The aim of this study is to observe glycemic changes after emphasizing the importance of lifestyle modification in patients with mild or moderately uncontrolled type 2 diabetes.
Materials and Methods
We examined 51 type 2 diabetic patients with 7.0-9.0% hemoglobin A1c (HbA1c) who preferred to change their lifestyle rather than followed the recommendation of medication change. At the enrollment, the study subjects completed questionnaires about diet and exercise. After 3 months, HbA1c levels were determined and questionnaires on the change of lifestyle were accomplished. We divided the study subjects into 3 groups: improved (more than 0.3% decrease of HbA1c), aggravated (more than 0.3% increase of HbA1c) and not changed (-0.3%
Among the total 51 subjects, 18 patients (35.3%) showed the decreased levels of HbA1c after 3 months with mean change of -0.74±0.27%, and HbA1c values of 11 patients (21.5%) were less than 7%. In addition, the HbA1c level was significantly reduced in patients who reportedly followed the lifestyle modification such as diet and exercise for 3 months, compared with the one obtained from patients who refused this lifestyle change (p=0.002).
In this study, 35.3% of the patients with mild or moderately uncontrolled type 2 diabetes showed the significant improvement of HbA1c levels after 3 months by simply regulating their daily diet and exercise without change of medication. This suggests that the lifestyle modification is significantly associated with the improvement of glucose control.
Diabetes mellitus; glycemic control; lifestyle; modification
Mitochondria are key organelles dedicated to energy production. Crif1, which interacts with the large subunit of the mitochondrial ribosome, is indispensable for the mitochondrial translation and membrane insertion of respiratory subunits. To explore the physiological function of Crif1 in the heart, Crif1f/f mice were crossed with Myh6-cre/Esr1 transgenic mice, which harbor cardiomyocyte-specific Cre activity in a tamoxifen-dependent manner. The tamoxifen injections were given at six weeks postnatal, and the mutant mice survived only five months due to hypertrophic heart failure. In the mutant cardiac muscles, mitochondrial mass dramatically increased, while the inner structure was altered with lack of cristae. Mutant cardiac muscles showed decreased rates of oxygen consumption and ATP production, suggesting that Crif1 plays a critical role in the maintenance of both mitochondrial structure and respiration in cardiac muscles.
Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function.
Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1-deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses.
These data suggest that Mib1-mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus.
Mind bomb-1; Notch; Synaptic plasticity; Memory; Hippocampus
Phosphorylation of histone H3 on Ser-10 is regarded as an epigenetic mitotic marker and is tightly correlated with chromosome condensation during both mitosis and meiosis. However, it was also reported that histone H3 Ser-10 phosphorylation occurs when cells are exposed to various death stimuli, suggesting a potential role in the regulation of apoptosis. Here we report that histone H3 Ser-10 phosphorylation is mediated by the pro-apoptotic kinase protein kinase C (PKC) δ during apoptosis. We observed that PKCδ robustly phosphorylates histone H3 on Ser-10 both in vitro and in vivo. Ectopic expression of catalytically active PKCδ efficiently induces condensed chromatin structure in the nucleus. We also discovered that activation of PKCδ is required for histone H3 Ser-10 phosphorylation after treatment with DNA damaging agents during apoptosis. Collectively, these findings suggest that PKCδ is the kinase responsible for histone H3 Ser-10 phosphoryation during apoptosis and thus contributes to chromatin condensation together with other apoptosis-related histone modifications. As a result, histone H3 Ser-10 phosphorylation can be designated a new ‘apoptotic histone code’ mediated by PKCδ.
Peripheral arterial disease (PAD) is the narrowing of arteries due to plaque accumulation in the vascular walls. This leads to insufficient blood supply to the extremities and can ultimately cause cell death. Currently available methods are ineffective in diagnosing PAD in patients with calcified arteries, such as those with diabetes. In this paper we investigate the potential of dynamic diffuse optical tomography (DDOT) as an alternative way to assess PAD in the lower extremities. DDOT is a non-invasive, non-ionizing imaging modality that uses near-infrared light to create spatio-temporal maps of oxy- and deoxy-hemoglobin in tissue. We present three case studies in which we used DDOT to visualize vascular perfusion of a healthy volunteer, a PAD patient and a diabetic PAD patient with calcified arteries. These preliminary results show significant differences in DDOT time-traces and images between all three cases, underscoring the potential of DDOT as a new diagnostic tool.
(170.3880) Medical and biological imaging; (170.6960) Tomography
The mouse PERIOD1 (mPER1) protein, along with other clock proteins, plays a crucial role in the maintenance of circadian rhythms. mPER1 also provides an important link between the circadian system and the cell cycle system. Here we show that the circadian expression of mPER1 is regulated by rhythmic translational control of mPer1 mRNA together with transcriptional modulation. This time-dependent translation was controlled by an internal ribosomal entry site (IRES) element in the 5′ untranslated region (5′-UTR) of mPer1 mRNA along with the trans-acting factor mouse heterogeneous nuclear ribonucleoprotein Q (mhnRNP Q). Knockdown of mhnRNP Q caused a decrease in mPER1 levels and a slight delay in mPER1 expression without changing mRNA levels. The rate of IRES-mediated translation exhibits phase-dependent characteristics through rhythmic interactions between mPer1 mRNA and mhnRNP Q. Here, we demonstrate 5′-UTR-mediated rhythmic mPer1 translation and provide evidence for posttranscriptional regulation of the circadian rhythmicity of core clock genes.
The telomere integrity is maintained via replication machinery, telomere associated proteins and telomerase. Many telomere associated proteins are regulated in a cell cycle-dependent manner. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a single-stranded oligonucleotide binding protein, is thought to play a pivotal role in telomere maintenance. Here, we identified hnRNP A1 as a novel substrate for vaccinia-related kinase 1 (VRK1), a cell cycle regulating kinase. Phosphorylation by VRK1 potentiates the binding of hnRNP A1 to telomeric ssDNA and telomerase RNA in vitro and enhances its function for telomerase reaction. VRK1 deficiency induces a shortening of telomeres with an abnormal telomere arrangement and activation of DNA-damage signaling in mouse male germ cells. Together, our data suggest that VRK1 is required for telomere maintenance via phosphorylation of hnRNP A1, which regulates proteins associated with the telomere and telomerase RNA.
The Vaccinia-related kinase 1(VRK1), which is generally implicated in modulating cell cycle, plays important roles in mammalian gametogenesis. Female infertility in VRK1-deficient mice was reported to be caused by defective meiotic progression in oocyte at postovulatory stage. VRK1 roles in folliculogenesis, however, remain largely unknown. Here, accurate quantification of folliculogenesis is performed by a direct visualization of ‘intact’ ovary in 3-dimensions (3-D) using a synchrotron X-ray microtomography. In VRK1-deficient ovaries, the numbers of pre-antral and antral follicles are significantly reduced by 38% and 46%, respectively, comparing to control. The oocytes volumes in antral and Graffian follicles also decrease by 42% and 37% in the mutants, respectively, indicating defects in oocyte quality at preovulatory stage. Genetic analysis shows that gene expressions related to folliculogenesis are down-regulated in VRK1-deficient ovaries, implying defects in folliculogenesis. We suggest that VRK1 is required for both follicle development and oocyte growth in mammalian female reproduction system.
The mouse PERIOD1 (mPER1) plays an important role in the maintenance of circadian rhythm. Translation of mPer1 is directed by both a cap-dependent process and cap-independent translation mediated by an internal ribosomal entry site (IRES) in the 5′ untranslated region (UTR). Here, we compared mPer1 IRES activity with other cellular IRESs. We also found critical region in mPer1 5′UTR for heterogeneous nuclear ribonucleoprotein Q (HNRNPQ) binding. Deletion of HNRNPQ binding region markedly decreased IRES activity and disrupted rhythmicity. A mathematical model also suggests that rhythmic IRES-dependent translation is a key process in mPER1 oscillation. The IRES-mediated translation of mPer1 will help define the post-transcriptional regulation of the core clock genes.
High folate intake may increase the risk of cancer, especially in the elderly. The present study examined the effects of ageing and dietary folate on uracil misincorporation into DNA, which has a mutagenic effect, in the mouse colon and liver. Old (18 months; n 42) and young (4 months; n 42) male C57BL/6 mice were pair-fed with four different amino acid-defined diets for 20 weeks: folate deplete (0 mg/kg diet); folate replete (2 mg/kg diet); folate supplemented (8 mg/kg diet); folate deplete (0 mg/kg diet) with thymidine supplementation (1·8 g/kg diet). Thymidylate synthesis from uracil requires folate, but synthesis from thymidine is folate independent. Liver folate concentrations were determined by the Lactobacillus casei assay. Uracil misincorporation into DNA was measured by a GC/MS method. Liver folate concentrations demonstrated a stepwise increase across the spectrum of dietary folate levels in both old (P=0·003) and young (P<0·001) mice. Uracil content in colonic DNA was paradoxically increased in parallel with increasing dietary folate among the young mice (P trend=0·033), but differences were not observed in the old mice. The mean values of uracil in liver DNA, in contrast, decreased with increasing dietary folate among the old mice, but it did not reach a statistically significant level (P<0·1). Compared with the folate-deplete group, thymidine supplementation reduced uracil misincorporation into the liver DNA of aged mice (P=0·026). The present study suggests that the effects of folate and thymidine supplementation on uracil misincorporation into DNA differ depending on age and tissue. Further studies are needed to clarify the significance of increased uracil misincorporation into colonic DNA of folate-supplemented young mice.
Folate; Uracil; Thymidine; Colon; Liver; Mice
Patients with cervical spine instability and limited range of motion are challenge to anesthesiologists. It is important to consider alternatetive methods for securing the airway while maintaining neutral position and minimizing neck motion, because these patients are at increased risk for tracheal intubation failure and neurologic injury during airway management or position change. We experienced two cases that patients had cervical spine instability and severe limited range of motion due to the fusion of the entire cervical spine. One patient was a 6-year-old girl weighing 12.7 kg and had Klippel-Feil syndrome with Arnold-Chiari malformation, the other was a 24-year-old female weighing 31 kg and had juvenile rheumatoid arthritis. We successfully performed the intubation by using the fiberoptic intubation though a laryngeal mask airway in these two cases.
Arnorl-Chiari malformation; Difficult airway; Fiberoptic intubation; Juvenile rheumatoid arthritis; Klippel-Feil syndrome; Laryngeal mask airway
Disrupted cortical cytoarchitecture in cerebellum is a typical pathology in reeler. Particularly interesting are structural problems at the cellular level: dendritic morphology has important functional implication in signal processing. Here we describe a combinatorial imaging method of synchrotron X-ray microtomography with Golgi staining, which can deliver 3-dimensional(3-D) micro-architectures of Purkinje cell(PC) dendrites, and give access to quantitative information in 3-D geometry. In reeler, we visualized in 3-D geometry the shape alterations of planar PC dendrites (i.e., abnormal 3-D arborization). Despite these alterations, the 3-D quantitative analysis of the branching patterns showed no significant changes of the 77 ± 8° branch angle, whereas the branch segment length strongly increased with large fluctuations, comparing to control. The 3-D fractal dimension of the PCs decreased from 1.723 to 1.254, indicating a significant reduction of dendritic complexity. This study provides insights into etiologies and further potential treatment options for lissencephaly and various neurodevelopmental disorders.
Accurate assignment of monoisotopic precursor masses to tandem mass spectrometric (MS/MS) data is a fundamental and critically important step for successful peptide identifications in mass spectrometry based proteomics. Here we describe an integrated approach that combines three previously reported methods of treating MS/MS data for precursor mass refinement. This combined method, “integrated Post-Experiment Monoisotopic Mass Refinement” (iPE-MMR), integrates steps: 1) generation of refined MS/MS data by DeconMSn; 2) additional refinement of the resultant MS/MS data by a modified version of PE-MMR; 3) elimination of systematic errors of precursor masses using DtaRefinery. iPE-MMR is the first method that utilizes all MS information from multiple MS scans of a precursor ion including multiple charge states, in an MS scan, to determine precursor mass. By combining these methods, iPE-MMR increases sensitivity in peptide identification and provides increased accuracy when applied to complex high-throughput proteomics data.
Pepper anthracnose caused by Colletotrichum species is one of the most important limiting factors for pepper production in Korea, its management being strongly dependent on chemicals. The aim of this work was to evaluate the possibilities of using silver nanoparticles instead of commercial fungicides. In this study, we evaluated the effect of silver nanoparticles against pepper anthracnose under different culture conditions. Silver nanoparticles (WA-PR-WB13R) were applied at various concentrations to determine antifungal activities in vitro and in the field. The application of 100 ppm concentration of silver nanoparticles produced maximum inhibition of the growth of fungal hyphae as well as conidial germination in comparison to the control in vitro. In field trials, the inhibition of fungi was significantly high when silver nanoparticles were applied before disease outbreak on the plants. Scanning electron microscopy results indicated that the silver nanoparticles caused a detrimental effect on mycelial growth of Colletotrichum species.
Colletotrichum species; Fungicide; Inhibition effect; Silver nanoparticle
Daily mRNA oscillations of circadian clock genes largely depend on transcriptional regulation. However, several lines of evidence highlight the critical role of post-transcriptional regulation in the oscillations of circadian mRNA oscillations. Clearly, variations in the mRNA decay rate lead to changes in the cycling profiles. However, the mechanisms controlling the mRNA stability of clock genes are not fully understood. Here we demonstrate that the turnover rate of mouse Period3 (mPer3) mRNA is dramatically changed in a circadian phase-dependent manner. Furthermore, the circadian regulation of mPer3 mRNA stability requires the cooperative function of 5′- and 3′-untranslated regions (UTRs). Heterogeneous nuclear ribonucleoprotein Q (hnRNP Q) binds to both 5′- and 3′-UTR and triggers enhancement of translation and acceleration of mRNA decay. We propose the phase-dependent translation coupled mRNA decay mediated by hnRNP Q as a new regulatory mechanism of the rhythmically regulated decay of mPer3 mRNA.
Older age, dietary folate and chronic alcohol consumption are important risk factors for the development of colon cancer. The present study examined the effects of ageing, folate and alcohol on genomic and p16-specific DNA methylation, and p16 expression in the murine colon. Old (aged 18 months; n 70) and young (aged 4 months; n 70) male C57BL/6 mice were pair-fed either a Lieber-DeCarli liquid diet with alcohol (18 % of energy), a Lieber-DeCarli diet with alcohol (18 %) and reduced folate (0·25 mg folate/l) or an isoenergetic control diet (0·5 mg folate/l) for 5 or 10 weeks. Genomic DNA methylation, p16 promoter methylation and p16 gene expression were analysed by liquid chromatography–MS, methylation-specific PCR and real-time RT-PCR, respectively. Genomic DNA methylation was lower in the colon of old mice compared with young mice (P<0·02) at 10 weeks. Alcohol consumption did not alter genomic DNA methylation in the old mouse colon, whereas it tended to decrease genomic DNA methylation in young mice (P = 0·08). p16 Promoter methylation and expression were higher in the old mouse colon compared with the corresponding young groups. There was a positive correlation between p16 promoter methylation and p16 expression in the old mouse colon (P<0·02). In young mice the combination of alcohol and reduced dietary folate led to significantly decreased p16 expression compared with the control group (P<0·02). In conclusion, ageing and chronic alcohol consumption alter genomic DNA methylation, p16 promoter methylation and p16 gene expression in the mouse colon, and dietary folate availability can further modify the relationship with alcohol in the young mouse.
Alcohol; DNA methylation; p16; Folate; Ageing; Colon
A pro-apoptotic function of activated PKCδ may be mediated by several downstream nuclear regulators involved in apoptotic cell death. Vaccinia-related kinase 1 (VRK1) is a new nuclear target of PKCδ in the regulation of apoptotic cell death induced by DNA damage.
Vaccinia-related kinase 1 (VRK1) is a novel serine/threonine kinase that plays an important role in cell proliferation. However, little is known about the upstream regulators of VRK1 activity. Here we provide evidence for a role of protein kinase Cδ (PKCδ) in the regulation of murine VRK1. We show that PKCδ interacts with VRK1, phosphorylates the Ser-355 residue in the putative regulatory region, and negatively regulates its kinase activity in vitro. Intriguingly, PKCδ-induced cell death was facilitated by phosphorylation of VRK1 when cells were exposed to a DNA-damaging agent. In addition, p53 played a critical role in the regulation of DNA damage–induced cell death accompanied by PKCδ-mediated modulation of VRK1. In p53-deficient cells, PKCδ-mediated phosphorylation of VRK1 had no effect on cell viability. However, cells overexpressing p53 exhibited significant reduction of cell viability when cotransfected with both VRK1 and PKCδ. Taken together, these results indicate that PKCδ regulates phosphorylation and down-regulation of VRK1, thereby contributing to cell cycle arrest and apoptotic cell death in a p53-dependent manner.
Vaccinia-related kinase 1 (VRK1) is a crucial protein kinase for mitotic regulation. VRK1 is known to play a role in germ cell development, and its deficiency results in sterility. Here we describe that VRK1 is essential for the maintenance of spermatogonial stem cells. To determine whether VRK1 plays a role in these cells, we assessed the population size of undifferentiated spermatogonia. Flow cytometry analyses showed that the number of undifferentiated spermatogonia was markedly reduced in VRK1-deficient testes. VRK1 was highly expressed in spermatogonial populations, and approximately 66% of undifferentiated spermatogonia that were sorted as an Ep-CAM+/c-kit−/alpha-6-integrin+ population showed a positive signal for VRK1. Undifferentiated stem cells expressing Plzf and Oct4 but not c-kit also expressed VRK1, suggesting that VRK1 is an intrinsic factor for the maintenance of spermatogonial stem cells. Microarray analyses of the global testicular transcriptome and quantitative RT-PCR of VRK1-deficient testes revealed significantly reduced expression levels of undifferentiated spermatogonial marker genes in early postnatal mice. Together, these results suggest that VRK1 is required for the proliferation and differentiation of undifferentiated spermatogonia, which are essential for spermatogenic cell maintenance.
Experimental studies demonstrated that maternal exposure to certain environmental and dietary factors during early embryonic development can influence the phenotype of offspring as well as the risk of disease development at the later life. DNA methylation, an epigenetic phenomenon, has been suggested as a mechanism by which maternal nutrients affect the phenotype of their offspring in both honeybee and agouti mouse models. Phenotypic changes through DNA methylation can be linked to folate metabolism by the knowledge that folate, a coenzyme of one-carbon metabolism, is directly involved in methyl group transfer for DNA methylation. During the fetal period, organ-specific DNA methylation patterns are established through epigenetic reprogramming. However, established DNA methylation patterns are not immutable and can be modified during our life time by the environment. Aberrant changes in DNA methylation with diet may lead to the development of age-associated diseases including cancer. It is also known that the aging process by itself is accompanied by alterations in DNA methylation. Diminished activity of DNA methyltransferases (Dnmts) can be a potential mechanism for the decreased genomic DNA methylation during aging, along with reduced folate intake and altered folate metabolism. Progressive hypermethylation in promoter regions of certain genes is observed throughout aging and repression of tumor suppressors induced by this epigenetic mechanism appears to be associated with cancer development. In this review we address the effect of folate on early development and aging through an epigenetic mechanism, DNA methylation.
DNA methylation; folate; embryonic development; aging; carcinogenesis
The traditional belief that obesity is protective against osteoporosis has been questioned. Recent epidemiologic studies show that body fat itself may be a risk factor for osteoporosis and bone fractures. Accumulating evidence suggests that metabolic syndrome and the individual components of metabolic syndrome such as hypertension, increased triglycerides, and reduced high-density lipoprotein cholesterol are also risk factors for low bone mineral density. Using a cross sectional study design, we evaluated the associations between obesity or metabolic syndrome and bone mineral density (BMD) or vertebral fracture.
Materials and Methods
A total of 907 postmenopausal healthy female subjects, aged 60-79 years, were recruited from woman hospitals in Seoul, South Korea. BMD, vetebral fracture, bone markers, and body composition including body weight, body mass index (BMI), percentage body fat, and waist circumference were measured.
After adjusting for age, smoking status, alcohol consumption, total calcium intake, and total energy intake, waist circumference was negatively related to BMD of all sites (lumbar BMD p = 0.037, all sites of femur BMD p < 0.001) whereas body weight was still positively related to BMD of all sites (p < 0.001). Percentage body fat and waist circumference were much higher in the fracture group than the non-fracture group (p = 0.0383, 0.082 respectively). Serum glucose levels were postively correlated to lumbar BMD (p = 0.016), femoral neck BMD (p = 0.0335), and femoral trochanter BMD (p = 0.0082). Serum high density lipoprotein cholesterol (HDLC) was positively related to femoral trochanter BMD (p = 0.0366) and was lower in the control group than the fracture group (p = 0.011).
In contrast to the effect favorable body weight on bone mineral density, high percentage body fat and waist circumference are related to low BMD and a vertebral fracture. Some components of metabolic syndrome were related to BMD and a vertebral fracture.
Obesity; metabolic syndrome; bone mineral density; vertebral fracture
The mammalian circadian rhythm is observed not only at the suprachiasmatic nucleus, a master pacemaker, but also throughout the peripheral tissues. Its conserved molecular basis has been thought to consist of intracellular transcriptional feedback loops of key clock genes. However, little is known about posttranscriptional regulation of these genes. In the present study, we investigated the role of the 3′-untranslated region (3′UTR) of the mouse cryptochrome 1 (mcry1) gene at the posttranscriptional level. Mature mcry1 mRNA has a 610-nucleotide 3′UTR and mediates its own degradation. The middle part of the 3′UTR contains a destabilizing cis-acting element. The deletion of this element led to a dramatic increase in mRNA stability, and heterogeneous nuclear ribonucleoprotein D (hnRNP D) was identified as an RNA binding protein responsible for this effect. Cytoplasmic hnRNP D levels displayed a pattern that was reciprocal to the mcry1 oscillation. Knockdown of hnRNP D stabilized mcry1 mRNA and resulted in enhancement of the oscillation amplitude and a slight delay of the phase. Our results suggest that hnRNP D plays a role as a fine regulator contributing to the mcry1 mRNA turnover rate and the modulation of circadian rhythm.
The physiological and behavioral circadian rhythms of most creatures are controlled by a harmony of functional relationships between clock genes. In mammals, several core clock genes show rhythmic profiles of their mRNA and protein expression. Among them, Rev-erb α functions as a transcriptional repressor, affecting expression patterns of other clock genes. For the continuous and robust oscillation of the molecular clock system, the levels of Rev-erb α protein are expected to be tightly regulated with the correct timing. Here, we demonstrate that Rev-erb α has an internal ribosomal entry site (IRES) in its 5′ untranslated region. Furthermore, we demonstrate that heterogeneous nuclear ribonucleoprotein Q and polypyrimidine tract-binding protein (PTB) modulate the IRES-mediated translation of Rev-erb α. We suggest that the rhythmic binding affinity of hnRNP Q to the Rev-erb α IRES and the change in PTB cytosolic levels lead to maintenance of the oscillation profile of the Rev-erb α protein.
Orphan lung diseases are defined as lung diseases with a prevalence of 1 or less in 2,000 individuals. Despite an increase in the numbers of patients with such diseases, few studies on Korean children have appeared. To obtain epidemiologic and demographic data on these diseases, we systematically reviewed reports on pediatric orphan lung diseases in Korea over the last 50 years.
We reviewed 223 articles that have appeared since 1958 on orphan lung diseases in Korean children. These articles described a total of 519 patients aged between 0 and 18 years. We classified patients by year of publication, diagnosis, geographic region, and journal.
Of 519 patients, 401 had congenital cystic lung diseases and 66 had bronchiolitis obliterans. About 80% of patients were described in reports published in three journals, Pediatric Allergy and Respiratory Disease (Korea), the Korean Journal of Pediatrics, and the Korean Journal of Thoracic and Cardiovascular Surgery, in which papers on 157 (30.2%), 138 (26.6%), and 111 (21.4%) patients appeared, respectively. The frequency of publication of case reports has increased since 1990. Of the 519 patients, 401 (77.3%) were from Seoul/Gyeonggi-do and 72 (13.9%) from Busan/Gyeongsangnam-do.
The prevalence of pediatric orphan lung disease has increased since 1990, and some provinces of Korea have a higher incidence of these diseases than do others. Studies exploring the incidence of pediatric orphan lung diseases in Korea are needed for effective disease management.
Orphan lung diseases; Congenital cystic lung disease
Interleukin 6 (IL6) is a pleiotropic cytokine that not only affects the immune system, but also plays an active role in many physiological events in various organs. Notably, 35% of systemic IL6 originates from adipose tissues under noninflammatory conditions. Here, we describe a previously unknown function of melanocortins in regulating Il6 gene expression and production in 3T3-L1 adipocytes through membrane receptors which are called melanocortin receptors (MCRs). Of the five MCRs that have been cloned, MC2R and MC5R are expressed during adipocyte differentiation. α-Melanocyte-stimulating hormone (α-MSH) or ACTH treatment of 3T3-L1 adipocytes induces Il6 gene expression and production in a time- and concentration-dependent manner via various signaling pathways including the protein kinase A, p38 mitogen-activated protein kinase, cJun N-terminal kinase, and IκB kinase pathways. Specific inhibition of MC2R and MC5R expression with short interfering Mc2r and Mc5r RNAs significantly attenuated the α-MSH-induced increase of intracellular cAMP and both the level of Il6 mRNA and secretion of IL6 in 3T3-L1 adipocytes. Finally, when injected into mouse tail vein, α-MSH dramatically increased the Il6 transcript levels in epididymal fat pads. These results suggest that α-MSH in addition to ACTH may function as a regulator of inflammation by regulating cytokine production.
Missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, cause clinically similar but distinctive disorders, LEOPARD (LS) and Noonan (NS) syndromes. The LS is an autosomal dominant disorder with pleomorphic developmental abnormalities including lentigines, cardiac defects, short stature and deafness. Biochemical analyses indicated that LS alleles engender loss-of-function (LOF) effects, while NS mutations result in gain-of-function (GOF). These biochemical findings lead to an enigma that how PTPN11 mutations with opposite effects on function result in disorders that are so similar. To study the developmental effects of the commonest LS PTPN11 alleles (Y279C and T468M), we generated LS transgenic fruitflies using corkscrew (csw), the Drosophila orthologue of PTPN11. Ubiquitous expression of the LS csw mutant alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were GOF phenotypes mediated by increased RAS/MAPK signaling and requiring the LS mutant’s residual phosphatase activity. Our findings provide the first evidence that LS mutant alleles have GOF developmental effects despite reduced phosphatase activity, providing a rationale for how PTPN11 mutations with GOF and LOF produce similar but distinctive syndromes.