Numerous hypotheses have been put forth over the years to explain the development of bipolar disorder. Of these, circadian rhythm hypotheses have gained much importance of late. While the hypothalamus-pituitary-adrenal (HPA) axis hyperactivation hypothesis and the monoamine hypothesis somewhat explain the pathogenic mechanism of depression, they do not provide an explanation for the development of mania/hypomania. Interestingly, all patients with bipolar disorder display significant disruption of circadian rhythms and sleep/wake cycles throughout their mood cycles. Indeed, mice carrying the Clock gene mutation exhibit an overall behavioral profile that is similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, and lower anxiety. It was recently reported that monoamine signaling is in fact regulated by the circadian system. Thus, circadian rhythm instability, imposed on the dysregulation of HPA axis and monoamine system, may in turn increase individual susceptibility for switching from depression to mania/hypomania. In addition to addressing the pathophysiologic mechanism underlying the manic switch, circadian rhythm hypotheses can explain other bipolar disorder-related phenomena such as treatment resistant depression and mixed features.
Animals ; Bipolar Disorder* ; Chronobiology Disorders ; Circadian Rhythm* ; Depression ; Depressive Disorder, Treatment-Resistant ; Humans ; Mice

BACKGROUND: Hes6 is a transcriptional regulator that induces transcriptional activation by binding to transcription repressor Hes1 and suppressing its activity. Hes6 is controlled by the ubiquitin-proteosome-mediated degradation system. Here we investigated the sumoylation of Hes6 and its functional role in its rhythmic expression. METHODS: Hes6, SUMO, and ubiquitin were transfected into HeLa cells and the expression pattern was observed by Western blot and immunoprecipitation. To confirm the effect of sumoylation on the rhythmic expression of Hes6, we generated mouse Hes6 promoter-driven GFP-Hes6 fusion constructs and expressed these constructs in NIH 3T3 cells. RESULTS: Overexpression of SUMO led to sumoylation of Hes6 at both lysine 27 and 30. Protein stability of Hes6 was decreased by sumoylation. Moreover, expression of a Hes6 sumoylation-defective mutant, the 2KR (K27/30R) mutant, or co-expression of SUMO protease SUSP1 with native Hes6, strongly reduced ubiquitination. In addition, sumoylation was associated with both the rhythmic expression and transcriptional regulation of Hes6. Wild type Hes6 showed oscillatory expression with about 2-hour periodicity, whereas the 2KR mutant displayed a longer period. Furthermore, sumoylation of Hes6 derepressed Hes1-induced transcriptional repression. CONCLUSION: Hes6 sumoylation plays an important role in the regulation of its stability and Hes1-mediated transcription. These results suggest that sumoylation may be crucial for rhythmic expression of Hes6 and downstream target genes.
Animals ; Blotting, Western ; HeLa Cells ; Humans ; Immunoprecipitation ; Lysine ; Mice ; NIH 3T3 Cells ; Periodicity ; Protein Stability ; Proteolysis* ; Repression, Psychology ; Sumoylation* ; Transcriptional Activation ; Ubiquitin ; Ubiquitination

When we deal with maxillary and mandibular anterior dental arches showing problems in occlusal relation and aesthetics caused by malformations of teeth and congenital missing, et al during the orthodontic treatment, we could not often decide the functional occlusion by only relying on the orthodontic treatment. If orthodontists can predict what kinds of treatments are needed for functional occlusion in maxillary and mandibular anterior dental arches, they can not only effectively treat patients but also facilitate the cooperation with other field during the treatment. Our previous research showed the correlation among intercanine width, segment depth and arch perimeter by using the Korean normal occlusion model. At this time, we produced the computer application program by taking advantage of this correlation. And then, we applied this program to setting up the treatment plans for 2 patients with the damaged maxillary and mandibular dentures. With the help of this program, we could not only easily acquire the information about the change of variables required by treatment plans but also understand the change of the anterior dental occlusion corresponding to the change of each variables such as the intercanine width, segment depth and arch perimeter. Later, if we can have the information about the relationship between the change of the angle of incisors depending on facial types and arch forms and, in addition, can acquire the appropriate intercanine width, we can have the ability to produce the 3 dimensional occlusogram for the anterior dental arch forms.
Dental Arch* ; Dental Occlusion ; Dentures ; Esthetics ; Humans ; Incisor ; Tooth

This study was designed to investigate the position of anteroposterior center of resistance for genuine intrusion and the mode of change of the minimum distal force for simultanous intrusion and retraction of the upper and lower incisors according to the increase of labial inclination. For this purpose, we used the three-piece intrusion arch appliance and three-dimensional finite element models of upper and lower incisors. 1. Positions of the center of resistance in upper incisors according to the increase of the labial inclination were as follows; 1) In normal inclination situation, the center of resistance was located in 6mm behind the distal surface of the lateral incisor bracket. 2) In 10degrees increase of the labial inclination situation, the center of resistance was located in 9mm behind the distal surface of the lateral incisor bracket. 3) In 20degrees increase of the labial inclination situation, the center of resistance was located in 12m behind the distal surface of the lateral incisor bracket. 4) In 30degrees increase of the labial inclination situation, the center of resistance was located in 16m behind the distal surface of the lateral incisor bracket. 2. Positions of the center of resistance in lower incisors according to the increase of the labial inclination were as follows; 1) In normal inclination situation, the center of resistance was located in 10mm behind the distal surface of the lateral incisor bracket. 2) In 10degrees increase of the labial inclination situation, the center of resistance was located in 13mm behind the distal surface of the lateral incisor bracket. 3) In 20degrees increase of the labial inclination situation, the center of resistance was located in 15m behind the distal surface of the lateral incisor bracket. 4) In 30degrees increase of the labial inclination situation, the center of resistance was located in 18m behind the distal surface of the lateral incisor bracket. 3. The patterns of stress distribution were as follows; 1) There were even compressive stresses in and periodontal ligament when intrusion force was applied through determined center of resistance. 2) There were gradual increase of complexity in compressive stress distribution pattern with increase of the labial inclination when intrusion and retraction force were applied simultaneously.
Finite Element Analysis* ; Incisor* ; Periodontal Ligament

Background: This study aimed to identify chronicity predictors of pediatric primary immune thrombocytopenia (ITP). Methods: This study retrospectively reviewed the medical records of patients with primary pediatric ITP admitted to a tertiary medical center between 2010 and 2021.Forty-five patients with a platelet count ＜20,000/L at the time of diagnosis who were treated with intravenous immunoglobulin (IVIG) were enrolled in this study. Results: According to the disease phase, 28, 6, and 11 patients were classified into the newly diagnosed (ND), persistent, and chronic groups, respectively. The number of patients over 6 years of age was significantly higher in the chronic group than in the ND and persistent groups. After 14 days of IVIG treatment, more patients had a complete response in the non-chronic groups than in the chronic group. In univariate analysis of risk factor for chronic ITP, age 6 years or older and IVIG dose ＜2 g/kg were found to be risk factors for chronic ITP, and these two factors were also confirmed as significant risk factors in multivariate analysis. Conclusion In conclusion, in our study, patients over 6 years of age, and those who received IVIG doses less than 2 g/kg were more likely to progress to chronic ITP.

BACKGROUND: Elevation in plasma homocysteine has been widely studied as an independent risk factor for atherosclerosis. And epidemiologic studies have demonstrated that the persons who take the folate and vitamin B6 have lower incidence of atherosclerotic vascular disease and lower plasma homocysteine level. But, not yet the effects of vitamin B6 and folate on the level of plasma homocysteine and brachial artery dilation on healthy subjects was not evaluated. METHODS: We evaluated the effects of 50 mg of vitamin B6 and 1 mg of folate on endothelial function, plasma homocysteine levels to one healthy postmenoausal woman and nineteen men in a randomized, double-blind, placebo-controlled, crossover design. RESULTS: In our study, supplement of vitamin B6 and folate significantly lowered plasma homocysteine level (placebo : folate =6.56 +1.55 micromol/L vs. 5.37 +1.04 micromol/L, p=.001). But, there were no statistically significant increament of flow-mediated dilation (FMD) compared to placebo (placebo : folate =5.12 +3.26% vs. 6.69 +2.60%, p=.070) and there were no significant correlation between the improvement of homocysteine level and increament of flow mediated dilation on healthy subjects. CONCLUSION: Compared to persons with absolute or relative hyper-homocysteinemia, our study did not show such favorable effects in healthy persons. So further studies must to be held to discover the effect of folate and vitamine B6 in healthy persons.
Atherosclerosis ; Brachial Artery* ; Cross-Over Studies ; Female ; Folic Acid* ; Homocysteine* ; Humans ; Incidence ; Male ; Plasma* ; Risk Factors ; Vascular Diseases ; Vitamin B 6* ; Vitamins*

BACKGROUND AND OBJECTIVES: Primary coronary stenting has been shown to be an effective reperfusion therapy for acute myocardial infarction(AMI). However, few data exist regarding long-term follow-up. We examine the long-term clinical and angiographic outcomes after primary coronary stenting in the early setting of AMI. METHODS: Between September 1995 to October 1999, coronary stenting was attempted in 181 consecutive patients admitted with the diagnosis of AMI within 6 hours from the onset of the chest pain. Clinical events, including death, MI, coronary bypass surgery and repeat angioplasty, were recorded for 1 year. Angiogram were obtained at baseline, after stent, at 2 weeks and 6 months. RESULTS: 168 patients(92.8%) of all patients had complete 1 year clinical follow-up. In-hospital deaths occured in 5 patients(3%). One hundred five patients(62.5%) had follow-up angiography at 6.4+/-2.1 months after stent implantation and restenosis occured in 21.9%. Clinical events after 1 year included death in 6.5%, myocardial infarction in 1.2%, bypass surgery in 1.8% and repeat angioplasty in 7.7%. Freedom from any adverse cardiac event at 1 year was 82.2%. CONCLUSION: Primary stenting is safe and feasible in patients of AMI, even in large thrombus containing lesion and results in excellent long-term outcomes.
Angiography ; Angioplasty ; Chest Pain ; Diagnosis ; Follow-Up Studies ; Freedom ; Humans ; Infarction* ; Myocardial Infarction ; Reperfusion ; Stents* ; Thrombosis

As a consequence of the Earth's rotation, almost all organisms experience day and night cycles within a 24-hr period. To adapt and synchronize biological rhythms to external daily cycles, organisms have evolved an internal time-keeping system. In mammals, the master circadian pacemaker residing in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus generates circadian rhythmicity and orchestrates numerous subsidiary local clocks in other regions of the brain and peripheral tissues. Regardless of their locations, these circadian clocks are cell-autonomous and self-sustainable, implicating rhythmic oscillations in a variety of biochemical and metabolic processes. A group of core clock genes provides interlocking molecular feedback loops that drive the circadian rhythm even at the single-cell level. In addition to the core transcription/translation feedback loops, post-translational modifications also contribute to the fine regulation of molecular circadian clocks. In this article, we briefly review the molecular mechanisms and post-translational modifications of mammalian circadian clock regulation. We also discuss the organization of and communication between central and peripheral circadian oscillators of the mammalian circadian clock.
Brain ; Circadian Clocks ; Circadian Rhythm ; Hypothalamus, Anterior ; Mammals ; Protein Processing, Post-Translational ; Suprachiasmatic Nucleus

BACKGROUND: In mammals, the master circadian pacemaker is localized in an area of the ventral hypothalamus known as the suprachiasmatic nucleus (SCN). Previous studies have shown that pacemaker neurons in the SCN are highly coupled to one another, and this coupling is crucial for intrinsic self-sustainability of the SCN central clock, which is distinguished from peripheral oscillators. One plausible mechanism underlying the intercellular communication may involve direct electrical connections mediated by gap junctions. METHODS: We examined the effect of mefloquine, a neuronal gap junction blocker, on circadian Period 2 (Per2) gene oscillation in SCN slice cultures prepared from Per2::luciferase (PER2::LUC) knock-in mice using a real-time bioluminescence measurement system. RESULTS: Administration of mefloquine causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression. Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythms. CONCLUSION: These findings suggest that neuronal gap junctions play an important role in synchronizing the central pacemaker neurons and contribute to the distinct self-sustainability of the SCN master clock.
Animals ; Circadian Rhythm ; Electrical Synapses ; Gap Junctions* ; Hypothalamus ; Luminescent Measurements ; Mammals ; Mefloquine* ; Mice* ; Neurons ; Phase Transition ; Suprachiasmatic Nucleus*

No abstract available.
Neurosecretory Systems