey. Few had a stepped approach to insomnia management, as recommended by National Institute for Health and Care Excellence (NICE) guidelines. The most common treatments available were sleep hygiene education and medication, offered by 94 and 88% of respondents, respectively. Analysis of telephone interviews revealed four main themes: insomnia as a normal occurrence in prison; the problem of medication in prison; the negative impact of the prison environment; and effective management of insomnia in prison. The current findings suggest that logistical, ethical and security barriers and a lack of staff knowledge and training impact negatively on the management of insomnia in prison. © 2017 European Sleep Research Society.

Health economics of insomnia therapy: implications for policy.

Science.gov (United States)

Botteman, Marc

2009-09-01

Chronic primary insomnia is a major public health problem causing significant burden for those affected. Rising health care costs may cause increased financial pressures on governments and private payers, forcing stricter cost-control measures and, as a result, insomnia, often considered a lifestyle condition, may not receive the proper attention it deserves. In order to highlight the benefits that can be achieved through successful treatment of insomnia, there is a need for further comparative studies of existing and emerging treatments, cost burden of illness and cost-effectiveness analyses. Health economic assessment of insomnia and its treatments is an emerging area. The development of comprehensive assessment of insomnia treatments, however, has been hindered by complexities and gaps in the available data. Health economic models of insomnia, such as the one detailed here, should enable researchers to better address the effects of different treatments on clinical and economic measures for insomnia and related comorbidities. It is apparent that research into the cost-effectiveness of therapies for insomnia is in its infancy and further work is needed.

Insomnia, platelet serotonin and platelet monoamine oxidase in chronic alcoholism.

Science.gov (United States)

Nenadic Sviglin, Korona; Nedic, Gordana; Nikolac, Matea; Mustapic, Maja; Muck-Seler, Dorotea; Borovecki, Fran; Pivac, Nela

2011-08-18

Insomnia is a common sleep disorder frequently occurring in chronic alcoholic patients. Neurobiological basis of insomnia, as well as of alcoholism, is associated with disrupted functions of the main neurotransmitter systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Blood platelets are considered a limited peripheral model for the central 5-HT neurons, since both platelets and central 5-HT synaptosomes have similar dynamics of 5-HT. Platelet 5-HT concentration and platelet monoamine oxidase type B (MAO-B) are assumed to represent biomarkers for particular symptoms and behaviors in psychiatric disorders. The hypothesis of this study was that platelet 5-HT concentration and platelet MAO-B activity will be altered in chronic alcoholic patients with insomnia compared to comparable values in patients without insomnia. The study included 498 subjects: 395 male and 103 female medication-free patients with alcohol dependence and 502 healthy control subjects: 325 men and 177 women. The effects of early, middle and late insomnia (evaluated using the Hamilton Depression Rating Scale), as well as sex, age and smoking on platelet 5-HT concentration and platelet MAO-B activity were evaluated using one-way ANOVA and multiple regression analysis by the stepwise method. Platelet 5-HT concentration, but not platelet MAO-B activity, was significantly reduced in alcoholic patients with insomnia compared to patients without insomnia. Multiple regression analysis revealed that platelet 5-HT concentration was affected by middle insomnia, smoking and sex, while platelet MAO activity was affected only by sex and age. The present and previous data suggest that platelet 5-HT concentration might be used, after controlling for sex and smoking, as a biomarker for insomnia in alcoholism, PTSD and in rotating shift workers. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Orexin in sleep, addiction and more: is the perfect insomnia drug at hand?

Science.gov (United States)

Hoyer, Daniel; Jacobson, Laura H

2013-12-01

Orexins A and B (hypocretins 1 and 2) and their two receptors (OX1R and OX2R) were discovered in 1998 by two different groups. Orexin A and B are derived from the differential processing of a common precursor, the prepro-orexin peptide. The neuropeptides are expressed in a few thousand cells located in the lateral hypothalamus (LH), but their projections and receptor distribution are widespread throughout the brain. Remarkably, prepro peptide and double (OX1R/OX2R) receptor knock out (KO) mice reproduce a sleep phenotype known in humans and dogs as narcolepsy/cataplexy. In humans, this disease is characterized by the absence of orexin producing cells in the LH, and severely depleted levels of orexin the cerebrospinal fluid. Null mutation of the individual OX1R or OX2R in mice substantially ameliorates the narcolepsy/cataplexy phenotype compared to the OX1R/OX2R KO, and highlights specific roles of the individual receptors in sleep architecture, the OX1R KO demonstrating an a attenuated sleep phenotype relative to the OX2R KO. It has therefore been suggested that orexin is a master regulator of the sleep-wake cycle, with high activity of the LH orexin cells during wake and almost none during sleep. Less than 10years later, the first orexin antagonist, almorexant, a dual orexin receptor antagonist (DORA), was reported to be effective in inducing sleep in volunteers and insomnia patients. Although development was stopped for almorexant and for Glaxo's DORA SB-649868, no less than 4 orexin receptor antagonists have reached phase II for insomnia, including Filorexant (MK-6096) and Suvorexant (MK-4305) from Merck. Suvorexant has since progressed to Phase III and dossier submission to the FDA. These four compounds are reported as DORAs, however, they equilibrate very slowly at one and/or the other orexin receptor, and thus at equilibrium may show more or less selectivity for OX1R or OX2R. The appropriate balance of antagonism of the two receptors for sleep is a point of

Characterisation of a C1qtnf5 Ser163Arg knock-in mouse model of late-onset retinal macular degeneration.

Directory of Open Access Journals (Sweden)

Xinhua Shu

Full Text Available A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse "knock-in" model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct.

Significance of perfectionism in understanding different forms of insomnia

OpenAIRE

Totić-Poznanović Sanja; Šaula-Marojević Biljana; Zebić Mirjana

2012-01-01

Introduction. Studies consistently show a connection between perfectionism as a multidimensional construct with various psychological and psychopathological states and characteristics. However, studies that analyze the connection between this concept and sleep disturbances, especially modalities of insomnia, are rare. Objective. The aim of this study was to examine whether dimensions of perfectionism can explain different forms of insomnia; difficulties initiating sleep (insomnia early)...

Insomnia

Science.gov (United States)

... and others. Remaining passively awake. Also called paradoxical intention, this involves avoiding any effort to fall asleep. ... person for your sessions. However, phone consultation, CDs, books or websites on CBT techniques and insomnia also ...

Insomnia

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... Medicine clinical practice guideline. Journal of Clinical Sleep Medicine. 2017;13:307. Jan. 30, 2018 Original article: http://www.mayoclinic.org/diseases-conditions/insomnia/in-depth/sleeping-pills/ART-20043959 . Mayo Clinic Footer Legal Conditions and Terms Any use of this site ...

Neurobehavioral performance impairment in insomnia: relationships with self-reported sleep and daytime functioning.

Science.gov (United States)

Shekleton, Julia A; Flynn-Evans, Erin E; Miller, Belinda; Epstein, Lawrence J; Kirsch, Douglas; Brogna, Lauren A; Burke, Liza M; Bremer, Erin; Murray, Jade M; Gehrman, Philip; Lockley, Steven W; Rajaratnam, Shantha M W

2014-01-01

Despite the high prevalence of insomnia, daytime consequences of the disorder are poorly characterized. This study aimed to identify neurobehavioral impairments associated with insomnia, and to investigate relationships between these impairments and subjective ratings of sleep and daytime dysfunction. Cross-sectional, multicenter study. Three sleep laboratories in the USA and Australia. Seventy-six individuals who met the Research Diagnostic Criteria (RDC) for Primary Insomnia, Psychophysiological Insomnia, Paradoxical Insomnia, and/or Idiopathic Childhood Insomnia (44F, 35.8 ± 12.0 years [mean ± SD]) and 20 healthy controls (14F, 34.8 ± 12.1 years). N/A. Participants completed a 7-day sleep-wake diary, questionnaires assessing daytime dysfunction, and a neurobehavioral test battery every 60-180 minutes during an afternoon/evening sleep laboratory visit. Included were tasks assessing sustained and switching attention, working memory, subjective sleepiness, and effort. Switching attention and working memory were significantly worse in insomnia patients than controls, while no differences were found for simple or complex sustained attention tasks. Poorer sustained attention in the control, but not the insomnia group, was significantly associated with increased subjective sleepiness. In insomnia patients, poorer sustained attention performance was associated with reduced health-related quality of life and increased insomnia severity. We found that insomnia patients exhibit deficits in higher level neurobehavioral functioning, but not in basic attention. The findings indicate that neurobehavioral deficits in insomnia are due to neurobiological alterations, rather than sleepiness resulting from chronic sleep deficiency.

The role of hypnosis and related techniques in insomnia

Directory of Open Access Journals (Sweden)

Serban Ionela Lacramioara

2013-01-01

Full Text Available Hypnosis is a widespread technique in psychotherapy with applicability in various psychiatric and psychosomatic disorders. Although there are very few studies in this area of research, some results argue in favor of using hypnosis for various sleep disorders. Insomnia is a common health problem, in both primary form and associated with other pathologies, causing a reduction of self-efficiency/cognitive abilities and an overall decreased life quality. Classical psychotropic medication that is commonly used to treat insomnia can cause significant side effects, produce phenomena of dependence and is generally effective only during the period of treatment. Since the current means of pharmacologic treatment for insomnia present significant limitations, especially when treating chronic insomnia, a more suitable alternative could be attained by non-pharmacological approaches such as hypnosis.

Chronic insomnia cases detection with the help of Athens Insomnia Scale and SF-36 health survey

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Wasiewicz, P.; Skalski, M.; Fornal-Pawlowska, Malgorzata

2011-10-01

Standardization of the diagnostic process of insomnia is a highly important task in clinical practice, epidemiological considerations and treatment outcomes assessment. In this paper we describe standard surveys relationships within cluster groups with the same insomnia degrees.

Mechanism of Mongolian medical warm acupuncture in treating insomnia by regulating miR-101a in rats with insomnia.

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Bo, Agula; Si, Lengge; Wang, Yuehong; Bao, Lidao; Yuan, Hongwei

2017-07-01

MicroRNAs (miRNAs or miRs) and the target genes before and after warm acupuncture at the genetic level were assessed, and the cytokines and neurotransmitters related to insomnia were studied. Male Sprague-Dawley rats were used to create PCPA insomnia rat models and randomly divided into the normal, model, warm acupuncture, and drug groups. The Dinghui Acupoint, Heyi Acupoint, and Xin Acupoint were inserted in the Mongolian medicine warm acupuncture group. The differential expression profile of microRNA in the brain tissue of the insomnia rats was determined before and after Mongolian medicine warm acupuncture for establishment of miR-101a mimics and inhibitor. qPCR was used to detect the expression level of miR-101a. Western blotting was used to detect the expression level of PAX8. The rats receiving Mongolian medicine warm acupuncture had 141 miRNAs with differential expression compared with the normal rats. The expression level of miR-101a in the cells of the hippocampus of the insomnia rats transfected with miR-101a mimics increased significantly at 72 h (Pwarm acupuncture or western medicine treatment (Pwarm acupuncture is directly associated with PAX8 regulation.

Insomnia in a displaced population is related to war-associated remembered stress.

Science.gov (United States)

Basishvili, Tamar; Eliozishvili, Marine; Maisuradze, Lia; Lortkipanidze, Nani; Nachkebia, Nargiz; Oniani, Tengiz; Gvilia, Irma; Darchia, Nato

2012-08-01

Although traumatic events are presumed to cause sleep disturbances, particularly insomnia, sleep in populations subjected to forced displacement has received little attention. The present study examined the prevalence of insomnia and associated factors in internally displaced persons (IDPs) from Abkhazia 15 years after displacement to Tbilisi. Detailed subjective information about sleep-wake habits, sleep-related and stress-related parameters were obtained from 87 IDPs categorized into good sleepers and insomniacs. The Insomnia Severity Index, Perceived Stress Scale and Beck Depression Inventory were administered. The incidence of insomnia was 41.4%. The majority of insomniacs strongly believed that war-related stress accounted for the onset of their insomnia. Stepwise regression (95% confidence interval) revealed four variables significantly associated with insomnia status: self-estimated influence of war related stress (odds ratio (OR) = 2.51), frequency of nightmares (OR = 1.6), Perceived Stress Scale score (OR = 1.14) and Beck Depression Inventory score (OR = 1.12). Insomnia in IDPs was strongly related to war-associated remembered stress. ‛Over thinking' about major stress exposure enhanced IDPs' vulnerability to insomnia. These findings have implications for the management of insomnia and associated impairment of daytime functioning in IDPs. Copyright © 2011 John Wiley & Sons, Ltd.

Insomnia, dreams, and suicide: Connecting links

OpenAIRE

Sagar B Karia; Nirali Mehta; Devavrat Harshe; Avinash De Sousa; Nilesh Shah

2016-01-01

Introduction: A growing empirical literature has examined insomnia symptoms as a possible risk factor for a range of suicidal behavior. Not much literature is available in normal adolescent population. Aims: The aim is to find insomnia prevalence, studying various dream factors, and suicidality prevalence among students of various courses. To check if there is a relation between insomnia and suicidal behavior and dreams, particularly nightmares and suicide. Materials and Methods: A total of 4...

Insomnia in childhood and adolescence: clinical aspects, diagnosis, and therapeutic approach.

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Nunes, Magda Lahorgue; Bruni, Oliviero

2015-01-01

To review the clinical characteristics, comorbidities, and management of insomnia in childhood and adolescence. This was a non-systematic literature review carried out in the PubMed database, from where articles published in the last five years were selected, using the key word "insomnia" and the pediatric age group filter. Additionally, the study also included articles and classic textbooks of the literature on the subject. During childhood, there is a predominance of behavioral insomnia as a form of sleep-onset association disorder (SOAD) and/or limit-setting sleep disorder. Adolescent insomnia is more associated with sleep hygiene problems and delayed sleep phase. Psychiatric (anxiety, depression) or neurodevelopmental disorders (attention deficit disorder, autism, epilepsy) frequently occur in association with or as a comorbidity of insomnia. Insomnia complaints in children and adolescents should be taken into account and appropriately investigated by the pediatrician, considering the association with several comorbidities, which must also be diagnosed. The main causes of insomnia and triggering factors vary according to age and development level. The therapeutic approach must include sleep hygiene and behavioral techniques and, in individual cases, pharmacological treatment. Copyright © 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Ionization in the Knock Zone of an Internal-combustion Engine

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Hasting, Charles E

1940-01-01

The ionization in the knock zone of an internal-combustion engine was investigated. A suspected correlation between the intensity of knock and the degree of ionization was verified and an oscillation in the degree of ionization corresponding in frequency to the knock vibrations in the cylinder pressure was observed.

Sleep System Sensitization: Evidence for Changing Roles of Etiological Factors in Insomnia

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Kalmbach, David A.; Pillai, Vivek; Arnedt, J. Todd; Anderson, Jason R.; Drake, Christopher L.

2016-01-01

Objectives To test for sensitization of the sleep system in response to insomnia development and major life stress. In addition, to evaluate the impact on depression and anxiety associated with sleep system sensitization. Methods A longitudinal study with three annual assessments. The community-based sample included 262 adults with no history of insomnia or depression who developed insomnia 1 year after baseline (67.6% female; 44.0±13.4y). Measures included the Ford Insomnia Response to Stress Test to assess sleep reactivity, Quick Inventory of Depressive Symptomatology, and Beck Anxiety Inventory. Insomnia classification was based on DSM-IV criteria. Sleep system sensitization was operationally defined as significant increases in sleep reactivity. Results Sensitization of the sleep system was observed from baseline to insomnia onset at 1-y follow-up among insomniacs with low premorbid vulnerability (pinsomnia remission (pinsomnia onset. The impact of sensitization on depression was stable at 2-y follow-up (p=.01). Conclusions Evidence supports sensitization of the sleep system as consequence of insomnia development and major life stress among individuals with low premorbid sleep reactivity. Sleep system sensitization may serve as a mechanism by which insomnia is perpetuated. Harmful effects of the sensitization process may increase risk for insomnia-related depression and anxiety. PMID:27448474

Manifestations of Insomnia in Sleep Apnea: Implications for Screening and Treatment.

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Bailes, Sally; Rizzo, Dorrie; Baltzan, Marc; Grad, Roland; Pavilanis, Alan; Creti, Laura; Fichten, Catherine S; Libman, Eva

2016-01-01

The aims of this study were to examine the presence, type, and severity of insomnia complaints in obstructive sleep apnea (OSA) patients and to assess the utility of the Sleep Symptom Checklist (SSC) for case identification in primary care. Participants were 88 OSA patients, 57 cognitive-behavioral therapy for insomnia (CBT-I) patients, and 14 healthy controls (Ctrl). Each completed a sleep questionnaire as well as the SSC, which includes insomnia, daytime functioning, psychological, and sleep disorder subscales. Results showed that OSA patients could be grouped according to 3 insomnia patterns: no insomnia (OSA), n = 21; insomnia (OSA-I), n = 30, with a subjective complaint and disrupted sleep; and noncomplaining poor sleepers (OSA-I-NC), n = 37. Comparisons among the OSA, CBT-I, and Ctrl groups demonstrate distinct profiles on the SSC subscales, indicating its potential utility for both case identification and treatment planning.

Pharmacotherapy of Pediatric Insomnia

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Owens, Judith A.

2009-01-01

General guidelines for the use of medication to treat pediatric insomnia are presented. It should be noted that medication is not the first treatment choice and should be viewed within the context of a more comprehensive treatment plan. The pharmacological and clinical properties of over the counter medications and FDA-approved insomnia drugs are…

Insomnia and its associations in patients with recurrent glial neoplasms

OpenAIRE

Robertson, Matthew E.; McSherry, Frances; Herndon, James E.; Peters, Katherine B.

2016-01-01

Background Patient with neurological disorders and cancer can develop sleep disturbance, in particular insomnia. Etiology of insomnia is multi-factorial in primary brain tumour patients with possible causes including corticosteroids, psychoactive medications, co-morbid psychiatric/medical conditions, and damage to neuronal tissue. Findings To understand better insomnia in recurrent glioma patients, a single-center retrospective analysis was performed looking at recurrent glioma patients from ...

Reducing dysfunctional beliefs about sleep does not significantly improve insomnia in cognitive behavioral therapy.

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Okajima, Isa; Nakajima, Shun; Ochi, Moeko; Inoue, Yuichi

2014-01-01

The present study examined to examine whether improvement of insomnia is mediated by a reduction in sleep-related dysfunctional beliefs through cognitive behavioral therapy for insomnia. In total, 64 patients with chronic insomnia received cognitive behavioral therapy for insomnia consisting of 6 biweekly individual treatment sessions of 50 minutes in length. Participants were asked to complete the Athens Insomnia Scale and the Dysfunctional Beliefs and Attitudes about Sleep scale both at the baseline and at the end of treatment. The results showed that although cognitive behavioral therapy for insomnia greatly reduced individuals' scores on both scales, the decrease in dysfunctional beliefs and attitudes about sleep with treatment did not seem to mediate improvement in insomnia. The findings suggest that sleep-related dysfunctional beliefs endorsed by patients with chronic insomnia may be attenuated by cognitive behavioral therapy for insomnia, but changes in such beliefs are not likely to play a crucial role in reducing the severity of insomnia.

Effects of Cognitive Behavioral Therapy for Insomnia on Suicidal Ideation in Veterans

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Trockel, Mickey; Karlin, Bradley E.; Taylor, C. Barr; Brown, Gregory K.; Manber, Rachel

2015-01-01

Objective: To examine the effects of cognitive behavioral therapy for insomnia (CBT-I) on suicidal ideation among Veterans with insomnia. Design: Longitudinal data collected in the course of an uncontrolled evaluation of a large-scale CBT-I training program. Setting: Outpatient and residential treatment facilities. Participants: Four hundred five Veterans presenting for treatment of insomnia. Interventions: Cognitive behavioral therapy for insomnia. Measurement and Results: At baseline, 32% of patients, compared with 21% at final assessment, endorsed some level of suicidal ideation [χ2(df = 1) = 125; P suicidal ideation. The effect of change in insomnia severity on change in depression severity was also significant. After controlling for change in depression severity and other variables in the model, the effect of change in insomnia severity on change in suicidal ideation remained significant. Conclusion: This evaluation of the largest dissemination of cognitive behavioral therapy for insomnia (CBT-I) in the United States found a clinically meaningful reduction in suicidal ideation among Veterans receiving CBT-I. The mechanisms by which effective treatment of insomnia with CBT-I reduces suicide risk are unknown and warrant investigation. The current results may have significant public health implications for preventing suicide among Veterans. Citation: Trockel M, Karlin BE, Taylor CB, Brown GK, Manber R. Effects of cognitive behavioral therapy for insomnia on suicidal ideation in veterans. SLEEP 2015;38(2):259–265. PMID:25515115

Qualitative Studies of Insomnia: Current State of Knowledge in the Field

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Araújo, Taís; Jarrin, Denise C.; Leanza, Yvan; Vallières, Annie; Morin, Charles M.

2016-01-01

Summary Despite its high prevalence and burden, insomnia is often trivialized, under-diagnosed, and under-treated in practice. Little information is available on the subjective experience and perceived consequences of insomnia, help-seeking behaviors, and treatment preferences. The use of qualitative approaches (e.g., ethnography, phenomenology, grounded theory) may help gain a better understanding of this sleep disorder. The present paper summarizes the evidence derived from insomnia studies using a qualitative research methodology (e.g., focus group, semi-structured interviews). A systematic review of the literature was conducted using PsycINFO and Medline databases. The review yielded 22 studies and the quality of the methodology of each of them was evaluated systematically using the CASP appraisal tool. Selected articles possess at least a very good methodological rigor and they were categorized according to their main focus: “Experience of insomnia”, “Management of insomnia” and “Medicalization of insomnia”. The main findings indicate that: 1) insomnia is often experienced as a 24-hour problem and is perceived to affect several domains of life, 2) a sense of frustration and misunderstanding is very common among insomnia patients, which is possibly due to a mismatch between patients’ and health care professionals’ perspectives on insomnia and its treatment, 3) health care professionals pay more attention to sleep hygiene education and medication therapies and less to the patient’s subjective experience of insomnia, and 4) health care professionals are often unaware of non-pharmacological interventions other than sleep hygiene education. An important implication of these findings is the need to develop new clinical measures with a broader scope on insomnia and more targeted treatments that take into account the patient’s experience of insomnia. Greater use of qualitative approaches in future research may produce novel and more contextualized

Proton knock-out in Hall A

International Nuclear Information System (INIS)

Jager, K. de

2003-01-01

Proton knock-out is studied in a broad program in Hall A at Jefferson Lab. The first experiment performed in Hall A studied the 16 O(e,e'p) reaction. Since then proton knock-out experiments have studied a variety of aspects of that reaction, from single-nucleon properties to its mechanism, such as final-state interactions and two-body currents, in nuclei from 2 H to 16 O. In this review the accomplishments of this program will be summarized and an outlook given of expected future results. (orig.)

Neurobehavioral Performance Impairment in Insomnia: Relationships with Self-Reported Sleep and Daytime Functioning

Science.gov (United States)

Shekleton, Julia A.; Flynn-Evans, Erin E.; Miller, Belinda; Epstein, Lawrence J.; Kirsch, Douglas; Brogna, Lauren A.; Burke, Liza M.; Bremer, Erin; Murray, Jade M.; Gehrman, Philip; Lockley, Steven W.; Rajaratnam, Shantha M. W.

2014-01-01

Study Objectives: Despite the high prevalence of insomnia, daytime consequences of the disorder are poorly characterized. This study aimed to identify neurobehavioral impairments associated with insomnia, and to investigate relationships between these impairments and subjective ratings of sleep and daytime dysfunction. Design: Cross-sectional, multicenter study. Setting: Three sleep laboratories in the USA and Australia. Patients: Seventy-six individuals who met the Research Diagnostic Criteria (RDC) for Primary Insomnia, Psychophysiological Insomnia, Paradoxical Insomnia, and/or Idiopathic Childhood Insomnia (44F, 35.8 ± 12.0 years [mean ± SD]) and 20 healthy controls (14F, 34.8 ± 12.1 years). Interventions: N/A. Measurements and Results: Participants completed a 7-day sleep-wake diary, questionnaires assessing daytime dysfunction, and a neurobehavioral test battery every 60-180 minutes during an afternoon/evening sleep laboratory visit. Included were tasks assessing sustained and switching attention, working memory, subjective sleepiness, and effort. Switching attention and working memory were significantly worse in insomnia patients than controls, while no differences were found for simple or complex sustained attention tasks. Poorer sustained attention in the control, but not the insomnia group, was significantly associated with increased subjective sleepiness. In insomnia patients, poorer sustained attention performance was associated with reduced health-related quality of life and increased insomnia severity. Conclusions: We found that insomnia patients exhibit deficits in higher level neurobehavioral functioning, but not in basic attention. The findings indicate that neurobehavioral deficits in insomnia are due to neurobiological alterations, rather than sleepiness resulting from chronic sleep deficiency. Citation: Shekleton JA; Flynn-Evans EE; Miller B; Epstein LJ; Kirsch D; Brogna LA; Burke LM; Cremer E; Murray JM; Gehrman P; Lockley SW; Rajaratnam SMW

Cognitive Behavioral Therapy for Insomnia in the Context of Cardiovascular Conditions

OpenAIRE

Conley, Samantha; Redeker, Nancy S.

2015-01-01

Cardiovascular disease (CVD) is the leading cause of death worldwide and is associated with high levels of morbidity, disability and poor quality of life. The prevalence of insomnia symptoms and diagnosis of insomnia are high among those with CVD. Although insomnia appears to be important to CVD, less is known about the effects of insomnia treatment on important biological, sleep, symptom, quality of life, functional and morbidity or mortality outcomes in people with or at-risk for CVD. The p...

Outcomes of Cognitive-Behavioral Treatment for Insomnia on Insomnia, Depression, and Fatigue for Individuals with Multiple Sclerosis: A Case Series

OpenAIRE

Clancy, Megan; Drerup, Michelle; Sullivan, Amy Burleson

2015-01-01

Background: This clinical case series examined outcomes of cognitive-behavioral therapy for insomnia (CBT-I) in individuals with multiple sclerosis (MS). Current literature links insomnia with higher rates of depression and fatigue in individuals with MS. However, no research to date evaluates a targeted psychotherapeutic intervention for insomnia in this population.

Sleep Reactivity and Insomnia: Genetic and Environmental Influences

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Drake, Christopher L.; Friedman, Naomi P.; Wright, Kenneth P.; Roth, Thomas

2011-01-01

Study Objectives: Determine the genetic and environmental contributions to sleep reactivity and insomnia. Design: Population-based twin cohort. Participants: 1782 individual twins (988 monozygotic or MZ; 1,086 dizygotic or DZ), including 744 complete twin pairs (377 MZ and 367 DZ). Mean age was 22.5 ± 2.8 years; gender distribution was 59% women. Measurements: Sleep reactivity was measured using the Ford Insomnia Response to Stress Test (FIRST). The criterion for insomnia was having difficulty falling asleep, staying asleep, or nonrefreshing sleep “usually or always” for ≥ 1 month, with at least “somewhat” interference with daily functioning. Results: The prevalence of insomnia was 21%. Heritability estimates for sleep reactivity were 29% for females and 43% for males. The environmental variance for sleep reactivity was greater for females and entirely due to nonshared effects. Insomnia was 43% to 55% heritable for males and females, respectively; the sex difference was not significant. The genetic variances in insomnia and FIRST scores were correlated (r = 0.54 in females, r = 0.64 in males), as were the environmental variances (r = 0.32 in females, r = 0.37 in males). In terms of individual insomnia symptoms, difficulty staying asleep (25% to 35%) and nonrefreshing sleep (34% to 35%) showed relatively more genetic influences than difficulty falling asleep (0%). Conclusions: Sleep reactivity to stress has a substantial genetic component, as well as an environmental component. The finding that FIRST scores and insomnia symptoms share genetic influences is consistent with the hypothesis that sleep reactivity may be a genetic vulnerability for developing insomnia. Citation: Drake CL; Friedman NP; Wright KP; Roth T. Sleep reactivity and insomnia: genetic and environmental influences. SLEEP 2011;34(9):1179-1188. PMID:21886355

Professional correlates of insomnia.

Science.gov (United States)

Léger, Damien; Massuel, Marie-Anne; Metlaine, Arnaud

2006-02-01

Insomnia is a highly prevalent disorder that affects daytime functioning, behavior, and quality of life. Several reports have shown that insomnia impacts on the workforce and is associated with an increased risk of absenteeism. However, few workplace studies have been performed. Our study attempted to evaluate the professional correlates of insomnia by comparing a group of workers with insomnia to a matched group of good sleepers. The main objective measure was absenteeism. Accidents, self-esteem at work, job satisfaction, and efficiency at work were also investigated. Pairs of workers with insomnia (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition definition) and good sleepers, matched by age, sex, and occupational status, were interviewed by their occupational physician and also answered a self-administered questionnaire on work-related criteria. Objective data on absenteeism (number of days absent from work) were provided by the employers' health resource databases. Paris and the Ile de France region (France). Seven hundred eighty-five subjects completed the questionnaire. We retained 369 pair (ie, 738 subjects) for analysis. Insomniacs missed work twice as often as good sleepers. The difference between insomniacs and good sleepers in terms of absenteeism was particularly high for blue-collar workers (odds ratio = 3.0) and men (odds ratio = 2.31). Insomniacs had also a higher accident rate while driving and, strikingly, a 3-fold greater risk of having 2 or 3 serious road accidents. They also reported poor self-esteem at work, less job satisfaction, and less efficiency at work, compared with good sleepers. Our study found an objective increase in absenteeism in insomniacs compared with good sleepers.

New developments in cognitive behavioral therapy as the first-line treatment of insomnia

OpenAIRE

Siebern, Allison T; Manber, Rachel

2011-01-01

Allison T Siebern, Rachel ManberSleep Medicine Center, Stanford University School of Medicine, Redwood City, California, USAAbstract: Insomnia is the most common sleep disorder. Psychological, behavioral, and biological factors are implicated in the development and maintenance of insomnia as a disorder, although the etiology of insomnia remains under investigation, as it is still not fully understood. Cognitive behavioral therapy for insomnia (CBTI) is a treatment for insomnia that is grounde...

New developments in cognitive behavioral therapy as the first-line treatment of insomnia

Directory of Open Access Journals (Sweden)

Allison T Siebern

2011-02-01

Full Text Available Allison T Siebern, Rachel ManberSleep Medicine Center, Stanford University School of Medicine, Redwood City, California, USAAbstract: Insomnia is the most common sleep disorder. Psychological, behavioral, and biological factors are implicated in the development and maintenance of insomnia as a disorder, although the etiology of insomnia remains under investigation, as it is still not fully understood. Cognitive behavioral therapy for insomnia (CBTI is a treatment for insomnia that is grounded in the science of behavior change, psychological theories, and the science of sleep. There is strong empirical evidence that CBTI is effective. Recognition of CBTI as the first-line treatment for chronic insomnia (National Institutes of Health consensus, British Medical Association was based largely on evidence of its efficacy in primary insomnia. The aim of this article is to provide background information and review recent developments in CBTI, focusing on three domains: promising data on the use of CBTI when insomnia is experienced in the presence of comorbid conditions, new data on the use of CBTI as maintenance therapy, and emerging data on the delivery of CBTI through the use of technology and in primary care settings.Keywords: insomnia, CBTI, nonpharmacological treatment

Clinical practice guidelines for insomnia disorder | Malan | South ...

African Journals Online (AJOL)

Insomnia disorder is defined as difficulty in falling asleep, maintaining sleep, and early morning awakenings. Common daytime consequences experienced are fatigue, mood instability and impaired concentration. In chronic insomnia these symptoms persist over a period of at least three months. Chronic insomnia can also ...

European guideline for the diagnosis and treatment of insomnia.

Science.gov (United States)

Riemann, Dieter; Baglioni, Chiara; Bassetti, Claudio; Bjorvatn, Bjørn; Dolenc Groselj, Leja; Ellis, Jason G; Espie, Colin A; Garcia-Borreguero, Diego; Gjerstad, Michaela; Gonçalves, Marta; Hertenstein, Elisabeth; Jansson-Fröjmark, Markus; Jennum, Poul J; Leger, Damien; Nissen, Christoph; Parrino, Liborio; Paunio, Tiina; Pevernagie, Dirk; Verbraecken, Johan; Weeß, Hans-Günter; Wichniak, Adam; Zavalko, Irina; Arnardottir, Erna S; Deleanu, Oana-Claudia; Strazisar, Barbara; Zoetmulder, Marielle; Spiegelhalder, Kai

2017-12-01

This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (≤4 weeks; weak recommendation, moderate-quality evidence). Antihistamines

Psychosocial Correlates of Insomnia in an Adolescent Population

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Siomos, Konstantinos E.; Avagianou, Penelope-Alexia; Floros, Georgios D.; Skenteris, Nikolaos; Mouzas, Odysseas D.; Theodorou, Kyriaki; Angelopoulos, Nikiforos V.

2010-01-01

This study examines the nature of the relationship between psychosocial factors and insomnia complaints in an adolescent non-clinical population. It is a cross-sectional study of a stratified sample of 2,195 Greek adolescent high-school students. Subjects were given the Athens insomnia scale, the Symptom Checklist scale (SCL-90-R) and a…

Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models.

Science.gov (United States)

López-González, Irene; Viana, Rosa; Sanz, Pascual; Ferrer, Isidre

2017-07-01

Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a -/- (laforin knock-out) and Epm2b -/- (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences. C3ar1 and CxCl10 messenger RNAs (mRNAs) are significantly increased in Epm2a -/- mice aged 12 months when compared with age-matched controls, whereas C3ar1, C4b, Ccl4, CxCl10, Il1b, Il6, Tnfα, and Il10ra mRNAs are significantly upregulated in Epm2b -/- at the same age. This is accompanied by increased protein levels of IL1-β, IL6, TNFα, and Cox2 particularly in Epm2b -/- mice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b -/- mice. These findings show for the first time increased innate inflammatory responses in a neurodegenerative disease with polyglucosan intraneuronal deposits which increase with disease progression, in a way similar to what is seen in neurodegenerative diseases with abnormal protein aggregates. These findings also point to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD.

‘Folk theories’ about the causes of insomnia

OpenAIRE

Harvey, Allison G.; Soehner, Adriane; Lombrozo, Tania; Bélanger, Lynda; Rifkin, Jamie; Morin, Charles M.

2013-01-01

The present study investigates ‘folk theories’ about the causes of insomnia. Participants with insomnia (n = 69) completed a qualitative and quantitative assessment of their folk theories. The qualitative assessment was to speak aloud for 1 minute in response to: ‘What do you think causes your insomnia?’. The quantitative assessment involved completing the ‘Causal Attributions of My Insomnia Questionnaire’ (CAM-I), developed for this study. The three most common folk theories for both the cau...

[Daytime consequences of insomnia complaints in the French general population].

Science.gov (United States)

Ohayon, M M; Lemoine, P

2004-01-01

Insomnia is a frequent symptom in the general population; numerous studies have proven this. In the past years, classifications have gradually given more emphasis to daytime repercussions of insomnia and to their consequences on social and cognitive functioning. They are now integrated in the definition of insomnia and are used to quantify its severity. If the daytime consequences of insomnia are well known at the clinical level, there are few epidemiological data on this matter. The aim of this study was to assess the daytime repercussions of insomnia complaints in the general population of France. A representative sample (n=5,622) aged 15 or older was surveyed by telephone with the help of the sleep-EVAL expert system, a computer program specially designed to evaluate sleep disorders and to manage epidemiological investigations. Interviews have been completed for 80.8% of the solicited subjects (n=5,622). The variables considered comprised insomnia and its daytime repercussions on cognitive functioning, affective tone, daytime sleepiness and diurnal fatigue. Insomnia was found in 18.6% of the sample. The prevalence was higher in women (22.4%) than in men (14.5%, psleep. Nearly 75% of insomnia complainers reported having a disrupted sleep or waking up too early in the morning and about 40% said they had a non-restorative sleep. Repercussions on daytime functioning were reported by most insomnia subjects (67%). Repercussions on cognitive functioning changed according age, number of insomnia symptoms and the use of a psychotropic medication. A decreased efficiency was more likely to be reported by subjects between 15 and 44 years of age (OR: 2.9), those using a psychotropic (OR: 1.5), those reporting at least three insomnia symptoms (OR: 1.4) and women (OR: 1.4). The highest probability of the appearance of concentration difficulties was found in subjects younger than 65 Years, having a depressive disorder and using a psychotropic (15-44 years: OR 19.1; 45-64 years

New onset of insomnia in hospitalized patients in general medical wards: incidence, causes, and resolution rate

OpenAIRE

Ho, An; Raja, Bronson; Waldhorn, Richard; Baez, Valentina; Mohammed, Idiris

2017-01-01

ABSTRACT Background: Insomnia is common in hospitalized patients. However, no study has examined new onset of insomnia in patients without a prior history of insomnia. Objectives: Incidence of new onset of insomnia in inpatients, associated factors and resolution rate after 2 weeks. Method: This is a prospective observational study conducted at a community hospital. We used the Insomnia Severity Index questionnaire to screen for insomnia in all patients located in the general medical floors f...

Knocking out P2X receptors reduces transmitter secretion in taste buds.

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Huang, Yijen A; Stone, Leslie M; Pereira, Elizabeth; Yang, Ruibiao; Kinnamon, John C; Dvoryanchikov, Gennady; Chaudhari, Nirupa; Finger, Thomas E; Kinnamon, Sue C; Roper, Stephen D

2011-09-21

In response to gustatory stimulation, taste bud cells release a transmitter, ATP, that activates P2X2 and P2X3 receptors on gustatory afferent fibers. Taste behavior and gustatory neural responses are largely abolished in mice lacking P2X2 and P2X3 receptors [P2X2 and P2X3 double knock-out (DKO) mice]. The assumption has been that eliminating P2X2 and P2X3 receptors only removes postsynaptic targets but that transmitter secretion in mice is normal. Using functional imaging, ATP biosensor cells, and a cell-free assay for ATP, we tested this assumption. Surprisingly, although gustatory stimulation mobilizes Ca(2+) in taste Receptor (Type II) cells from DKO mice, as from wild-type (WT) mice, taste cells from DKO mice fail to release ATP when stimulated with tastants. ATP release could be elicited by depolarizing DKO Receptor cells with KCl, suggesting that ATP-release machinery remains functional in DKO taste buds. To explore the difference in ATP release across genotypes, we used reverse transcriptase (RT)-PCR, immunostaining, and histochemistry for key proteins underlying ATP secretion and degradation: Pannexin1, TRPM5, and NTPDase2 (ecto-ATPase) are indistinguishable between WT and DKO mice. The ultrastructure of contacts between taste cells and nerve fibers is also normal in the DKO mice. Finally, quantitative RT-PCR show that P2X4 and P2X7, potential modulators of ATP secretion, are similarly expressed in taste buds in WT and DKO taste buds. Importantly, we find that P2X2 is expressed in WT taste buds and appears to function as an autocrine, positive feedback signal to amplify taste-evoked ATP secretion.

Mouse nuclear myosin I knock-out shows interchangeability and redundancy of myosin isoforms in the cell nucleus.

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Venit, Tomáš; Dzijak, Rastislav; Kalendová, Alžběta; Kahle, Michal; Rohožková, Jana; Schmidt, Volker; Rülicke, Thomas; Rathkolb, Birgit; Hans, Wolfgang; Bohla, Alexander; Eickelberg, Oliver; Stoeger, Tobias; Wolf, Eckhard; Yildirim, Ali Önder; Gailus-Durner, Valérie; Fuchs, Helmut; de Angelis, Martin Hrabě; Hozák, Pavel

2013-01-01

Nuclear myosin I (NM1) is a nuclear isoform of the well-known "cytoplasmic" Myosin 1c protein (Myo1c). Located on the 11(th) chromosome in mice, NM1 results from an alternative start of transcription of the Myo1c gene adding an extra 16 amino acids at the N-terminus. Previous studies revealed its roles in RNA Polymerase I and RNA Polymerase II transcription, chromatin remodeling, and chromosomal movements. Its nuclear localization signal is localized in the middle of the molecule and therefore directs both Myosin 1c isoforms to the nucleus. In order to trace specific functions of the NM1 isoform, we generated mice lacking the NM1 start codon without affecting the cytoplasmic Myo1c protein. Mutant mice were analyzed in a comprehensive phenotypic screen in cooperation with the German Mouse Clinic. Strikingly, no obvious phenotype related to previously described functions has been observed. However, we found minor changes in bone mineral density and the number and size of red blood cells in knock-out mice, which are most probably not related to previously described functions of NM1 in the nucleus. In Myo1c/NM1 depleted U2OS cells, the level of Pol I transcription was restored by overexpression of shRNA-resistant mouse Myo1c. Moreover, we found Myo1c interacting with Pol II. The ratio between Myo1c and NM1 proteins were similar in the nucleus and deletion of NM1 did not cause any compensatory overexpression of Myo1c protein. We observed that Myo1c can replace NM1 in its nuclear functions. Amount of both proteins is nearly equal and NM1 knock-out does not cause any compensatory overexpression of Myo1c. We therefore suggest that both isoforms can substitute each other in nuclear processes.

Phenotypes of sleeplessness: stressing the need for psychodiagnostics in the assessment of insomnia.

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van de Laar, Merijn; Leufkens, Tim; Bakker, Bart; Pevernagie, Dirk; Overeem, Sebastiaan

2017-09-01

Insomnia is a too general term for various subtypes that might have different etiologies and therefore require different types of treatment. In this explorative study we used cluster analysis to distinguish different phenotypes in 218 patients with insomnia, taking into account several factors including sleep variables and characteristics related to personality and psychiatric comorbidity. Three clusters emerged from the analysis. The 'moderate insomnia with low psychopathology'-cluster was characterized by relatively normal personality traits, as well as normal levels of anxiety and depressive symptoms in the presence of moderate insomnia severity. The 'severe insomnia with moderate psychopathology'-cluster showed relatively high scores on the Insomnia Severity Index and scores on the sleep log that were indicative for severe insomnia. Anxiety and depressive symptoms were slightly above the cut-off and they were characterized by below average self-sufficiency and less goal-directed behavior. The 'early onset insomnia with high psychopathology'-cluster showed a much younger age and earlier insomnia onset than the other two groups. Anxiety and depressive symptoms were well above the cut-off score and the group consisted of a higher percentage of subjects with comorbid psychiatric disorders. This cluster showed a 'typical psychiatric' personality profile. Our findings stress the need for psychodiagnostic procedures next to a sleep-related diagnostic approach, especially in the younger insomnia patients. Specific treatment suggestions are given based on the three phenotypes.

Insomnia in a chronic musculoskeletal pain with disability population is independent of pain and depression.

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Asih, Sali; Neblett, Randy; Mayer, Tom G; Brede, Emily; Gatchel, Robert J

2014-09-01

Insomnia is frequently experienced by patients suffering from chronic musculoskeletal disorders but is often seen as simply a symptom of pain or depression and not as an independent disorder. Compared with those who experience only chronic pain, patients with both chronic pain and insomnia report higher pain intensity, more depressive symptoms, and greater distress. However, insomnia has not yet been systematically studied in a chronic musculoskeletal pain with disability population. This study assessed the prevalence and severity of patient-reported insomnia, as well as the relationship among insomnia, pain intensity, and depressive symptoms, in a chronic musculoskeletal pain with disability population. This was a retrospective study of prospectively captured data. A consecutive cohort of 326 chronic musculoskeletal pain with disability patients (85% with spinal injuries) entered a functional restoration treatment program. All patients signed a consent form to participate in this protocol. Insomnia was assessed with the Insomnia Severity Index, a validated patient-report measure of insomnia symptoms. Four patient groups were formed: no clinically significant insomnia (score, 0-7); subthreshold insomnia (score, 8-14); moderate clinical insomnia (score, 15-21); and severe clinical insomnia (score, 22-28). Three patterns of sleep disturbance were also evaluated: early, middle, and late insomnia. Additional validated psychosocial patient-reported data were collected, including the Pain Visual Analog Scale, the Beck Depression Inventory, the Oswestry Disability Index, and the Pain Disability Questionnaire. Patients completed a standard psychosocial assessment battery on admission to the functional restoration program. The program included a quantitatively directed exercise process in conjunction with a multimodal disability management approach. The four insomnia groups were compared on demographic and psychosocial variables. The shared variances among insomnia

Analysis on yin syndrome insomnia and yang syndrome insomnia%失眠的阴证阳证分类探析

Institute of Scientific and Technical Information of China (English)

唐娜娜; 余建玮; 吴长汶; 骆始华; 黄俊山; 刘中勇

2017-01-01

Sleeping and awaking of a man is compatible with the nature,in which movement of defensive qi between yin and yang is the root cause of sleeping and awaking.And besides,shen dominates sleeping.The insomnia based on wei yang ying yin theory is that if the causative factor of insomnia originated from the disorder of wei yang (defensive yang),there of it is yang syndrome;if the trigger was over-powerful wei yang,then it is insomnia of yang in the yang syndrome;if the cause was weak wei yang,then it is insomnia of yin in the yang syndrome.Likewise,if the trigger was the disorder of nutrient yin,then it is yin syndrome insomnia;if nutrient yin was too excessive,then it is insomnia of yang in the yin syndrome;if nutrient yin was too deficient,then it is insomnia of yin in the yin syndrome.Based on spirit dominated by heart mind theory:fire and heat harassing spirit is yang syndrome insomnia;excessive fire harassing heart is yang in the yang syndrome insomnia;deficient fire disturbing heart and mind is yin in the yang syndrome insomnia;the lack of cultivation of heart and mind is insomnia of yin syndrome,among which the trigger is deficiency,then insomnia belongs to yin in the yin syndrome,and the trigger is excess,then the insomnia is yang in the yin syndrome.This paper classified insomnia into two categories:the yin syndrome and yang syndrome for the sake of clinical practice.%人之寤寐是与自然相适应的结果,卫行于阴与阳,是寐与寤的根本原因,另外神主宰着睡眠.基于卫阳营阴理论引起的失眠:卫阳失调为阳证失眠,卫阳过强为阳中之阳证失眠,卫阳太弱为阳中之阴证失眠;营阴失调为阴证失眠,营阴过实为阴中之阳证失眠,营阴太虚为阴中之阴证失眠.基于心主神志理论引起的失眠:火热扰神为阳证失眠,实火扰心为阳中之阳证失眠,虚火扰心为阳中之阴证失眠;心神失养为阴证失眠,因虚致心神失养为阴中之阴证失眠,因实致心神失养为阴中之阳证失眠.文章对失眠进行阴证阳证的分类,以期为临床实践提供思路.

Gene cassette knock-in in mammalian cells and zygotes by enhanced MMEJ.

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Aida, Tomomi; Nakade, Shota; Sakuma, Tetsushi; Izu, Yayoi; Oishi, Ayu; Mochida, Keiji; Ishikubo, Harumi; Usami, Takako; Aizawa, Hidenori; Yamamoto, Takashi; Tanaka, Kohichi

2016-11-28

Although CRISPR/Cas enables one-step gene cassette knock-in, assembling targeting vectors containing long homology arms is a laborious process for high-throughput knock-in. We recently developed the CRISPR/Cas-based precise integration into the target chromosome (PITCh) system for a gene cassette knock-in without long homology arms mediated by microhomology-mediated end-joining. Here, we identified exonuclease 1 (Exo1) as an enhancer for PITCh in human cells. By combining the Exo1 and PITCh-directed donor vectors, we achieved convenient one-step knock-in of gene cassettes and floxed allele both in human cells and mouse zygotes. Our results provide a technical platform for high-throughput knock-in.

Study on insomnia and sleep quality in adolescents and their correlation analysis

Directory of Open Access Journals (Sweden)

Xian LUO

2017-09-01

Full Text Available Objective To investigate the correlation between insomnia and sleep quality in adolescents. Methods According to Insomnia Severity Index (ISI Chinese Version, 3342 students technician training in school were divided into non insomnia group (N = 2345 and insomnia group (N = 997. Sleep and emotional state were assessed by ISI Chinese Version, Pittsburgh Sleep Quality Index (PSQI, Epworth Sleepiness Scale (ESS, Self?Rating Anxiety Scale (SAS and Beck Depression Inventory (BDI. The social demographic data were collected simultaneously. Results The number of insomnia, daytime sleepiness, anxiety and depression in the population was 997 (29.83%, 568 (17.00%, 243 (7.27% and 1287 (38.51%, respectively. The comparison of social demographic data between 2 groups showed that the proportion of female (P = 0.000, poor physical condition (P = 0.000, non?only child (P = 0.006, high learning pressure (P = 0.000 and smoking (P = 0.027 in insomnia group were significantly higher than those in non insomnia group. The total scores of ISI Chinese Version (P = 0.000, ESS (P = 0.000, SAS (P = 0.000 and BDI (P = 0.000 in insomnia group were significantly higher than those in non insomnia group. Pearson correlation analysis showed that ISI Chinese Version and PSQI scores were positively correlated with ESS score (r = 0.361, P = 0.000; r = 0.064, P = 0.000, SAS score (r = 0.326, P = 0.000; r = 0.069, P = 0.000 and BDI score (r = 0.529, P = 0.000; r = 0.067, P = 0.000, and ISI Chinese Version had higher correlation (r = 0.300-0.600 with the above scores than PSQI (r < 0.100. Further partial correlation analysis showed that ISI Chinese Version score was negatively correlated with PSQI score (r = - 0.056, P = 0.001. Conclusions Higher proportion of female, worse physical condition, more non?only child, greater learning pressure and higher smoking rate were observed in insomnia group. Daytime sleepiness, anxiety and depression in insomnia group were more serious than those

Sleep problems in bipolar disorders: more than just insomnia.

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Steinan, M K; Scott, J; Lagerberg, T V; Melle, I; Andreassen, O A; Vaaler, A E; Morken, G

2016-05-01

Sleep problems in bipolar disorder (BD) are common, but reported rates vary from 10% to 80%, depending on definitions, methodologies and management of potential confounding factors. This multicenter study seeks to address these issues and also compares BD cases with Hypersomnia as well as the more commonly investigated Insomnia and No Sleep Problem groups. A cross-sectional comparison of sleep profiles in 563 BD I and II individuals who participated in a structured assessment of demographic, clinical, illness history and treatment variables. Over 40% cases met criteria for Insomnia and 29% for Hypersomnia. In univariate analysis, Insomnia was associated with BD II depression whilst Hypersomnia was associated with BD I depression or euthymia. After controlling for confounders and covariates, it was demonstrated that Hypersomnia cases were significantly more likely to be younger, have BD I and be prescribed antidepressants whilst Insomnia cases had longer illness durations and were more likely to be prescribed benzodiazepines and hypnotics. Whilst Insomnia symptoms are common in BD, Hypersomnia is a significant, frequently underexplored problem. Detailed analyses of large representative clinical samples are critical to extending our knowledge of differences between subgroups defined by sleep profile. © 2015 The Authors. Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.

Treatment of Insomnia With Traditional Chinese Herbal Medicine.

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Singh, Amrinder; Zhao, Kaicun

2017-01-01

Insomnia is a condition with sleep problems and many people suffered from it. Chronic insomnia can last for long time and it will severely affect people's health and the quality of life. In conventional medicine, the most commonly used the medicine is benzodiazepine. It is effective but also has significant side effects. Patients try to use some kinds of alternative medicines. Chinese medicinal herbs and formulas have been used in the treatment of insomnia for more than 2000 years in China. In recent decades, Chinese herbal medicine has been widely used in the Western countries. Many clinical studies including randomized controlled clinical trials and research on pharmacological action mechanisms of the herbs for treatment of insomnia have been conducted. It is very important and very helpful to review the published research papers to gather the available information for a critical analysis. This chapter evaluated the data from both of clinical studies and pharmacological researches on the therapeutic formulas and on some key herbs used in the treatment of insomnia. Clinical studies showed a very wide spectrum of herbs that were used in clinical treatment of insomnia. This was due to different syndrome patterns happened with insomnia. This brought complexity and difficulties to identify which are the essential key herbs or formulas. It was found Suanzaoren decoction (Ziziphus spinose decoction ) is the most frequently used formula for the treatment of insomnia. Based on the clinical data, several herbs were identified as most frequently used sedative and hypnotic herbs in Chinese herbal medicine including Suanzaoren (Ziziphus spinose ), Fuling (Poria cocos ), and Gancao (Glycyrrhiza uralensis ). The underlying pharmacological action mechanisms discovered in the studies on some key herbs used in the treatment of insomnia were evaluated. The major pharmacological action mechanisms shared by most of the sedative herbs are to act through the neurotransmitter gamma

Increased susceptibility to diet-induced obesity in histamine-deficient mice

DEFF Research Database (Denmark)

Jørgensen, Emilie A; Vogelsang, Thomas W; Knigge, Ulrich

2006-01-01

in the development of high-fat diet (HFD)-induced obesity. METHODS: Histamine-deficient histidine decarboxylase knock-out (HDC-KO) mice and C57BL/6J wild-type (WT) mice were given either a standard diet (STD) or HFD for 8 weeks. Body weight, 24-hour caloric intake, epididymal adipose tissue size, plasma leptin...... weeks, whereas a significant difference in body weight gain was first observed after 5 weeks in WT mice. After 8 weeks 24-hour caloric intake was significantly lower in HFD- than in STD-fed WT mice. In HDC-KO mice no difference in caloric intake was observed between HFD- and STD-fed mice. After 8 weeks...

Simplified sleep restriction for insomnia in general practice: a randomised controlled trial.

Science.gov (United States)

Falloon, Karen; Elley, C Raina; Fernando, Antonio; Lee, Arier C; Arroll, Bruce

2015-08-01

Insomnia is common in primary care. Cognitive behavioural therapy for insomnia (CBT-I) is effective but requires more time than is available in the general practice consultation. Sleep restriction is one behavioural component of CBT-I. To assess whether simplified sleep restriction (SSR) can be effective in improving sleep in primary insomnia. Randomised controlled trial of patients in urban general practice settings in Auckland, New Zealand. Adults with persistent primary insomnia and no mental health or significant comorbidity were eligible. Intervention patients received SSR instructions and sleep hygiene advice. Control patients received sleep hygiene advice alone. Primary outcomes included change in sleep quality at 6 months measured by the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and sleep efficiency (SE%). The proportion of participants reaching a predefined 'insomnia remission' treatment response was calculated. Ninety-seven patients were randomised and 94 (97%) completed the study. At 6-month follow-up, SSR participants had improved PSQI scores (6.2 versus 8.4, Pinsomnia, the adjusted odds ratio for insomnia remission was 2.7 (95% CI = 1.1 to 6.5). There were no significant differences in other outcomes or adverse effects. SSR is an effective brief intervention in adults with primary insomnia and no comorbidities, suitable for use in general practice. © British Journal of General Practice 2015.

Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aβ accumulation.

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Tong, Leslie M; Djukic, Biljana; Arnold, Christine; Gillespie, Anna K; Yoon, Seo Yeon; Wang, Max M; Zhang, Olivia; Knoferle, Johanna; Rubenstein, John L R; Alvarez-Buylla, Arturo; Huang, Yadong

2014-07-16

Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases. Copyright © 2014 the authors 0270-6474/14/349506-10$15.00/0.

Ayurvedic therapy (shirodhara) for insomnia: a case series.

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Vinjamury, Sivarama Prasad; Vinjamury, Manjusha; der Martirosian, Claudia; Miller, Judith

2014-01-01

Insomnia is one of the most common complaints faced by primary care practitioners after pain. Non-pharmacological management of Insomnia that is noninvasive is gaining interest among patients with insomnia. To determine the feasibility of recruiting and retaining participants in a clinical trial on shirodhara, Ayurvedic oil dripping therapy, for insomnia in the United States and also to investigate the therapeutic usefulness of Shirodhara for insomnia using standardized outcome measures. Case series. Shirodhara with Brahmi oil was done for 45 minutes on each participant for 5 consecutive days. Insomnia Severity Index (ISI) was used to evaluate the severity of insomnia as well as to determine the response to Shirodhara therapy. Data were collected at baseline, end of the treatment (day 5) and 1 week after the treatment ended (follow-up). Two males and eight females with a mean age of 40 years (range 23 to 72), SD ± 14.2, were enrolled in the study. One dropped out of the study, but all remaining nine participants experienced improvement at the end of treatment. The percentage of improvement range varied from 3.85% to 69.57%. At follow-up, most participants continued to improve. Comparison of means between baseline and day 5 indicated an overall significant improvement (P insomnia. It is feasible to recruit and retain participants for such therapies in the United States. It is important to validate these findings and investigate the mechanism of action using a larger sample and rigorous research design.

Insomnia and limb pain in hemodialysis patients: What is the share of restless leg syndrome?

Directory of Open Access Journals (Sweden)

Majid Malaki

2012-01-01

Full Text Available Insomnia and limb pain are common problems in dialysis patients. In addition, restless leg syndrome (RLS as a specific cause of insomnia and limb pain has been reported in many studies. The purpose of this study was to estimate incidence of insomnia and RLS as a cause of insomnia in these patients. Twenty-six patients undergoing hemodialysis were investigated for insomnia, limb pain and RLS as per the defined criteria. They were evaluated for dialysis quality, dialysis duration, hemoglobin, serum phosphorous, ionized calcium, iron and ferritin levels. These variables between patients with insomnia and those with normal sleep were evaluated by independent "t" test. Without considering the etiology or pathogenesis of insomnia, we evaluated the occurrence of insomnia and limb pain in these patients, and specifically, restless leg syndrome. Insomnia and limb pain were common in dialytic patients. 46% of patients had insomnia. 91% of sleepless group had limb pain as a persistent, annoying complaint. Limb pain was not seen in groups with a normal sleep pattern. Restless leg syndrome was found in 8% of total cases (2 out of 26 and 17% among the insomnia group (2 out of 12. In spite of high incidence of insomnia among patients undergoing regular hemodialysis, role of RLS is trivial. There is a strong relationship between hemoglobin levels and duration of renal replacement therapy to insomnia occurrence.

Insomnia and limb pain in hemodialysis patients: what is the share of restless leg syndrome?

Science.gov (United States)

Malaki, Majid; Mortazavi, Fakhr Sadat; Moazemi, Sussan; Shoaran, Maryam

2012-01-01

Insomnia and limb pain are common problems in dialysis patients. In addition, restless leg syndrome (RLS) as a specific cause of insomnia and limb pain has been reported in many studies. The purpose of this study was to estimate incidence of insomnia and RLS as a cause of insomnia in these patients. Twenty-six patients undergoing hemodialysis were investigated for insomnia, limb pain and RLS as per the defined criteria. They were evaluated for dialysis quality, dialysis duration, hemoglobin, serum phosphorous, ionized calcium, iron and ferritin levels. These variables between patients with insomnia and those with normal sleep were evaluated by independent "t" test. Without considering the etiology or pathogenesis of insomnia, we evaluated the occurrence of insomnia and limb pain in these patients, and specifically, restless leg syndrome. Insomnia and limb pain were common in dialytic patients. 46% of patients had insomnia. 91% of sleepless group had limb pain as a persistent, annoying complaint. Limb pain was not seen in groups with a normal sleep pattern. Restless leg syndrome was found in 8% of total cases (2 out of 26) and 17% among the insomnia group (2 out of 12). In spite of high incidence of insomnia among patients undergoing regular hemodialysis, role of RLS is trivial. There is a strong relationship between hemoglobin levels and duration of renal replacement therapy to insomnia occurrence.

Treatment agreement, adherence, and outcome in cognitive behavioral treatments for insomnia.

Science.gov (United States)

Dong, Lu; Soehner, Adriane M; Bélanger, Lynda; Morin, Charles M; Harvey, Allison G

2018-03-01

Patient adherence has been identified as an important barrier to the implementation of evidence-based psychological treatments. In cognitive behavioral treatments (CBT) for insomnia, the current study examined (a) the validity of therapist ratings of patient agreement and adherence against an established behavioral measure of adherence, and (b) the relationship between treatment agreement, adherence, and outcome. Participants were 188 adults meeting DSM-IV-TR criteria for chronic insomnia who were randomized to receive behavior therapy, cognitive therapy, or CBT for insomnia. Treatment agreement/adherence was measured by (a) weekly therapist ratings of patient agreement and homework completion, and (b) adherence to behavioral strategies (ABS) derived from patient-reported sleep diary. Outcome measures were Insomnia Severity Index and insomnia remission (Insomnia Severity Index adherence, and ABS measures during treatment significantly predicted insomnia remission at posttreatment, and all but therapist rating of homework completion predicted remission at 6-month follow-up. Greater patient agreement and adherence (therapist ratings and ABS) during treatment predicted better treatment outcome. Therapist-rated treatment agreement and adherence correspond well with patient-reported sleep diary-derived adherence measure. These simple, deployable therapist-rated patient agreement and adherence can potentially be useful for treatments for other disorders. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Easi-CRISPR for creating knock-in and conditional knockout mouse models using long ssDNA donors.

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Miura, Hiromi; Quadros, Rolen M; Gurumurthy, Channabasavaiah B; Ohtsuka, Masato

2018-01-01

CRISPR/Cas9-based genome editing can easily generate knockout mouse models by disrupting the gene sequence, but its efficiency for creating models that require either insertion of exogenous DNA (knock-in) or replacement of genomic segments is very poor. The majority of mouse models used in research involve knock-in (reporters or recombinases) or gene replacement (e.g., conditional knockout alleles containing exons flanked by LoxP sites). A few methods for creating such models have been reported that use double-stranded DNA as donors, but their efficiency is typically 1-10% and therefore not suitable for routine use. We recently demonstrated that long single-stranded DNAs (ssDNAs) serve as very efficient donors, both for insertion and for gene replacement. We call this method efficient additions with ssDNA inserts-CRISPR (Easi-CRISPR) because it is a highly efficient technology (efficiency is typically 30-60% and reaches as high as 100% in some cases). The protocol takes ∼2 months to generate the founder mice.

Sleep apnea in patients reporting insomnia or restless legs symptoms.

Science.gov (United States)

Bianchi, M T; Goparaju, B; Moro, M

2016-01-01

Insomnia and restless legs syndrome (RLS) are defined by self-reported symptoms, and polysomnography (PSG) is not routinely indicated. Occult obstructive sleep apnea (OSA), common even in asymptomatic adults, may complicate management of patients presenting with insomnia or restless legs. To this end, we investigated objective sleep apnea metrics in a large retrospective cohort according to self-reported symptom profiles. We compared sleep apnea findings in patients referred to our center according to self-reported symptoms associated with insomnia, sleep apnea, and restless legs. The cohort included over 1900 adults who underwent diagnostic (n = 1418) or split-night (n = 504) PSGs and completed a symptom and medical history questionnaire. More than 30% of patients who did not endorse any OSA symptoms, but did endorse insomnia or restless legs symptoms, were found to have OSA based on apnea-hypopnea index (AHI) >5 during overnight laboratory testing. Regression models of the full cohort showed that the risk of OSA was related, as expected, to older age, male sex, elevated body mass index, and presence of OSA symptoms. The presence of insomnia symptoms did not alter the risk of OSA. The presence of restless legs symptoms showed a small odds ratio for lowered OSA risk. Objective evidence of OSA occurs similarly in those with insomnia or restless legs symptoms, even among those without self-reported OSA symptoms. Providers should be aware of the potential for occult OSA in populations with insomnia and restless legs, which may complicate their management in addition to presenting an independent medical risk itself. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pharmacological Management of Treatment-Induced Insomnia in ADHD

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Kratochvil, Christopher J.; Lake, Marybeth; Pliszka, Steven R.; Walkup, John T.

2005-01-01

A 7-year-old girl with attention-deficit/hyperactivity disorder (ADHD), combined subtype, and oppositional defiant disorder presents with a complaint of marked insomnia. Her parents describe 60 to 90 minutes of nightly initial insomnia that began with the initiation of 36 mg OROS methylphenidate (Concerta) 2 months ago. Behavioral interventions…

Heritability of insomnia symptoms in youth and their relationship to depression and anxiety.

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Gehrman, Philip R; Meltzer, Lisa J; Moore, Melisa; Pack, Allan I; Perlis, Michael L; Eaves, Lindon J; Silberg, Judy L

2011-12-01

Insomnia is a highly prevalent sleep disorder yet little is known about the role of genetic factors in its pathophysiology. The aim of this study was to examine the relative contributions of genetic and environmental factors in explaining variability in insomnia symptoms. Traditional twin design. Academic medical center. 1412 twin pairs aged 8-16 years (48.8% MZ, 47.2% DZ, 4.0% indeterminate). None. Ratings of insomnia symptoms, depression, and overanxious disorder were made by trained interviewers based on DSM-III-R criteria. ACE models were conducted using Mx statistical software. Insomnia symptoms were prevalent in this sample based both on parental (6.6%) and youth (19.5%) reports. The overall heritability of insomnia symptoms was modest (30.7%), with the remaining variance attributed to unique environmental effects. There was no evidence of sex differences in the prevalence of insomnia symptoms or in the contribution of genetic and environmental effects. In multivariate models, there was support for insomnia-specific unique environmental effects over and above overlapping effects with depression and overanxious disorder, but no evidence for insomnia-specific genetic effects. Genetic factors play a modest role in the etiology of insomnia symptoms in 8-16 year-olds. These effects overlap with the genetics of depression and overanxious disorder. Further work is needed to determine which genes confer risk for all three disorders.

The evaluation of selected insomnia predictors in adolescents and young adults with cystic fibrosis.

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Tomaszek, Lucyna; Cepuch, Grazyna; Pawlik, Lidia

2018-03-21

The purpose of the study was to assess the incidence of insomnia in adolescents and young adults with cystic fibrosis and its impact on the quality of life, and to examine whether demographic and clinical factors and negative emotional states are predictors of insomnia in these patients. The study was conducted among 95 cystic fibrosis patients aged 14-25 years. The study used a personal questionnaire survey, the Athens Insomnia Scale, the Cystic Fibrosis Quality of Life Questionnaire, the Hospital Anxiety and Depression Scale, and the Numeric Rating Scale. Insomnia was diagnosed in 38% of cystic fibrosis patients. In patients with insomnia, the level of anxiety (Me: 10 vs. 4; P=0.000) and depression (Me: 6.5 vs. 2; P=0.000) was significantly higher than in the good sleep quality group. The risk of insomnia increases as anxiety (OR: 4.31; 95% CI: 2.20 to 8.41) and depressive symptoms exacerbate (OR: 4.98; 95% CI: 1.84 to 13.43). Insomnia significantly worsens the quality of life in cystic fibrosis patients (ß =-0.5, P=0.000). Insomnia affects a large percentage of cystic fibrosis patients, and anxiety and depression are factors that increase the risk of insomnia. Insomnia decreases the quality of life in cystic fibrosis patients.

L-citrulline protects from kidney damage in type 1 diabetic mice.

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Maritza J Romero

2013-12-01

Full Text Available Rationale. Diabetic nephropathy is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of L-arginine (L-arg, the substrate for endothelial nitric oxide synthase (eNOS, failed to improve vascular function. L-citrulline (L-cit supplementation not only increases L-arg synthesis, but also inhibits cytosolic arginase I (Arg I, a competitor of eNOS for the use of L-arg, in the vasculature. Aims. To investigate whether L-cit treatment reduces diabetic nephropathy in streptozotocin (STZ-induced type 1 diabetes in mice and rats and to study its effects on arginase II (ArgII function, the main renal isoform. Methods. STZ-C57BL6 mice received L-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and L-cit-treated STZ-rats were evaluated. Results. L-cit exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, L-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 wks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater BUN levels, hypertrophy, and dilated tubules than diabetic wild type mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic wild type animals. L-cit also restored NO/ROS balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, L-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1beta and IL-12(p70 generation in the human proximal tubular cells. Conclusions. L-cit supplementation established an anti-inflammatory profile and significantly preserved the nephron function during type 1

Magnetic Resonance Spectroscopy in Patients with Insomnia: A Repeated Measurement Study.

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Kai Spiegelhalder

Full Text Available Chronic insomnia is one of the most prevalent central nervous system disorders. It is characterized by increased arousal levels, however, the neurobiological causes and correlates of hyperarousal in insomnia remain to be further determined. In the current study, magnetic resonance spectroscopy was used in the morning and evening in a well-characterized sample of 20 primary insomnia patients (12 females; 8 males; 42.7 ± 13.4 years and 20 healthy good sleepers (12 females; 8 males; 44.1 ± 10.6 years. The most important inhibitory and excitatory neurotransmitters of the central nervous system, γ-aminobutyric acid (GABA and glutamate/glutamine (Glx, were assessed in the anterior cingulate cortex (ACC and dorsolateral prefrontal cortex (DLPFC. The primary hypothesis, a diurnal effect on GABA levels in patients with insomnia, could not be confirmed. Moreover, the current results did not support previous findings of altered GABA levels in individuals with insomnia. Exploratory analyses, however, suggested that GABA levels in the ACC may be positively associated with habitual sleep duration, and, thus, reduced GABA levels may be a trait marker of objective sleep disturbances. Moreover, there was a significant GROUP x MEASUREMENT TIME interaction effect on Glx in the DLPFC with increasing Glx levels across the day in the patients but not in the control group. Therefore, Glx levels may reflect hyperarousal at bedtime in those with insomnia. Future confirmatory studies should include larger sample sizes to investigate brain metabolites in different subgroups of insomnia.

Music for insomnia in adults.

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Jespersen, Kira V; Koenig, Julian; Jennum, Poul; Vuust, Peter

2015-08-13

Insomnia is a common sleep disorder in modern society. It causes reduced quality of life and is associated with impairments in physical and mental health. Listening to music is widely used as a sleep aid, but it remains unclear if it can actually improve insomnia in adults. To assess the effects of listening to music on insomnia in adults and to assess the influence of specific variables that may moderate the effect. We searched CENTRAL, PubMed, Embase, nine other databases and two trials registers in May 2015. In addition, we handsearched specific music therapy journals, reference lists of included studies, and contacted authors of published studies to identify additional studies eligible for inclusion, including any unpublished or ongoing trials. Randomised controlled trials and quasi-randomised controlled trials that compared the effects of listening to music with no treatment or treatment-as-usual on sleep improvement in adults with insomnia. Two authors independently screened abstracts, selected studies, assessed risk of bias, and extracted data from all studies eligible for inclusion. Data on pre-defined outcome measures were subjected to meta-analyses when consistently reported by at least two studies. We undertook meta-analyses using both fixed-effect and random-effects models. Heterogeneity across included studies was assessed using the I² statistic. We included six studies comprising a total of 314 participants. The studies examined the effect of listening to pre-recorded music daily, for 25 to 60 minutes, for a period of three days to five weeks.Based on the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) approach, we judged the evidence from five studies that measured the effect of music listening on sleep quality to be of moderate quality. We judged the evidence from one study that examined other aspects of sleep (see below) to be of low quality. We downgraded the quality of the evidence mainly because of limitations in

Reducing Dysfunctional Beliefs about Sleep Does Not Significantly Improve Insomnia in Cognitive Behavioral Therapy

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Okajima, Isa; Nakajima, Shun; Ochi, Moeko; Inoue, Yuichi

2014-01-01

The present study examined to examine whether improvement of insomnia is mediated by a reduction in sleep-related dysfunctional beliefs through cognitive behavioral therapy for insomnia. In total, 64 patients with chronic insomnia received cognitive behavioral therapy for insomnia consisting of 6 biweekly individual treatment sessions of 50 minutes in length. Participants were asked to complete the Athens Insomnia Scale and the Dysfunctional Beliefs and Attitudes about Sleep scale both at the...

Insomnia and sleep misperception.

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Bastien, C H; Ceklic, T; St-Hilaire, P; Desmarais, F; Pérusse, A D; Lefrançois, J; Pedneault-Drolet, M

2014-10-01

Sleep misperception is often observed in insomnia individuals (INS). The extent of misperception varies between different types of INS. The following paper comprised sections which will be aimed at studying the sleep EEG and compares it to subjective reports of sleep in individuals suffering from either psychophysiological insomnia or paradoxical insomnia and good sleeper controls. The EEG can be studied without any intervention (thus using the raw data) via either PSG or fine quantitative EEG analyses (power spectral analysis [PSA]), identifying EEG patterns as in the case of cyclic alternating patterns (CAPs) or by decorticating the EEG while scoring the different transient or phasic events (K-Complexes or sleep spindles). One can also act on the on-going EEG by delivering stimuli so to study their impact on cortical measures as in the case of event-related potential studies (ERPs). From the paucity of studies available using these different techniques, a general conclusion can be reached: sleep misperception is not an easy phenomenon to quantify and its clinical value is not well recognized. Still, while none of the techniques or EEG measures defined in the paper is available and/or recommended to diagnose insomnia, ERPs might be the most indicated technique to study hyperarousal and sleep quality in different types of INS. More research shall also be dedicated to EEG patterns and transient phasic events as these EEG scoring techniques can offer a unique insight of sleep misperception. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Insomnia: clinical experience with zolpidem (sanval

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Yakov Iosifovich Levin

2010-01-01

Full Text Available The paper describes the present view of the problem of insomnia and gives a classification of sleep disorders and basic methods for their drug and non-drug therapy. Emphasis is placed on the role of the objective sleep study - polysomnography. The use of the current hypnotics belonging to a three Zs group and the minimization of administration of benzodiazepines are most important in pharmacotherapy for insomnia. The results of a clinical polysomnographic study of the effect of Zolpidem (Sanval in patients with insomnia are presented. The subjective evaluation of the beneficial effect of a 10-day course of Sanval is confirmed by the objective studies of the sleep pattern undergoing positive changes in the most important indicators, such as the process of falling asleep, the time of intrasleep awakenings, and the duration of Δ-sleep. The high safety and good tolerability of Sanval permit the latter to be assessed as an effective agent for the treatment of insomnia.

Optimized knock-in of point mutations in zebrafish using CRISPR/Cas9.

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Prykhozhij, Sergey V; Fuller, Charlotte; Steele, Shelby L; Veinotte, Chansey J; Razaghi, Babak; Robitaille, Johane M; McMaster, Christopher R; Shlien, Adam; Malkin, David; Berman, Jason N

2018-06-14

We have optimized point mutation knock-ins into zebrafish genomic sites using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 reagents and single-stranded oligodeoxynucleotides. The efficiency of knock-ins was assessed by a novel application of allele-specific polymerase chain reaction and confirmed by high-throughput sequencing. Anti-sense asymmetric oligo design was found to be the most successful optimization strategy. However, cut site proximity to the mutation and phosphorothioate oligo modifications also greatly improved knock-in efficiency. A previously unrecognized risk of off-target trans knock-ins was identified that we obviated through the development of a workflow for correct knock-in detection. Together these strategies greatly facilitate the study of human genetic diseases in zebrafish, with additional applicability to enhance CRISPR-based approaches in other animal model systems.

Increased use-dependent plasticity in chronic insomnia.

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Salas, Rachel E; Galea, Joseph M; Gamaldo, Alyssa A; Gamaldo, Charlene E; Allen, Richard P; Smith, Michael T; Cantarero, Gabriela; Lam, Barbara D; Celnik, Pablo A

2014-03-01

During normal sleep several neuroplasticity changes occur, some of which are considered to be fundamental to strengthen memories. Given the evidence linking sleep to neuroplasticity, it is conceivable that individuals with chronic sleep disruption, such as patients with chronic insomnia (CI), would experience abnormalities in neuroplastic processes during daytime. Protocols testing use-dependent plasticity (UDP), one of the mechanisms underlying formation of motor memories traces, provide a sensitive measure to assess neuroplasticity in the context of motor training. A well-established transcranial magnetic stimulation (TMS) paradigm was used to evaluate the ability of patients with CI and age-matched good sleeper controls to undergo UDP. We also investigated the effect of insomnia on intracortical motor excitability measures reflecting GABAergic and glutamatergic mechanisms. Human Brain Physiology Laboratory, Johns Hopkins Medical Institutions. We found that patients with CI experienced increased UDP changes relative to controls. This effect was not due to differences in motor training. In addition, patients with CI showed enhanced intracortical facilitation relative to controls, in the absence of changes in intracortical inhibitory measures. This study provides the first evidence that patients with chronic insomnia have an increased plasticity response to physical exercise, possibly due to larger activation of glutamatergic mechanisms. This suggests a heightened state of neuroplasticity, which may reflect a form of maladaptive plasticity, similar to what has been described in dystonia patients and chronic phantom pain after amputation. These results could lead to development of novel treatments for chronic insomnia.

Effectiveness of Cognitive- behavioral Group Therapy on Insomnia Symptoms in Students

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A Abollahi

2015-04-01

Full Text Available Background & aim: Insomnias is associated with considerable problems in educational, vocational, social and familial performance. The purpose of present research was to investigate the effectiveness of Cognitive-Behavior group therapy on improvement of insomnia symptoms in students. Methods: The present clinical trial study was conducted on twenty-four students who were randomly assigned into two groups of case and the control (n = 12. The experimental group was participated in eight sessions of cognitive behavior therapy, while the control group received no intervention. Research tools include the Pittsburgh Sleep Quality Index and the Insomnia Severity Index that completed by both participants. Data were analyzed using ANOVA, t-test. Results: Analysis of covariance showed that the performance of cognitive behavioral therapy may improve symptoms and reduce the severity of insomnia in the experimental group compared with the control group (p < 0.05. Conclusion: Group cognitive-behavioral therapy is effective on symptoms of insomnia in students.

Media use and insomnia after terror attacks in France.

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Goodwin, Robin; Lemola, Sakari; Ben-Ezra, Menachem

2018-03-01

Direct exposure to traumatic events often precipitates sleep disorders. Sleep disturbance has also been observed amongst those indirectly exposed to trauma, via mass media. However, previous work has focused on traditional media use, rather than contemporary social media. We tested associations between both traditional and social media consumption and insomnia symptoms following 2015 terror attacks in Paris France, controlling for location and post-traumatic symptomology. 1878 respondents, selected to represent the national French population, completed an internet survey a month after the Bataclan attacks (response rate 72%). Respondents indicated different media use, post-traumatic stress and insomnia. Controlling for demographics, location and PTSD, insomnia was associated with both traditional (β 0.10, P = .001) and social media use (β 0.12, P = .001). Associations between social media and insomnia were independent of traditional media use. Interventions targeted at social media may be particularly important following mass trauma. Copyright © 2017 Elsevier Ltd. All rights reserved.

Is exercise an alternative treatment for chronic insomnia?

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Giselle Soares Passos

Full Text Available The purposes of this systematic/critical review are: 1 to identify studies on the effects of exercise on chronic insomnia and sleep complaints in middle-aged and older adults and to compare the results of exercise with those obtained with hypnotic medications and 2 to discuss potential mechanisms by which exercise could promote sleep in insomniac patients. We identified studies from 1983 through 2011 using MEDLINE, SCOPUS and Web of Science. For systematic analyses, only studies assessing the chronic effects of exercise on sleep in people with sleep complaints or chronic insomnia were considered. We used the following keywords when searching for articles: insomnia, sleep, sleep complaints, exercise and physical activity. For a critical review, studies were selected on the effects of exercise and possible mechanisms that may explain the effects of exercise on insomnia. We identified five studies that met our inclusion criteria for systematic review. Exercise training is effective at decreasing sleep complaints and insomnia. Aerobic exercise has been more extensively studied, and its effects are similar to those observed after hypnotic medication use. Mechanisms are proposed to explain the effects of exercise on insomnia. There is additional documented evidence on the antidepressant and anti-anxiety effects of exercise. Exercise is effective to decrease sleep complaints and to treat chronic insomnia. Exercise presented similar results when compared with hypnotics; however, prospective studies comparing the effects of exercise with medical and non-medical treatments are warranted before including exercise as a first-line treatment for chronic insomnia are necessary.

Insomnia among Adolescents: Implications for Counselors.

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Morrison, Jack R.

Adolescent underachievers may be, in fact, victims of insomnia or other types of sleep disorders. Insomnia is a greatly overlooked affliction that affects approximately 13% of the adolescent population, creating daytime side-effects that could impair intellectual functioning, such as imposing learning constraints. Poor sleepers among the…

Insomnia: psychological and neurobiological aspects and non-pharmacological treatments.

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Molen, Yara Fleury; Carvalho, Luciane Bizari Coin; Prado, Lucila Bizari Fernandes do; Prado, Gilmar Fernandes do

2014-01-01

Insomnia involves difficulty in falling asleep, maintaining sleep or having refreshing sleep. This review gathers the existing informations seeking to explain insomnia, including those that focus on psychological aspects and those considered neurobiological. Insomnia has been defined in psychological (cognitive components, such as worries and rumination, and behavioral aspects, such as classic conditioning) and physiological terms (increased metabolic rate, with increased muscle tone, heart rate and temperature). From the neurobiological point of view, there are two perspectives: one which proposes that insomnia occurs in association with a failure to inhibit wakefulness and another that considers hyperarousal as having an important role in the physiology of sleep. The non-pharmacological interventions developed to face different aspects of insomnia are presented.

Mendengarkan Murattal Al-Qur'an Untuk Menurunkan Tingkat Insomnia

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Wulandari, Etik Dwi; Trimulyaningsih, Nita

2015-01-01

This research aimed to understand the effect of listening murattal Al-Qur'an to insomnia score. The hypothesis of this research is listening murattal Al-Qur'an can reduce insomnia level. Subjects participated in this research were two university students from Faculty of Psychology and Social Culture, major Psychology, Department of Psychology at the Islamic University of Indonesia, who were diagnosed with insomnia. The data was collected with KSPBJ - Insomnia Rating Scale, monitoring scale an...

Mendengarkan Murattal Al-Qur'an untuk Menurunkan Tingkat Insomnia

OpenAIRE

Wulandari, Etik Dwi; Trimulyaningsih, Nita

2015-01-01

This research aimed to understand the effect of listening murattal Al-Qur'an to insomnia score. The hypothesis of this research is listening murattal Al-Qur'an can reduce insomnia level. Subjects participated in this research were two university students from Faculty of Psychology and Social Culture, major Psychology, Department of Psychology at the Islamic University of Indonesia, who were diagnosed with insomnia. The data was collected with KSPBJ - Insomnia Rating Scale, monitoring scale an...

Epidemiologia da insônia Epidemiology of the insomnia

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José Carlos Souza

2004-04-01

Full Text Available Os autores fizeram uma ampla revisão da literatura científica mundial sobre a epidemiologia da insônia, o mais prevalente dos distúrbios do sono. Foi feito um levantamento bibliográfico, no período de janeiro de 2002 a novembro de 2003, das publicações dos últimos 30 anos, nos bancos de dados MEDLINE e LILACS, sobre a definição e prevalência da insônia, além de suas conseqüências socioeconômicas. As palavras-chaves pesquisadas foram: distúrbio de iniciar o sono, distúrbio de manutenção do sono, distúrbio do despertar precoce, insônia, distúrbios do sono, prevalência da insônia, conseqüências da insônia. Observou-se uma grande variação dos critérios de definição da insônia, dos desenhos metodológicos e dos resultados dos estudos epidemiológicos, o que prejudicou as comparações dos dados das várias pesquisas. As futuras linhas de pesquisa sobre a epidemiologia da insônia devem se embasar em um consenso sobre sua definição e critérios metodológicos mais bem-definidos.A vast literature review on the insomnia epidemiology, the most common sleep disorder, using MEDLINE and LILACS last 30 years of data, was performed from January 2002 to November 2003. The key-words were: sleep initiation disorders, sleep maintenance disorders, early awakening disorder, insomnia, sleep disorders, insomnia prevalence, insomnia consequences. Several insomnia definition criteria and epidemiology researches methods, with data comparison difficulties, were noticed. In the future it will be necessary similar insomnia definition and epidemiology studies criteria.

Prison life: television, sports, work, stress and insomnia in a remand prison.

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Elger, Bernice S

2009-01-01

To compare how prisoners complaining of insomnia and prisoners without sleep problems describe their daily activities, stress factors and the perceived reasons for their sleep quality in prison. 102 randomly chosen remanded prisoners complaining of insomnia and 61 randomly chosen prisoners who did not complain of insomnia. Prisoners complaining of insomnia and those reporting good sleep differed significantly in their lifestyle in prison. A significantly higher percentage of the former than of the latter reported writing letters, diaries or a book in prison, as well as doing "arts-related" activities such as painting and listening to music. A significantly higher percentage of non insomniac prisoners than of prisoners complaining of insomnia practiced sports in prison, watched television, and spent their day discussing and meeting other detainees. PSQI and GHQ scores were significantly different between insomniac and non insomniac prisoners. Insomniac prisoners complained significantly more often than non-insomniac prisoners about sleep disturbances, in the first place by roommates, but also by guards. Activities in prison and stressful events were significant factors associated with the variable "insomnia versus no insomnia" Worries about medical problems (odds ratio: 12.9), being separated or divorced (odds ratio: 8.8), having experienced stressful events during the past week (odds ratio: 8.7), "art" activity (odds ratio: 8.6), and having a GHQ score>10 (odds ratio: 7.7) had the highest odds ratios among the tested covariates. No sports in prison and some activities were also predictors of insomnia when entered separately or conditionally. Our study provides arguments on how to alleviate insomnia in prison: changing conditions of imprisonment is of public health benefit. Increased opportunities to practice sports in prison as well as adequate care for medical problems and psychological support to reduce context related stress should be routinely offered to

Factors Associated with Insomnia among Elderly Patients Attending a Geriatric Centre in Nigeria

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Adetola M. Ogunbode

2014-01-01

Full Text Available Background. Insomnia is a form of chronic sleep problem of public health importance which impacts the life of elderly people negatively. Methods. Cross-sectional study of 843 elderly patients aged 60 years and above who presented consecutively at Geriatric Centre, University College Hospital, Ibadan, Nigeria. The World Health Organization Composite International Diagnostic Interview was used to diagnose insomnia. We assessed the following candidate variables which may be associated with insomnia such as socidemographic characteristics, morbidities, and lifestyle habits. Statistical analysis was done with SPSS 17. Results. The point prevalence of insomnia was 27.5%. Insomnia was significantly associated with being female, not being currently married, having formal education, living below the poverty line, and not being physically active. Health complaints of abdominal pain, generalized body pain, and persistent headaches were significantly associated with insomnia. Conclusion. The high prevalence of insomnia among elderly patients in this setting calls for concerted effort by healthcare workers to educate the elderly on lifestyle modification.

Association between report of insomnia and daytime functioning.

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Ustinov, Yuriy; Lichstein, Kenneth L; Wal, Gregory S Vander; Taylor, Daniel J; Riedel, Brant W; Bush, Andrew J

2010-01-01

The relationship between reports of insomnia and daytime functioning was investigated using hierarchical regression. The presence or absence of a report of insomnia was the predictor of primary interest. A number of covariates were included in the model: demographic variables, health variables, and quantitative sleep parameters. Data were collected from a community sample in the Memphis, Tennessee area. Data from 734 volunteers, ranging in age from 20 to 96years were analyzed. The sample included 235 individuals who reported having chronic insomnia and 499 individuals who reported no sleep problems. Participants completed a 2-week sleep diary, a battery of daytime functioning questionnaires, and a medical disorders checklist. Demographic information was also collected. The daytime functioning assessment included the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Epworth Sleepiness Scale, the Insomnia Impact Scale, and the Fatigue Severity Scale. The hierarchical regression model included four sets. The first three sets consisted of 18 variables capturing demographic, health, and sleep diary parameters. The fourth set included a single dichotomous variable representing the presence or absence of a report of insomnia. Reports of insomnia were a significant predictor of all five daytime functioning measures, which is consistent with previous research. We also showed that reports of insomnia were able to uniquely explain a significant amount of variability in self-reported daytime functioning after controlling for demographics, health, and sleep diary variables. The pattern of individual variables that reached significance in the first three sets varied depending on which daytime functioning measure was predicted, however, age, the presence of pain, the presence of mental health problems, SOL, and WASO were the most commonly significant predictors of poor daytime functioning from these sets across measures. Individuals' perceptions of their sleep are

[SLEEP QUALITY, EXCESSIVE DAYTIME SLEEPINESS AND INSOMNIA IN CHILEAN PARALYMPIC ATHLETES].

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Durán Agüero, Samuel; Arroyo Jofre, Patricio; Varas Standen, Camila; Herrera-Valenzuela, Tomas; Moya Cantillana, Cristobal; Pereira Robledo, Rodolfo; Valdés-Badilla, Pablo

2015-12-01

the sleep takes part in diverse biological and physiological functions, associating his restriction, with minor performance in the sport, nevertheless the quantity and quality of sleep is not known in paralympic athletes. to determine the sleep quality, insomnia and excessive daytime sleepiness in Chilean paralympic athletes. descriptive transverse Study, the sample included 33 paralympic athletes (24.2% women), those who were practicing swimming, tennis of table, football 5, powerlifting and tennis chair. The studied variables measured up across two surveys of dream: the Questionnaire of Insomnia and the Pittsburgh Sleep Quality Index. the paralympic athletes sleep were 6.9 } 1.4 hours, 27.7% presents daytime sleepiness, 69.6 % insomnia (Survey of insomnia =7), whereas 78.7 % exhibits a bad sleep quality. The age showed a positive correlation with latency to the sleep (r=0.417 *), the insomnia with latency to the sleep (r=0.462 **), the Pittsburg score was correlated negatively by the sleep duration (r =-0.323) and latency to the sleep is correlated positively by the Pittsburgh score (r=0.603 **). the chilean paralympic athletes, present a low sleep quality, insomnia and excessive daytime sleepiness, situation that might influence negatively the sports performance. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

[Clinical practice guideline. Diagnosis and treatment of insomnia in the elderly].

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Medina-Chávez, Juan Humberto; Fuentes-Alexandro, Salvador Amadeo; Gil-Palafox, Irwin Bernardo; Adame-Galván, Lorena; Solís-Lam, Fernando; Sánchez-Herrera, Lucía Yveth; Sánchez-Narváez, Francisco

2014-01-01

Insomnia is the difficulty to initiate or to maintain sleep. It also has to do with waking up too early at least for a month. A patient with insomnia has daytime consequences such as fatigue, sleepiness, changes in mood, lose of concentration, as well as changes in his social performance and his family relationships, among others. The relationship between this disorder and physical and mental health is important due to the impact that it has on the quality of life and life expectancy of those who suffer from it. Unfortunately, insomnia usually goes unnoticed or untreated, which contributes to the onset or worsening of psychiatric and medical conditions. This exacerbates the problem of insomnia in the elderly people. In relation to the treatment it is recommended: 1) the search and management of secondary causes of insomnia, 2) a non-drug therapy that includes sleep hygiene measures, 3) pharmacotherapy. It is not recommended to start a treatment with a hypnotic drug without rule out medications or diseases that cause or exacerbate insomnia. It is not recommended the use of narcoleptics, melatonin, antihistamines or long half-life benzodiazepines. The consequences include limitations on activities of daily living, loss of functionality, impaired quality of life, increased morbidity and mortality, as well as the worsening of preexisting chronic conditions.

Behavioral Profiles Associated with Objective Sleep Duration in Young Children with Insomnia Symptoms.

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Calhoun, Susan L; Fernandez-Mendoza, Julio; Vgontzas, Alexandros N; Mayes, Susan D; Liao, Duanping; Bixler, Edward O

2017-02-01

Based on previous studies reporting on the association of objective sleep duration and physiologic changes (i.e., increased cortisol) in children, we examined the role of objective sleep duration on differentiating behavioral profiles in children with insomnia symptoms. Seven hundred children (ages 5-12, 47.8% male) from the Penn State Child Cohort underwent a nine-hour polysomnography and parent completed Pediatric Behavior Scale. Insomnia symptoms were defined as parent report of difficulty falling and/or staying asleep, sleep disordered breathing as an AHI of ≥1, and objective short sleep duration as a total sleep time insomnia symptoms demonstrated more overall behavioral problems than controls. Significant interactions between insomnia symptoms and objective sleep duration on scores of externalizing behaviors, mood variability and school problems were found. Profile analyses showed that children with insomnia symptoms and normal sleep duration were associated with clinically elevated externalizing behaviors, inattention, mood variability, and school problems, while children with insomnia and short sleep duration were associated with an overall elevated profile in which internalizing behaviors were more prominent. Childhood insomnia symptoms are associated with a wide array of behavioral problems, for which objective sleep duration is useful in differentiating behavioral profiles. Children with insomnia symptoms and normal sleep duration had a behavioral profile consistent with limit-setting and rule-breaking behaviors, while children with insomnia symptoms and short sleep duration had a behavioral profile more consistent with internalizing behaviors resembling that of psychophysiological disorders.

Experience in Differentiation and Treatment of Stubborn Insomnia

Institute of Scientific and Technical Information of China (English)

无

2001-01-01

@@Stubborn insomnia is characterized by: a) a long course of illness, lasting over 3 months; b) ineffectiveness of the routine treatment; c) the patient can sleep no more than 2 hours at night; d) the patient has a low spirit, palpitation, poor memory, viscera function disorder, all seriously affecting the patient's life and work. The following is an account of the author's clinical experience in treating stubborn insomnia.

Knock-in Luciferase Reporter Mice for In Vivo Monitoring of CREB Activity.

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Dmitry Akhmedov

Full Text Available The cAMP response element binding protein (CREB is induced during fasting in the liver, where it stimulates transcription of rate-limiting gluconeogenic genes to maintain metabolic homeostasis. Adenoviral and transgenic CREB reporters have been used to monitor hepatic CREB activity non-invasively using bioluminescence reporter imaging. However, adenoviral vectors and randomly inserted transgenes have several limitations. To overcome disadvantages of the currently used strategies, we created a ROSA26 knock-in CREB reporter mouse line (ROSA26-CRE-luc. cAMP-inducing ligands stimulate the reporter in primary hepatocytes and myocytes from ROSA26-CRE-luc animals. In vivo, these animals exhibit little hepatic CREB activity in the ad libitum fed state but robust induction after fasting. Strikingly, CREB was markedly stimulated in liver, but not in skeletal muscle, after overnight voluntary wheel-running exercise, uncovering differential regulation of CREB in these tissues under catabolic states. The ROSA26-CRE-luc mouse line is a useful resource to study dynamics of CREB activity longitudinally in vivo and can be used as a source of primary cells for analysis of CREB regulatory pathways ex vivo.

Indiplon in the management of insomnia

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Michael D Lemon

2009-05-01

Full Text Available Michael D Lemon1, Joe D Strain2, Annie M Hegg1, Debra K Farver3 1Department of Pharmacy Practice, South Dakota State University College of Pharmacy, VA Black Hills Health Care System, Fort Meade, SD, USA; 2Department of Pharmacy Practice, South Dakota State University College of  Pharmacy, Rapid City Regional Hospital, Rapid City, SD, USA; 3Department of Pharmacy Practice, South Dakota State University College of Pharmacy, South Dakota Human Services Center, Yankton, SD, USAAbstract: Indiplon is a novel pyrazolopyrimidine, nonbenzodiazepine γ-aminobutyric acid (GABA agonist studied for the treatment of insomnia. This article reviews the chemistry, pharmacology, clinical pharmacokinetics, drug interactions, clinical trials, safety, tolerability, contraindications, use in special populations, and dosing of indiplon. OVID, International Pharmaceutical Abstracts (IPA, and PubMed databases were searched (1966 to February 2009 for the keywords indiplon, NBI-34060, and insomnia. References of key articles were also reviewed to identify additional publications. Only English language articles were selected for review. Indiplon has been shown to have high affinity and selectivity for the GABAα1 receptor subunit associated with sedation. In clinical studies, indiplon has demonstrated efficacy in improving latency to sleep onset, latency to persistent sleep, total sleep time, wake time after sleep onset, number of awakenings after sleep onset, and overall sleep quality when compared to placebo. Indiplon has a favorable safety profile with limited rebound insomnia and no tolerance. Neurocrine Biosciences, Incorporated received an Approvable Letter from the United States Food and Drug Administration in December 2007 for the indiplon IR 5 mg and 10 mg capsules based on meeting three additional requirements. At the time of this writing, indiplon remains unapproved.Keywords: indiplon, insomnia, NBI-34060

Alpha-wave frequency characteristics in health and insomnia during sleep.

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Schwabedal, Justus T C; Riedl, Maik; Penzel, Thomas; Wessel, Niels

2016-06-01

Appearances of alpha waves in the sleep electrencephalogram indicate physiological, brief states of awakening that lie in between wakefulness and sleep. These microstates may also cause the loss in sleep quality experienced by individuals suffering from insomnia. To distinguish such pathological awakenings from physiological ones, differences in alpha-wave characteristics between transient awakening and wakefulness observed before the onset of sleep were studied. In polysomnographic datasets of sleep-healthy participants (n = 18) and patients with insomnia (n = 10), alpha waves were extracted from the relaxed, wake state before sleep onset, wake after sleep-onset periods and arousals of sleep. In these, alpha frequency and variability were determined as the median and standard deviation of inverse peak-to-peak intervals. Before sleep onset, patients with insomnia showed a decreased alpha variability compared with healthy participants (P insomnia, alpha variability increased for short wake after sleep-onset periods. Major differences between the two groups were encountered during arousal. In particular, the alpha frequency in patients with insomnia rebounded to wake levels, while the frequency in healthy participants remained at the reduced level of short wake after sleep-onset periods. Reductions in alpha frequency during wake after sleep-onset periods may be related to the microstate between sleep and wakefulness that was described for such brief awakenings. Reduced alpha variability before sleep may indicate a dysfunction of the alpha generation mechanism in insomnia. Alpha characteristics may also prove valuable in the study of other sleep and attention disorders. © 2016 European Sleep Research Society.

Insomnia: psychological and neurobiological aspects and non-pharmacological treatments

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Yara Fleury Molen

2014-01-01

Full Text Available Insomnia involves difficulty in falling asleep, maintaining sleep or having refreshing sleep. This review gathers the existing informations seeking to explain insomnia, including those that focus on psychological aspects and those considered neurobiological. Insomnia has been defined in psychological (cognitive components, such as worries and rumination, and behavioral aspects, such as classic conditioning and physiological terms (increased metabolic rate, with increased muscle tone, heart rate and temperature. From the neurobiological point of view, there are two perspectives: one which proposes that insomnia occurs in association with a failure to inhibit wakefulness and another that considers hyperarousal as having an important role in the physiology of sleep. The non-pharmacological interventions developed to face different aspects of insomnia are presented.

Assessment and treatment of insomnia in adult patients with alcohol use disorders.

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Brower, Kirk J

2015-06-01

Insomnia in patients with alcohol dependence has increasingly become a target of treatment due to its prevalence, persistence, and associations with relapse and suicidal thoughts, as well as randomized controlled studies demonstrating efficacy with behavior therapies and non-addictive medications. This article focuses on assessing and treating insomnia that persists despite 4 or more weeks of sobriety in alcohol-dependent adults. Selecting among the various options for treatment follows a comprehensive assessment of insomnia and its multifactorial causes. In addition to chronic, heavy alcohol consumption and its effects on sleep regulatory systems, contributing factors include premorbid insomnia; co-occurring medical, psychiatric, and other sleep disorders; use of other substances and medications; stress; environmental factors; and inadequate sleep hygiene. The assessment makes use of history, rating scales, and sleep diaries as well as physical, mental status, and laboratory examinations to rule out these factors. Polysomnography is indicated when another sleep disorder is suspected, such as sleep apnea or periodic limb movement disorder, or when insomnia is resistant to treatment. Sobriety remains a necessary, first-line treatment for insomnia, and most patients will have some improvement. If insomnia-specific treatment is needed, then brief behavioral therapies are the treatment of choice, because they have shown long-lasting benefit without worsening of drinking outcomes. Medications work faster, but they generally work only as long as they are taken. Melatonin agonists; sedating antidepressants, anticonvulsants, and antipsychotics; and benzodiazepine receptor agonists each have their benefits and risks, which must be weighed and monitored to optimize outcomes. Some relapse prevention medications may also have sleep-promoting activity. Although it is assumed that treatment for insomnia will help prevent relapse, this has not been firmly established. Therefore

Evaluating DSM-5 Insomnia Disorder and the Treatment of Sleep Problems in a Psychiatric Population.

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Seow, Lee Seng Esmond; Verma, Swapna Kamal; Mok, Yee Ming; Kumar, Sunita; Chang, Sherilyn; Satghare, Pratika; Hombali, Aditi; Vaingankar, Janhavi; Chong, Siow Ann; Subramaniam, Mythily

2018-02-15

With the introduction of insomnia disorder in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), greater emphasis has been placed on the diagnosis and treatment of sleep disorder even in the presence of a coexisting mental disorder. The current study seeks to explore the clinical picture of insomnia in the context of psychiatric disorders commonly associated with sleep complaints by assessing the prevalence and correlates of DSM-5 insomnia disorder, and examining the extent to which insomnia symptoms have been addressed in this population. Four hundred treatment-seeking outpatients suffering from depressive, bipolar affective, anxiety, and schizophrenia spectrum disorders were recruited. DSM-5 insomnia was established using the modified Brief Insomnia Questionnaire. Differences in sociodemographic factors, clinical status, impairment outcomes, and mental health services utilization were compared. Information on patients' help-seeking experiences for insomnia-related symptoms was collected to determine the treatment received and treatment effectiveness. Almost one-third of our sample (31.8%) had DSM-5 insomnia disorder. Those with insomnia disorder had significantly higher impairment outcomes than their counterparts but no group difference was observed for mental health services utilization. Findings based on past treatment contact for sleep problems suggest that diagnosis and treatment of insomnia is lacking in this population. With the new calling from DSM-5, clinicians treating psychiatric patients should view insomnia less as a symptom of their mental illnesses and treat clinical insomnia as a primary disorder. Patients should also be educated on the importance of reporting and treating their sleep complaints. Nonmedical (cognitive and behavioral) interventions for insomnia need to be further explored given their proven clinical effectiveness. © 2018 American Academy of Sleep Medicine

[Insomnia. A severe health care problem].

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Sánchez-Cárdenas, Ana Gabriela; Navarro-Gerrard, Christian; Nellen-Hummel, Haiko; Halabe-Cherem, José

2016-01-01

The magnitude which sleep has on personal well-being is similar to the effects of diet and exercise. Sleep deprivation has severe negative effects on an individual's overall health, and this is usually overseen. From 30 to 40 % of the population has presented insomnia at a certain moment of life and from 9 to 15 % have evolved into a chronic and severe insomnia. Recent investigations have related sleep deprivation with obesity, metabolic disorders, heart disease, mental health problems and dementia. Recently, more investigations have focused on the multiple alterations suffered by the immune system in cases of sleep deprivation. In order to make an opportune diagnosis of insomnia, it is vital to obtain a detailed history of the patients' sleep habits. In the physical exam one must search for signs and symptoms which might suggest an organic cause that generates the patient's insomnia. One of the pillars in treatment of these patients consists in acquiring an adequate sleep hygiene based on the optimization of the environment and the behavior that are associated with sleep.

A Knock-in Reporter for a Novel AR-Targeted Therapy

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2016-05-01

AWARD NUMBER: W81XWH-15-1-0049 TITLE: A Knock -in Reporter for a Novel AR-Targeted Therapy PRINCIPAL INVESTIGATOR: Chunhong Yan, Ph.D...5a. CONTRACT NUMBER A Knock -in Reporter for a Novel AR-Targeted Therapy 5b. GRANT NUMBER W81XWH-15-1-0049 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...enhancer. While the knock -in reporter is expected to faithfully reproduce chemical responses of the endogenous AR gene, we carried out a pilot screen

[Management of insomnia and hypersomnia associated with psychiatric disorders].

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Uchiyama, Makoto; Suzuki, Masahiro; Konno, Chisato; Furihata, Ryuji; Osaki, Koichi; Konno, Michiko; Takahashi, Sakae

2010-01-01

Most psychiatric disorders, such as schizophrenia, mood disorders, or neurotic disorders are associated with sleep disorders of various kinds, among which insomnia is most prevalent and important in psychiatric practice. Almost all patients suffering from major depression complain of insomnia. Pharmacological treatment of insomnia associated with major depression shortens the duration to achieve remission of depression. Insomnia has been recently reported to be a risk factor for depression. Hypersomnia is also a major sleep problem in patient suffering from depression. There have been no clinical guide to treat the symptoms of hypersomnia in depression, but some clinical trials treating them with NDRI or adjunctive administration of psychostimulants. In patients with schizophrenia, insomnia is often an early indicator of the aggravation of psychotic symptoms. Electroencephalographic sleep studies have also revealed sleep abnormalities characteristic to mood disorders, schizophrenia and anxiety disorders. A shortened REM sleep latency has been regarded as a biological marker of depression. Reduced amount of deep Non-REM sleep has been reported to be correlated with negative symptoms of schizophrenia. Recently, REM sleep abnormalities were found in teenagers having post-traumatic stress disorder after a boat accident. Although these facts indicate that insomnia plays an important role in the development of psychiatric disorders, there are few hypotheses explaining the cause and effect of insomnia in these disorders. Here, we reviewed recent articles on insomnia and hypersomnia associated with psychiatric disorders together with their clinical managements.

Psychiatric disorders moderate the relationship between insomnia and cognitive problems in military soldiers.

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Brownlow, Janeese A; Klingaman, Elizabeth A; Boland, Elaine M; Brewster, Glenna S; Gehrman, Philip R

2017-10-15

There has been a great deal of research on the comorbidity of insomnia and psychiatric disorders, but much of the existing data is based on small samples and does not assess the full diagnostic criteria for each disorder. Further, the exact nature of the relationship between these conditions and their impact on cognitive problems are under-researched in military samples. Data were collected from the All Army Study of the Army Study to Assess Risk and Resilience in Service members (unweighted N = 21, 449; weighted N = 674,335; 18-61 years; 13.5% female). Participants completed the Brief Insomnia Questionnaire to assess for insomnia disorder and a self-administered version of the Composite International Diagnostic Interview Screening Scales to assess for psychiatric disorders and cognitive problems. Military soldiers with current major depressive episode (MDE) had the highest prevalence of insomnia disorder (INS; 85.0%), followed by current generalized anxiety disorder (GAD; 82.6%) and current posttraumatic stress disorder (PTSD; 69.7%), respectively. Significant interactions were found between insomnia and psychiatric disorders; specifically, MDE, PTSD, and GAD status influenced the relationship between insomnia and memory/concentration problems. Cross-sectional nature of the assessment and the absence of a comprehensive neurocognitive battery. Psychiatric disorders moderated the relationship between insomnia and memory/concentration problems, suggesting that psychiatric disorders contribute unique variance to cognitive problems even though they are associated with insomnia disorder. Results highlight the importance of considering both insomnia and psychiatric disorders in the diagnosis and treatment of cognitive deficits in military soldiers. Copyright © 2017 Elsevier B.V. All rights reserved.

Is insomnia associated with deficits in neuropsychological functioning? Evidence from a population-based study.

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Goldman-Mellor, Sidra; Caspi, Avshalom; Gregory, Alice M; Harrington, HonaLee; Poulton, Richie; Moffitt, Terrie E

2015-04-01

People with insomnia complain of cognitive deficits in daily life. Results from empirical studies examining associations between insomnia and cognitive impairment, however, are mixed. Research is needed that compares treatment-seeking and community-based insomnia study samples, measures subjective as well as objective cognitive functioning, and considers participants' pre-insomnia cognitive function. We used data from the Dunedin Study, a representative birth cohort of 1,037 individuals, to examine whether insomnia in early midlife was associated with subjective and objective cognitive functioning. We also tested whether individuals with insomnia who reported seeking treatment for their sleep problems (treatment-seekers) showed greater impairment than other individuals with insomnia (non-treatment-seekers). The role of key confounders, including childhood cognitive ability and comorbid health conditions, was evaluated. Insomnia was diagnosed at age 38 according to DSM-IV criteria. Objective neuropsychological assessments at age 38 included the WAIS-IV IQ test, the Wechsler Memory Scale, and the Trail-Making Test. Childhood cognitive functioning was assessed using the Wechsler Intelligence Scale for Children-Revised (WISC-R). A total of 949 cohort members were assessed for insomnia symptoms and other study measures at age 38. Although cohort members with insomnia (n = 186, 19.6%) had greater subjective cognitive impairment than their peers at age 38, they did not exhibit greater objective impairment on formal testing. Treatment-seekers, however, exhibited significant objective impairment compared to non-treatment-seekers. Controlling for comorbidity, daytime impairment, and medications slightly decreased this association. Childhood cognitive deficits antedated the adult cognitive deficits of treatment-seekers. Links between insomnia and cognitive impairment may be strongest among individuals who seek clinical treatment. Clinicians should take into account the

Clinical management of behavioral insomnia of childhood

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Vriend J

2011-06-01

Full Text Available Jennifer Vriend1, Penny Corkum21Clinical Psychology PhD Program, Dalhousie University, Halifax, Nova Scotia, Canada; 2Department of Psychology, Dalhousie University, Halifax, Nova Scotia, CanadaAbstract: Behavioral insomnia is highly prevalent, affecting approximately 25% of children. It involves difficulties initiating and maintaining sleep and frequently results in inadequate sleep, leading to an array of negative effects for both the child and the child’s family. In this paper, we describe a variety of empirically supported behavioral interventions for insomnia from infancy through adolescence. We explore how biological, cognitive, and psychosocial developmental changes contribute to behavioral insomnia and how these changes may affect sleep and behavioral interventions. We also discuss barriers that prevent families from accessing interventions, including why many empirically-supported behavioral interventions are overlooked by health care providers.Keywords: sleep, behavioral insomnia, treatment, infants, children, adolescents

Cognitive behavioral therapy in persons with comorbid insomnia: A meta-analysis.

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Geiger-Brown, Jeanne M; Rogers, Valerie E; Liu, Wen; Ludeman, Emilie M; Downton, Katherine D; Diaz-Abad, Montserrat

2015-10-01

Cognitive behavioral therapy for insomnia (CBT-I) is effective for treatment of primary insomnia. There has been no synthesis of studies quantifying this effect on insomnia comorbid with medical and psychiatric disorders using rigorous selection criteria. The objective of this study was to quantify the effect of CBT-I in studies including patients with medical or psychiatric disorders. Studies were identified from 1985 through February 2014 using multiple databases and bibliography searches. Inclusion was limited to randomized controlled trials of CBT-I in adult patients with insomnia diagnosed using standardized criteria, who additionally had a comorbid medical or psychiatric condition. Twenty-three studies including 1379 patients met inclusion criteria. Based on weighted mean differences, CBT-I improved subjective sleep quality post-treatment, with large treatment effects for the insomnia severity index and Pittsburgh sleep quality index. Sleep diaries showed a 20 min reduction in sleep onset latency and wake after sleep onset, 17 min improvement in total sleep time, and 9% improvement in sleep efficiency post-treatment, similar to findings of meta-analyses of CBT-I in older adults. Treatment effects were durable up to 18 mo. Results of actigraphy were similar to but of smaller magnitude than subjective measures. CBT-I is an effective, durable treatment for comorbid insomnia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Heart rate and heart rate variability modification in chronic insomnia patients.

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Farina, Benedetto; Dittoni, Serena; Colicchio, Salvatore; Testani, Elisa; Losurdo, Anna; Gnoni, Valentina; Di Blasi, Chiara; Brunetti, Riccardo; Contardi, Anna; Mazza, Salvatore; Della Marca, Giacomo

2014-01-01

Chronic insomnia is highly prevalent in the general population, provoking personal distress and increased risk for psychiatric and medical disorders. Autonomic hyper-arousal could be a pathogenic mechanism of chronic primary insomnia. The aim of this study was to investigate autonomic activity in patients with chronic primary insomnia by means of heart rate variability (HRV) analysis. Eighty-five consecutive patients affected by chronic primary insomnia were enrolled (38 men and 47 women; mean age: 53.2 ± 13.6). Patients were compared with a control group composed of 55 healthy participants matched for age and gender (23 men and 32 women; mean age: 54.2 ± 13.9). Patients underwent an insomnia study protocol that included subjective sleep evaluation, psychometric measures, and home-based polysomnography with evaluation of HRV in wake before sleep, in all sleep stages, and in wake after final awakening. Patients showed modifications of heart rate and HRV parameters, consistent with increased sympathetic activity, while awake before sleep and during Stage-2 non-REM sleep. No significant differences between insomniacs and controls could be detected during slow-wave sleep, REM sleep, and post-sleep wake. These results are consistent with the hypothesis that autonomic hyper-arousal is a major pathogenic mechanism in primary insomnia, and confirm that this condition is associated with an increased cardiovascular risk.

Insomnia Severity Index: psychometric properties with Chinese community-dwelling older people.

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Yu, Doris S F

2010-10-01

This paper is a report of a study to evaluate the psychometric properties of the Chinese version of the Insomnia Severity Index. Despite the high prevalence of insomnia in older people and its detrimental impact on well-being and healthcare costs, this problem is almost always undetected and consequently under-treated. The Insomnia Severity Index is psychometrically sound in measuring perceived insomnia severity. However, it has had very limited application in non-White populations. An instrument validation study was carried out between October 2008 and April 2009. The Insomnia Severity Index was translated into Chinese using Brislin's model and administered to a convenience sample of 585 older Chinese people recruited from three community centres for elders. Other instruments were also administered, including the Chinese version of the Pittsburgh Sleep Quality Index and the Geriatric Depression Scale. Cronbach's alpha of the Chinese version of the Insomnia Severity Index was 0.81, with item-to-total correlations in the range of 0.34-0.67. Construct validity was supported by its moderate relationship with the Chinese Pittsburgh Sleep Quality Index and sleep efficiency. The Chinese version of the Insomnia Severity Index also indicated more severe level of insomnia in older people who reported depressed mood on the Geriatric Depression Scale. Discriminant validity was supported as the Chinese version of the Insomnia Severity Index could discriminate poorer sleepers from normal sleepers. Exploratory factor analysis identified a two-factor structure for the Chinese version of the Insomnia Severity Index in measuring the severity and impacts of insomnia on the Chinese older people. The Chinese version of the Insomnia Severity Index is a culturally-relevant and psychometrically-sound instrument for assessing severity and impact of insomnia in Chinese community-dwelling older people. Nurses can use this tool to assess older people's perceptions of insomnia. © 2010 The

Wake up to insomnia: future approaches to the management of insomnia

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Mohammad Tahir Hussain

2011-01-01

Full Text Available Mohammad Tahir Hussain, Steven A. SheaDivision of Sleep Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USAInsomnia is rife. Acutely, almost every individual has experienced a poor night’s sleep, and many short-term remedies for insomnia are tried, including over-the-counter sleep aids and alcohol. Chronic insomnia is the most common sleep disorder, affecting nearly 40 million Americans and accounting for nearly one-third of adults. The annual cost associated with this disorder in the US is estimated at over $15 billionand over $100 billion for indirect costs, such as costs of self-medication, health care-related costs due to exacerbations of comorbid conditions, and costs of reduced productivity.  

Reduced anterior internal capsule white matter integrity in primary insomnia.

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Spiegelhalder, Kai; Regen, Wolfram; Prem, Martin; Baglioni, Chiara; Nissen, Christoph; Feige, Bernd; Schnell, Susanne; Kiselev, Valerij G; Hennig, Jürgen; Riemann, Dieter

2014-07-01

Chronic insomnia is one of the most prevalent central nervous system diseases, however, its neurobiology is poorly understood. Up to now, nothing is known about the integrity of white matter tracts in insomnia patients. In this study, diffusion tensor imaging (DTI) was used in a well-characterized sample of primary insomnia (PI) patients and good sleeper controls to fill this void. Voxelwise between-group comparisons of fractional anisotropy (FA) were performed in 24 PI patients (10 males; 14 females; 42.7 ± 14.5 years) and 35 healthy good sleepers (15 males; 20 females; 40.1 ± 9.1 years) with age and sex as covariates. PI patients showed reduced FA values within the right anterior internal capsule and a trend for reduced FA values in the left anterior internal capsule. The results suggest that insomnia is associated with a reduced integrity of white matter tracts in the anterior internal capsule indicating that disturbed fronto-subcortical connectivity may be a cause or consequence of the disorder.

Patient-reported outcomes in insomnia: development of a conceptual framework and endpoint model.

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Kleinman, Leah; Buysse, Daniel J; Harding, Gale; Lichstein, Kenneth; Kalsekar, Anupama; Roth, Thomas

2013-01-01

This article describes qualitative research conducted with patients with clinical diagnoses of insomnia and focuses on the development of a conceptual framework and endpoint model that identifies a hierarchy and interrelationships of potential outcomes in insomnia research. Focus groups were convened to discuss how patients experience insomnia and to generate items for patient-reported questionnaires on insomnia and associated daytime consequences. Results for the focus group produced two conceptual frameworks: one for sleep and one for daytime impairment. Each conceptual framework consists of hypothesized domains and items in each domain based on patient language taken from the focus group. These item pools may ultimately serve as a basis to develop new questionnaires to assess insomnia.

Does mental health history explain gender disparities in insomnia symptoms among young adults?

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Hale, Lauren; Do, D Phuong; Basurto-Davila, Ricardo; Heron, Melonie; Finch, Brian K; Dubowitz, Tamara; Lurie, Nicole; Bird, Chloe E

2009-12-01

Insomnia is the most commonly reported sleep disorder, characterized by trouble falling asleep, staying asleep, or waking up too early. Previous epidemiological data reveal that women are more likely than men to suffer from insomnia symptoms. We investigate the role that mental health history plays in explaining the gender disparity in insomnia symptoms. Using logistic regression, we analyze National Health and Nutritional Examination Survey (NHANES) III interview and laboratory data, merged with data on sociodemographic characteristics of the residential census tract of respondents. Our sample includes 5469 young adults (ages 20-39) from 1429 census tracts. Consistent with previous research, we find that women are more likely to report insomnia symptoms compared to men (16.7% vs. 9.2%). However, in contrast to previous work, we show that the difference between women's and men's odds of insomnia becomes statistically insignificant after adjusting for history of mental health conditions (OR=1.08, p>.05). The gender disparity in insomnia symptoms may be driven by higher prevalence of affective disorders among women. This finding has implications for clinical treatment of both insomnia and depression, especially among women.

Clinical Update on Epidemiology, Pathogenesis, and Nonpharmacological Treatment of Insomnia

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Mustafa Kahriman

2006-04-01

Full Text Available Scientific background: Insomnia is by far the most common form of sleep disturbance. Most typically, insomnia has been defined as the symptom of difficulty initiating or maintaining sleep and more rarely as an inability to obtain restorative sleep. Insomnia disorders are most often classified as either primary or secondary to other sleep, psychiatric, or medical conditions, although it is often difficult in practice to determine true causality of insomnia or there may be more than one cause (comorbid conditions. Increasing age, female sex, and psychiatric and medical disorders are consistent risk factors for insomnia. Insomnia is associated with significant social, medical, and financial consequences including impaired social functioning and quality of life, increased risk for psychiatric disorders, and increased health care costs. The clinical assessment of insomnia is based on a careful clinical interview, often supplemented by sleep questionnaires, sleep logs, and psychological testing. Polysomnography is indicated only in selected cases when specific sleep pathologies are suspected. Assessment: A large proportion of insomnia sufferers go undiagnosed, and therefore untreated, by their doctors, and many of these patients incur considerable personal, vocational, and health-related consequences as a result. Insomnia can be triggered by a variety of precipitating events, but when it becomes a chronic problem, psychological and behavioral factors are almost always involved in perpetuating or exacerbating sleep disturbances over time. Psychological and behavioral therapies for primary insomnia include sleep restriction, stimulus control therapy, relaxation training, cognitive strategies, and a combination of those methods, referred to as cognitive behavior therapy of insomnia. Results of the controlled clinical trials indicate that 70% to 80% of patients with primary insomnia partially benefit from cognitive behavior therapy. Although only 20% to

Changes in Cognitive Performance Are Associated with Changes in Sleep in Older Adults With Insomnia.

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Wilckens, Kristine A; Hall, Martica H; Nebes, Robert D; Monk, Timothy H; Buysse, Daniel J

2016-01-01

The present study examined sleep features associated with cognition in older adults and examined whether sleep changes following insomnia treatment were associated with cognitive improvements. Polysomnography and cognition (recall, working memory, and reasoning) were assessed before and after an insomnia intervention (Brief Behavioral Treatment of Insomnia [BBTI] or information control [IC]) in 77 older adults with insomnia. Baseline wake-after-sleep-onset (WASO) was associated with recall. Greater NREM (nonrapid eye movement) delta power and lower NREM sigma power were associated with greater working memory and reasoning. The insomnia intervention did not improve performance. However, increased absolute delta power and decreased relative sigma power were associated with improved reasoning. Findings suggest that improvements in executive function may occur with changes in NREM architecture.

Prescriptions of Chinese Herbal Medicines for Insomnia in Taiwan during 2002

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Chen, Fang-Pey; Jong, Maw-Shiou; Chen, Yu-Chun; Kung, Yen-Ying; Chen, Tzeng-Ji; Chen, Fun-Jou; Hwang, Shinn-Jang

2011-01-01

Chinese herbal medicine (CHM) has been commonly used for treating insomnia in Asian countries for centuries. The aim of this study was to conduct a large-scale pharmaco-epidemiologic study and evaluate the frequency and patterns of CHM use in treating insomnia. We obtained the traditional Chinese medicine (TCM) outpatient claims from the National Health Insurance in Taiwan for the year 2002. Patients with insomnia were identified from the diagnostic code of International Classification of Disease among claimed visiting files. Corresponding prescription files were analyzed, and an association rule was applied to evaluate the co-prescription of CHM. Results showed that there were 16 134 subjects who visited TCM clinics for insomnia in Taiwan during 2002 and received a total of 29 801 CHM prescriptions. Subjects between 40 and 49 years of age comprised the largest number of those treated (25.3%). In addition, female subjects used CHMs for insomnia more frequently than male subjects (female : male = 1.94 : 1). There was an average of 4.8 items prescribed in the form of either an individual Chinese herb or formula in a single CHM prescription for insomnia. Shou-wu-teng (Polygonum multiflorum) was the most commonly prescribed single Chinese herb, while Suan-zao-ren-tang was the most commonly prescribed Chinese herbal formula. According to the association rule, the most commonly prescribed CHM drug combination was Suan-zao-ren-tang plus Long-dan-xie-gan-tang, while the most commonly prescribed triple drug combination was Suan-zao-ren-tang, Albizia julibrissin, and P. multiflorum. Nevertheless, further clinical trials are needed to evaluate the efficacy and safety of these CHMs for treating insomnia. PMID:19339485

Insomnia is a frequent finding in adults with Asperger syndrome

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von Wendt Lennart

2003-10-01

Full Text Available Abstract Background Asperger syndrome (AS is a neurodevelopmental disorder belonging to autism spectrum disorders with prevalence rate of 0,35% in school-age children. It has been most extensively studied in childhood while there is scarcity of reports concerning adulthood of AS subjects despite the lifelong nature of this syndrome. In children with Asperger syndrome the initiation and continuity of sleep is disturbed because of the neuropsychiatric deficits inherent of AS. It is probable that sleep difficulties are present in adulthood as well. Our hypothesis was that adults with AS suffer from difficulty in initiating and maintaining sleep and nonrestorative sleep (insomnia. Methods 20 AS without medication were compared with 10 healthy controls devoid of neuropsychiatric anamnesis. Clinical examination, blood test battery and head MRI excluded confounding somatic illnesses. Structured psychiatric interview for axis-I and axis-II disorders were given to both groups as well as Beck Depression Inventory and Wechsler adult intelligence scale, revised version. Sleep quality was assessed with sleep questionnaire, sleep diary during 6 consecutive days and description of possible sleep problems by the participants own words was requested. Results compared with controls and with normative values of good sleep, AS adults had frequent insomnia. In sleep questionnaire 90% (18/20, in sleep diary 75% (15/20 and in free description 85% (17/20 displayed insomnia. There was a substantial psychiatric comorbidity with only 4 AS subject devoid of other axis-I or axis-II disorders besides AS. Also these persons displayed insomnia. It can be noted that the distribution of psychiatric diagnoses in AS subjects was virtually similar to that found among patient with chronic insomnia. Conclusions the neuropsychiatric deficits inherent of AS predispose both to insomnia and to anxiety and mood disorders. Therefore a careful assessment of sleep quality should be an

Insomnia in epilepsy is associated with continuing seizures and worse quality of life.

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Quigg, Mark; Gharai, Sean; Ruland, Jeff; Schroeder, Catherine; Hodges, Matthew; Ingersoll, Karen S; Thorndike, Frances P; Yan, Guofen; Ritterband, Lee M

2016-05-01

To evaluate how insomnia is associated with seizure control and quality of life in patients with epilepsy. Consecutive patients with epilepsy attending clinical visits were surveyed with the Insomnia Severity Index (ISI). Patients had to be treated with at least one anticonvulsant and could not have had documented psychogenic pseudoseizure. The presence or absence of seizures and quality of life (QOLIE-P-10) within the past 4 weeks was recorded. Other variables included demographic and clinical data, sleep-wake timing, the Hörne-Östberg Morningness-Eveningness Questionnaire (MEQ), sleepiness (Epworth Sleepiness Scale (ESS), and mood (Center for Epidemiologic Studies Depression Scale, CES-D). 207 patients completed surveys. 43% had clinically significant insomnia, and 51% had at least mild insomnia. 58% were seizure free. Mean ISI scores were significantly worse for those with continuing seizures, and more severe ISI scores correlated strongly with worse QOL. Younger age, shorter duration of epilepsy, use of sedative/hypnotics, medical and sleep comorbidities, delayed sleep timing and chronotype, excessive sleepiness, and depression were all associated with more severe insomnia. Those with unexpected health care visits over the most recent 4 weeks had worse insomnia. After adjustment for these covariates, more severe insomnia remained significantly associated with lack of seizure freedom and with worse QOL. Insomnia is common in epilepsy, and is associated with short term poor seizure control and worse QOL. Future studies must evaluate cause-and-effect relationships. Assessment of insomnia may be important in the comprehensive care of epilepsy and may influence control of epileptic seizures. Copyright © 2016 Elsevier B.V. All rights reserved.

Prevalence and Polysomnographic Correlates of Insomnia Comorbid with Medical Disorders

Science.gov (United States)

Budhiraja, Rohit; Roth, Thomas; Hudgel, David W.; Budhiraja, Pooja; Drake, Christopher L.

2011-01-01

Study Objectives: To determine the prevalence and polysomnographic correlates of insomnia in subjects with self-reported medical disorders. Design: Prospective cross-sectional study. Participants: Community-based sample of 3282 men and women aged 18 to 65 years old, with a subset who underwent polysomnography. Measurements: Self-reported measures of sleep habits and current health, and polysomnographic sleep variables. Results: The prevalence of insomnia was 21.4%. The adjusted odds of insomnia were 2.2 times as high in persons with any medical disorders as in those without medical disorders. Specifically, odds of insomnia were higher in people with heart disease (OR = 1.6 [95% CI: 1.2-23], P = 0.004), hypertension (1.5 [12-18], P insomnia increased with increasing number of medical disorders. However, polysomnographic sleep was not significantly different in persons with or without medical disorders for most disorders assessed. Conclusion: This large population-based study suggests that insomnia is highly prevalent in diverse chronic medical disorders. However, polysomnographic evidence of disturbed sleep is present in only a subset of comorbid insomnia populations. Citation: Budhiraja R; Roth T; Hudgel DW; Budhiraja P; Drake CL. Prevalence and polysomnographic correlates of insomnia comorbid with medical disorders. SLEEP 2011;34(7):859-867. PMID:21731135

Deletion of the γ-secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia.

Science.gov (United States)

Biundo, Fabrizio; Ishiwari, Keita; Del Prete, Dolores; D'Adamio, Luciano

2016-03-15

Mutations in BRI2/ITM2b genes cause Familial British and Danish Dementias (FBD and FDD), which are pathogenically similar to Familial Alzheimer Disease (FAD). BRI2 inhibits processing of Amyloid precursor protein (APP), a protein involved in FAD pathogenesis. Accumulation of a carboxyl-terminal APP metabolite -ß-CTF- causes memory deficits in a knock-in mouse model of FDD, called FDDKI.We have investigated further the pathogenic function of ß-CTF studying the effect of Aph1B/C deletion on FDDKI mice. This strategy is based on the evidence that deletion of Aph1B/C proteins, which are components of the γ-secretase that cleaves ß-CTF, results in stabilization of ß-CTF and a reduction of Aβ. We found that both the FDD mutation and the Aph1B/C deficiency mildly interfered with spatial long term memory, spatial working/short-term memory and long-term contextual fear memory. In addition, the Aph1BC deficiency induced deficits in long-term cued fear memory. Moreover, the two mutations have additive adverse effects as they compromise the accuracy of spatial long-term memory and induce spatial memory retention deficits in young mice. Overall, the data are consistent with a role for β-CTF in the genesis of memory deficits.

Evaluating DSM-5 Insomnia Disorder and the Treatment of Sleep Problems in a Psychiatric Population

Science.gov (United States)

Seow, Lee Seng Esmond; Verma, Swapna Kamal; Mok, Yee Ming; Kumar, Sunita; Chang, Sherilyn; Satghare, Pratika; Hombali, Aditi; Vaingankar, Janhavi; Chong, Siow Ann; Subramaniam, Mythily

2018-01-01

Study Objectives: With the introduction of insomnia disorder in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), greater emphasis has been placed on the diagnosis and treatment of sleep disorder even in the presence of a coexisting mental disorder. The current study seeks to explore the clinical picture of insomnia in the context of psychiatric disorders commonly associated with sleep complaints by assessing the prevalence and correlates of DSM-5 insomnia disorder, and examining the extent to which insomnia symptoms have been addressed in this population. Methods: Four hundred treatment-seeking outpatients suffering from depressive, bipolar affective, anxiety, and schizophrenia spectrum disorders were recruited. DSM-5 insomnia was established using the modified Brief Insomnia Questionnaire. Differences in sociodemographic factors, clinical status, impairment outcomes, and mental health services utilization were compared. Information on patients' help-seeking experiences for insomnia-related symptoms was collected to determine the treatment received and treatment effectiveness. Results: Almost one-third of our sample (31.8%) had DSM-5 insomnia disorder. Those with insomnia disorder had significantly higher impairment outcomes than their counterparts but no group difference was observed for mental health services utilization. Findings based on past treatment contact for sleep problems suggest that diagnosis and treatment of insomnia is lacking in this population. Conclusions: With the new calling from DSM-5, clinicians treating psychiatric patients should view insomnia less as a symptom of their mental illnesses and treat clinical insomnia as a primary disorder. Patients should also be educated on the importance of reporting and treating their sleep complaints. Nonmedical (cognitive and behavioral) interventions for insomnia need to be further explored given their proven clinical effectiveness. Citation: Seow LSE, Verma SK, Mok YM, Kumar

Insomnia and limb pain in hemodialysis patients: What is the share of restless leg syndrome?

OpenAIRE

Majid Malaki; Fakhr Sadat Mortazavi; Sussan Moazemi; Maryam Shoaran

2012-01-01

Insomnia and limb pain are common problems in dialysis patients. In addition, restless leg syndrome (RLS) as a specific cause of insomnia and limb pain has been reported in many studies. The purpose of this study was to estimate incidence of insomnia and RLS as a cause of insomnia in these patients. Twenty-six patients undergoing hemodialysis were investigated for insomnia, limb pain and RLS as per the defined criteria. They were evaluated for dialysis quality, dialysis duration, hemoglobin, ...

How do I best manage insomnia and other sleep disorders in older adults with cancer?

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Loh, Kah Poh; Burhenn, Peggy; Hurria, Arti; Zachariah, Finly; Mohile, Supriya Gupta

2016-11-01

Insomnia is common in older adults with cancer, with a reported prevalence of 19-60% in prior studies. Cancer treatments are associated with increased risk of insomnia or aggravation of pre-existing insomnia symptoms, and patients who are receiving active cancer treatments are more likely to report insomnia. Insomnia can lead to significant physical and psychological consequences with increased mortality. We discuss physiological sleep changes in older adults, and illustrated the various sleep disorders. We present a literature review on the prevalence and the effects of insomnia on the quality of life in older adults with cancer. We discuss the risk factors and presented a theoretical framework of insomnia in older adults with cancer. We present a case study to illustrate the assessment and management of insomnia in older adults with cancer, comparing and contrasting a number of tools for sleep assessment. There are currently no guidelines on the treatment of sleep disorders in older adults with cancer. We present an algorithm developed at the City of Hope Comprehensive Cancer Center by a multidisciplinary team for managing insomnia, using evidence-based pharmacologic and non-pharmacologic interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

Creation of knock out and knock in mice by CRISPR/Cas9 to validate candidate genes for human male infertility, interest, difficulties and feasibility.

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Kherraf, Zine-Eddine; Conne, Beatrice; Amiri-Yekta, Amir; Kent, Marie Christou; Coutton, Charles; Escoffier, Jessica; Nef, Serge; Arnoult, Christophe; Ray, Pierre F

2018-06-15

High throughput sequencing (HTS) and CRISPR/Cas9 are two recent technologies that are currently revolutionizing biological and clinical research. Both techniques are complementary as HTS permits to identify new genetic variants and genes involved in various pathologies and CRISPR/Cas9 permits to create animals or cell models to validate the effect of the identified variants, to characterize the pathogeny of the identified variants and the function of the genes of interest and ultimately to provide ways of correcting the molecular defects. We analyzed a cohort of 78 infertile men presenting with multiple morphological anomalies of the sperm flagella (MMAF), a severe form of male infertility. Using whole exome sequencing (WES), homozygous mutations in autosomal candidate genes were identified in 63% of the tested subjects. We decided to produce by CRISPR/cas9 four knock-out (KO) and one knock-in (KI) mouse lines to confirm these results and to increase our understanding of the physiopathology associated with these genetic variations. Overall 31% of the live pups obtained presented a mutational event in one of the targeted regions. All identified events were insertions or deletions localized near the PAM sequence. Surprisingly we observed a high rate of germline mosaicism as 30% of the F1 displayed a different mutation than the parental event characterized on somatic tissue (tail), indicating that CRISPR/Cas9 mutational events kept happening several cell divisions after the injection. Overall, we created mouse models for 5 distinct loci and in each case homozygous animals could be obtained in approximately 6 months. These results demonstrate that the combined use of WES and CRISPR/Cas9 is an efficient and timely strategy to identify and validate mutations responsible for infertility phenotypes in human. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular mechanisms of the sleep wake cycle : therapeutic applications to insomnia

OpenAIRE

Grima, Melanie; Hunter, Therese; Zhang, Yimeng

2017-01-01

The aim of this review is to explore the molecular mechanism and genetic components of the sleepwake cycle and insomnia. Moreover, we wanted to review the correlation between primary insomnia and its comorbidities. With this aim, a systematic review of recent evidence of the molecular and genetic mechanisms involved in the causation of primary insomnia, along with associations between primary insomnia and other diseases were conducted. Primary insomnia is a complex disorder which accounts for...

Correlates of general quality of life are different in patients with primary insomnia as compared to patients with insomnia and psychiatric comorbidity

NARCIS (Netherlands)

van de Laar, M.; Pevernagie, D.A.; van Mierlo, P.; Overeem, S.

2016-01-01

Chronic insomnia is known to have a negative influence on quality of life (QOL). To date, most studies on chronic insomnia have focused on health-related aspects of QOL. General QOL, which is a different construct, has not been studied in detail. Moreover, it is not known which factors are

Correlates of general quality of life are different in patients with primary insomnia as compared to patients with insomnia and psychiatric comorbidity

NARCIS (Netherlands)

Laar, M. van de; Pevernagie, D.; Mierlo, P. van; Overeem, S.

2017-01-01

Chronic insomnia is known to have a negative influence on quality of life (QOL). To date, most studies on chronic insomnia have focused on health-related aspects of QOL. General QOL, which is a different construct, has not been studied in detail. Moreover, it is not known which factors are

Alcohol use, anxiety, and insomnia in older adults with generalized anxiety disorder

Science.gov (United States)

Ivan, M. Cristina; Amspoker, Amber B.; Nadorff, Michael R.; Kunik, Mark E.; Cully, Jeffrey A.; Wilson, Nancy; Calleo, Jessica; Kraus-Schuman, Cynthia; Stanley, Melinda A.

2013-01-01

Objectives We examined the presence and frequency of alcohol consumption among older primary care patients with generalized anxiety disorder (GAD) and their relation to demographic variables, insomnia, worry, and anxiety. We expected alcohol-use distribution to be similar to previous reports and alcohol use to be associated with higher anxiety and insomnia. A third aim was to examine the moderating role of alcohol use on the relation between anxiety and insomnia. We expected alcohol use to worsen the relation between anxiety and insomnia. Design Baseline data from a randomized controlled trial Sample 223 patients, age 60 and older, with DSM-IV GAD diagnoses Setting Patients were recruited through internal medicine, family practice, and geriatric clinics at 2 diverse healthcare settings: Michael E. DeBakey Veterans Administration Medical Center and Baylor College of Medicine. Measurements Measures addressed alcohol use (presence and frequency); insomnia (Insomnia Severity Index); self-reported worry severity (Penn State Worry Questionnaire − Abbreviated); clinician-rated worry severity (Generalized Anxiety Disorder Severity Scale); self-reported anxiety severity (State-Trait Anxiety Inventory - Trait); and clinician-rated anxiety (Structured Interview Guidelines for the Hamilton Anxiety Rating Scale). Results Most patients endorsed alcohol use in the past month, but overall weekly frequency was low. Presence and frequency of use among patients with GAD were greater than in prior reports of primary care samples. Alcohol use among patients with GAD was associated with higher education and female gender. Higher education also was associated with more drinks per week, and Caucasians reported more drinks per week than African Americans. Alcohol use was associated with less severe insomnia, lower self-reported anxiety, and less clinician-rated worry and anxiety. More drinks per week were associated with lower clinician-rated anxiety. Moderation analyses revealed lower