Acute ischemic stroke secondary to aortic dissection (AoD) is challenging in the era of thrombolysis owing to the diagnostic difficulty within a narrow time window and the high risk of complications.
A 64-year-old woman with middle cerebral artery occlusion syndrome admitted to the emergency room within intravenous recombinant tissue plasminogen activator (rt-PA) time window. Her neurological symptoms improved during thrombolysis, but chest and abdominal pain developed. Repeated history-taking, physical examination, and imaging studies led to the timely diagnosis and surgical treatment of AoD, which produced a successful outcome.
Clinical suspicion is invaluable for the diagnosis of this rare cause of stroke. Considering the stroke mechanism and complications, the risks of thrombolysis might outweigh its benefits.
aortic dissection; ischemic stroke; thrombolysis; recombinant tissue plasminogen activator
The authors have treated chronic tinnitus patients using a combination of a simplified tinnitus retraining therapy (TRT) and medications, which we called modified TRT. In this clinical setting, we have attempted small-group counseling to find a time-effective equivalent of individual counseling. The aim of the present study was to evaluate the effectiveness of small-group counseling by comparing the treatment outcomes between individual and small-group counseling.
The patients who had distressing chronic tinnitus with normal hearing or mild hearing loss were included. The subjects were placed into the small-group (group 1:4) or the individual (group 1:1) counseling group, and underwent a modified TRT composed of a single session of directive counseling and ambient sound stimulation. In addition, alprazolam (0.25 mg) and ginkgo biloba extract (80 mg) were administered orally to the subjects for 3 months. The 3- and 6- month outcomes were assessed using the follow-up rates and tinnitus severity scores: awareness, tinnitus handicap inventory (THI), loudness, annoyance, and effect on life. The treatment responses were classified as improvement, no changes, and worsening.
Of the total 149 patients (77 in group 1:1; 72 in group 1:4), 104 patients completed the protocol at 3 months, and 55 patients at 6 months. The follow-up rates were similar in both groups. Over the period of 6 months, all scores declined significantly except the loudness score at 3 months in both groups. Treatment responses showed no between-group differences. The success rate based on THI was 70% in group 1:1, and 64% in group 1:4 at 6 months.
The small-group counseling of our modified TRT was comparable to the individual counseling for tinnitus relief. We suggest that this protocol can be implemented effectively in any crowded otolaryngology clinics.
Tinnitus; Tinnitus retraining therapy; Directive counseling; Benzodiazepines
Among the inflammatory mediators, phorbol 12-myristate 13-acetate (PMA) is associated with the regulation of MUC5B expression in the airway epithelial cells. Epigallocatechin-3-gallate (EGCG) is the major component of green tea extract. The biological activity of EGCG includes reduction of cholesterol and antioxidant activity, as well as anti-inflammatory effect. However, the precise action mechanism of anti-inflammatory effect of EGCG in the airway epithelial cells has not been fully defined. This study investigates the effect and the brief signaling pathway of EGCG on PMA-induced MUC5B expression in the airway epithelial cells.
In NCI-H292 airway epithelial cells, the effect and signaling pathway of EGCG on MUC5B expression were investigated using real-time polymerase chain reaction analysis, enzyme immunoassay, immunohistochemical analysis, gelatin zymography assay, and immunoblot analysis.
In NCI-H292 airway epithelial cells, PMA induced MUC5B expression, phosphorylation of p38 mitogen-activated protein kinase (MAPK), and matrix metalloproteinase-9 (MMP-9) expression and protein activity. EGCG significantly decreased PMA-induced MUC5B expression, phosphorylation of p38 MAPK, and MMP-9 expression and protein activity. SB203580 (p38 MAPK inhibitor) significantly decreased PMA-induced MMP-9 expression. In addition, SB203580 and MMP-9 I (MMP-9 inhibitor) significantly decreased PMA-induced MUC5B expression.
These results suggest that EGCG down-regulates PMA-induced MUC5B expression through the p38 MAPK dependent MMP-9 signaling pathway in human airway epithelial cells.
Epigallocatechin-3-gallate; MUC5B; p38; Matrix metalloproteinase-9; Airway epithelial cell
Nutritional imbalance-induced obesity causes a variety of diseases and in particular is an important cause of cognitive function decline. This study was performed on Sprague Dawley (SD) rats with 13-weeks of high fat diet-induced obesity in connection to the effects of regular exercise and dietary control for 8 weeks on the synaptic plasticity and cognitive abilities of brain.
Four weeks-old SD rats were adopted classified into normal-normal diet-sedentary (NNS, n = 8), obesity-high fat diet-sedentary (OHS, n = 8), obesity-high fat diet-training (OHT, n = 8), obesity-normal diet-sedentary (ONS, n = 8) and obesity- normal diet-training (ONT, n = 8). The exercise program consisted of a treadmill exercise administered at a speed of 8 m/min for 1–4 weeks, and 14 m/min for 5–8 weeks. The Western blot method was used to measure the expression of NGF, BDNF, p38MAPK and p-p38MAPK proteins in hippocampus of the brain, and expressions of NGF, BDNF, TrkA, TrkB, CREB and synapsin1 mRNA were analyzed through qRT-PCR.
The results suggest cognitive function-related protein levels and mRNA expression to be significantly decreased in the hippocampus of obese rats, and synaptic plasticity as well as cognitive function signaling sub-pathway factors were also significantly decreased. In addition, 8-weeks exercises and treatment by dietary change had induced significant increase of cognitive function-related protein levels and mRNA expression as well as synaptic plasticity and cognitive function signaling sub-pathway factors in obese rats. In particular, the combined treatment had presented even more positive effect.
Therefore, it was determined that the high fat diet-induced obesity decreases plasticity and cognitive function of the brain, but was identified as being improved by exercises and dietary changes. In particular, it is considered that regular exercise has positive effects on memory span and learning capacity unlike dietary control.
Exercise; Cognition function; Synaptic plasticity; High fat diet; Memory span
Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.
CASR; GCMB; Hypocalcemia; Hypoparathyroidism; Prepro-PTH
Females are more often affected by constipation than males, especially during pregnancy, which is related to the menstrual cycle. Although still controversial, alterations of progesterone and estrogen may be responsible. Therefore, this study was conducted in order to determine whether the female sex steroid hormone itself is responsible for development of constipation in both female and male mice. Administration of estrogen resulted in a decrease in weight of accumulated feces on days 2, 3, 4, and 5 in male mice and on day 5 in female mice, compared with the control group, but progesterone administration did not. Administration of estrogen resulted in a decrease in gastrointestinal movement, compared to normal; however, no significant change was observed by administration of progesterone. In conclusion, estrogen, rather than progesterone, may be a detrimental factor of constipation via decreased bowel movement in mice.
Constipation; Estrogen; Progesterone
Oplopanax elatus is a medicinal plant on the verge of extinction because of overexploitation. In the present study, the effects of various factors on enhancing somatic embryogenesis and plantlet conversion were studied. Mature seeds were collected from a total of 13 plants from 4 mountains in South Korea, and the genetic distances were calculated to analyze the effect of genotype on somatic embryogenesis. Results of cluster analysis and the unweighted-pair-group method with arithmetic mean of 13 genotypes indicated the presence of 3 main groups. Both genotype and explant type affected the induction of somatic embryos (SEs). Sorak 2 and root were found to be the most suitable genotype and explant type, respectively, for SE induction in O. elatus. Among the different types of carbon sources tested, 5% sucrose induced the maximum number of SEs. The formation and development of SEs were significantly influenced by culture density; thus, 10 mg embryonic callus was found to be the most suitable for SE induction. The highest rates of germination and SE conversion were obtained in a germination medium containing 1.8 gelrite and 3.2 g·l-1 agar. In addition, 80% of the plantlets that were transplanted into artificial soil acclimatized successfully. Thus, our results showed that the percentage survival of O. elatus during in vitro proliferation could be increased by optimizing to the somatic embryogenesis system.
Micropropagation; Oplopanax elatus; Conservation; Somatic embryogenesis; Regeneration
Sarcoidosis is a chronic multisystemic inflammatory disease of unknown etiology, which is characterized by noncaseating granulomatous inflammation of the involved organs. It is known that neurosarcoidosis involving the nervous system occurs in about 5% of patients with sarcoidosis. However, neurosarcoidosis without systemic involvement is extremely rare. We present a case of suspicious neurosarcoidosis affecting the pituitary gland, which was manifested as chronic uncontrolled headache, panhypopituitarism, central diabetes insipidus, and hypercalcemia. Though the biopsy at the pituitary lesion was not performed due to the high risk of surgical complication, treatment was needed urgently and we started steroid therapy. After steroid therapy, we observed the immediate symptom relief with improved hypercalcemia. According to the follow-up examination, no recurrent symptom was seen, and resolution of the pituitary lesion with improving panhypopituitarism was noted.
Chronic idiopathic urticaria (CIU) is a common cutaneous disorder but the influence of initial treatment modality on long-term control is not known. The aim of this study was to evaluate clinical features, and the influence of initial treatment modality on long-term control.
Methods and Results
641 CIU patients were enrolled from the allergy clinic in a tertiary referral hospital. Disease duration, aggravating factors and treatment modality at each visit were evaluated. Times required to reach a controlled state were analyzed according to initial treatment modality, using Kaplan-Meier survival curves, the Cox proportional-hazards model, and propensity scores. Female to male ratio was 1.7: 1; mean age at onset was 40.5 years. The most common aggravating factors were food (33.5%), stress (31.5%) and fatigue (21.6%). Most patients (82.2%) used H1-antihistamines alone as initial treatment while 17% used a combination treatment with oral corticosteroids. There was no significant difference in the time taken to reach a controlled state between patients treated with single vs multiple H1-antihistamines or between those who received H1-antihistamine monotherapy vs. a combination therapy with oral corticosteroids.
The time required to control CIU is not reduced by use of multiple H1-antihistamines or oral corticosteroids in the initial treatment.
Idiopathic anaphylaxis is characterized by recurrent anaphylaxis without a known trigger. The coexistence of acute liver injury with idiopathic anaphylaxis is rare, even in cases of severe anaphylaxis such as shock. An unusual case involving repeated episodes of anaphylactic shock accompanied by acute liver injury is described here. A 36-year-old woman who experienced anaphylaxis due to an unknown cause was referred to our hospital because of marked elevations in her liver enzyme levels. After a thorough evaluation to determine the cause of the acute liver injury, viral infection, drug use, and autoimmune hepatitis were excluded. The episodes were accompanied by elevated liver enzymes, which suggested that this was a case of anaphylaxis followed by acute liver injury. The patient will have to use self-injectable epinephrine to prevent future hepatic failure.
Idiopathic anaphylaxis; acute liver injury
There is no single blood marker for predicting the prognosis in ischemic stroke. A combination of multiple blood markers may enhance the ability to predict long-term outcome following ischemic stroke.
Blood concentrations of neuronal markers (neuron-specific enolase, visinin-like protein 1, heart type fatty acid binding protein (hFABP) and neuroglobin), astroglial markers (S100B and glial fibrillary acidic protein), inflammatory markers (IL-6, TNF-α, and C-reactive protein), blood-brain barrier marker (matrix metalloproteinase 9), and haemostatic markers (D-dimer and PAI-1) were measured within 24 hours after stroke onset. The discrimination and reclassification for favorable and poor outcome were compared after adding individual or a combination of blood markers to the clinical model of stroke outcome.
In multivariate analysis, natural log-transformed (log) IL-6 (odds ratio (OR): 1.75, 95% CI: 1.25 to 2.25, P = 0.001) and loghFABP (OR: 3.23, 95% CI: 1.44 to 7.27, P = 0.005) were independently associated with poor outcome. The addition of a single blood marker to the clinical model did not improve the discriminating ability of the clinical model of stroke outcome. However, the addition of the combination of logIL-6 and loghFABP to the clinical model showed improved discrimination (area under receiver operating characteristic (AUROC) curve: 0.939 versus 0.910, P = 0.03) and reclassification performance (net reclassification improvement index: 0.18, P = 0.005).
A combination of circulating IL-6 and hFABP level has an additive clinical value for the prediction of stroke outcome.
Here, we present a case of lung cancer in a 48-year-old male horse trainer. To the best of our knowledge, this is the first such case report to include an exposure assessment of respirable crystalline silica (RCS) as a quartz. The trainer had no family history of lung cancer. Although he had a 15 pack/year cigarette-smoking history, he had stopped smoking 12 years prior to his diagnosis. For the past 23 years, he had performed longeing, and trained 7-12 horses per day on longeing arena surfaces covered by recycled sands, the same surfaces used in race tracks. We investigated his workplace RCS exposure, and found it to be the likely cause of his lung cancer. The 8-hour time weight average range of RCS was 0.020 to 0.086 mg/m3 in the longeing arena. Horse trainers are exposed to RCS from the sand in longeing arenas, and the exposure level is high enough to have epidemiological ramifications for the occupational risk of lung cancer.
Lung cancer; Quartz; Risk assessment
The purpose of this study was to evaluate the relationship of pulmonary function impairment (PFI) and coronary artery calcification (CAC) by multi-detector computed tomography (MDCT), and the effect of pneumoconiosis on CAC or PFI.
Seventy-six subjects exposed to inorganic dusts underwent coronary artery calcium scoring by MDCT, spirometry, laboratory tests, and a standardized questionnaire. CAC was quantified using a commercial software (Rapidia ver. 2.8), and all the subjects were divided into two categories according to total calcium scores (TCSs), either the non-calcified (<1) or the calcified (≥1) group. Obstructive pulmonary function impairment (OPFI) was defined as forced expiratory volume in one second/forced vital capacity (FEV1/FVC, %)<70, and as FEV1/FVC (%)≥70 and FVC<80 for restrictive pulmonary function impairment (RPFI) by spirometry. All subjects were classified as either the case (profusion≥1/0) or the control (profusion≤0/1) group by pneumoconiosis findings on simple digital radiograph.
Of the 76 subjects, 35 subjects (46.1%) had a CAC. Age and hypertension were different significantly between the non-calcified and the calcified group (p<0.05). Subjects with pneumoconiosis were more frequent in the calcified group than those in the non-calcified group (p=0.099). FEV1/FVC (%) was significantly correlated with TCSs (r=-0.316, p=0.005). Subjects with OPFI tended to increase significantly with increasing of TCS (4.82, p=0.028), but not significantly in RPFI (2.18, p=0.140). Subjects with OPFI were significantly increased in the case group compared to those in the control group.
CAC is significantly correlated with OPFI, and CAC and OPFI may be affected by pneumoconiosis findings.
Coronary Vessels; Vascular Calcification; Spirometry; Pneumoconiosis; Pulmonary Function Tests
Type 1 diabetes (T1D) is caused by dysregulation of the immune system in the pancreatic islets, which eventually leads to insulin-producing pancreatic β-cell death and destabilization of glucose homeostasis. One of the major characteristics of T1D pathogenesis is the production of inflammatory mediators by macrophages that result in destruction or damage of pancreatic β-cells. In this study the inflammatory microenvironment of T1D was simulated with RAW264.7 cells and MIN6 cells, acting as macrophages and pancreatic β-cells respectably. In this setting, peroxiredoxin-1, an anti-oxidant enzyme was knocked down to observe its functions in the pathogenesis of T1D. RAW264.7 cells were primed with lipopolysaccharide and co-cultured with MIN6 cells while PRX-1 was knocked down in one or both cell types. Our results suggest that hindrance of PRX-1 activity or the deficiency of this enzyme in inflammatory conditions negatively affects pancreatic β-cell survival. The observed decrease in viability of MIN6 cells seems to be caused by nitric oxide production. Additionally, it seems that PRX-1 affects previously reported protective activity of IL-6 in pancreatic β cells as well. These results signify new, undiscovered roles for PRX-1 in inflammatory conditions and may contribute toward our understanding of autoimmunity.
Nitric oxide; Pancreatic β-cell; Peroxiredoxin; Type 1 diabetes
2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is an environmental toxicant with a polyhalogenated aromatic hydrocarbon structure and is one of the most toxic man-made chemicals. Exposure to 2,3,7,8-TCDD induces reproductive toxicity, immunotoxicity, and hepatotoxicity. In this study, we evaluated how 2,3,7,8-TCDD-induced hepatotoxicity affect the expression of heat shock proteins and antioxidant enzymes using the real-time polymerase chain reaction (PCR) in rat. 2,3,7,8-TCDD increased heat shock protein (Hsp27, α-B-crystallin, Mortalin, Hsp105, and Hsp90s) and antioxidant enzymes (SOD-3, GST and catalase) expression after a 1 day exposure in livers of rats, whereas heat shock protein (α-B-crystallin, Hsp90, and GRP78) and antioxidant enzymes (SOD-1, SOD-3, catalase, GST, and GPXs) expression decreased on day 2 and then slowly recovered back to control levels on day 8. These results suggest that heat shock proteins and antioxidant enzymes were induced as protective mechanisms against 2,3,7,8-TCDD induced hepatotoxicity, and that prolonged exposure depressed their levels, which recovered to control levels due to reduced 2,3,7,8-TCDD induced hepatotoxicity.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD); Antioxidant enzymes; Gene expression; Heat shock proteins; Real-time PCR
Carbon monoxide is a nonirritant, odorless, colorless gas. Its effects are prominent in organs most sensitive to oxygen deprivation, such as the heart, brain, and kidney. Although less frequently, an association between thromboembolic events and carbon monoxide poisoning has been shown in the literatures. In this case, we report a case of atrial thrombus associated with carbon monoxide poisoning.
Carbon monoxide; Intoxication; Thrombus
The prevalence of intervertebral disc herniation (IDH) of the thoracic spine is rare compared to the cervical or lumbar spine. In particular, IDH of the upper thoracic spine is extremely rare. We report the case of T1-2 IDH and its treatment, with a literature review. A 37-year-old male patient visited our hospital due to radiating pain at the left upper extremity and weakness of grip power. In cervical spine magnetic resonance images, T1-2 disc space showed herniated disc material and compressed T1 root was identified. Laminoforaminotomy was performed with a posterior approach. The radiating pain and weakness of grip power improved immediately after the surgery. Of patients who show radiating pain or numbness at the medial aspect of forearm, or weakness of intrinsic muscle of hand, can be suspected to have T1 radiculopathy. A detailed physical examination and a radiologic evaluation including this area should be required for the T1 radiculopathy.
Thoracic Vertebrae; Intervertebral Disc; Radiculopathy; Laminotomy
The purpose of this study was to investigate the clinical aspects of patients satisfying the Infectious Disease Society of America/American Thoracic Society (IDSA/ATS) minor severity criteria, focusing on their treatment response to empirical antibiotics. In total, 381 community-acquired pneumonia (CAP) patients who did not require mechanical ventilation or vasopressors at admission were enrolled, and 50 (13.1%) satisfied the minor severity criteria (i.e. , minor severe CAP [minor-SCAP]). The rates of new complication events and clinical treatment failure were significantly higher in the minor-SCAP group than in the control group (30.0% vs 2.1%, P < 0.001, and 42.0% vs 10.6%, P < 0.001, respectively), and the time to reach clinical stability was longer in the minor-SCAP group (8 days vs 3 days, P < 0.001). In a multivariate model, minor severity criteria (≥ 3) were significantly associated with treatment failure (odds ratio, 2.838; 95% confidence interval, 1.216 to 6.626), and for predicting treatment failure the value of the area under the receiver operating characteristic curve for minor criteria was 0.731, similar to other established scoring methods. The IDSA/ATS minor severity criteria can predict delayed treatment response and clinical treatment failure.
Minor Criteria; Pneumonia; Severe; Treatment Response
Metformin, an oral biguanide insulin-sensitizing agent, is well known to decrease appetite. Although there is evidence that metformin could affect the brain directly, the exact mechanism is not yet known.
To evaluate whether metformin induces anorexia via the hypothalamus, various concentrations of metformin were injected into the lateral ventricle of rats through a chronically implanted catheter and food intake was measured for 24 hours. The hypothalamic neuropeptides associated with regulation of food intake were also analyzed following 1 hour of intracerebroventricular (ICV) injections of metformin.
An ICV injection of metformin decreased food intake in a dose-dependent manner in unrestrained conscious rats. Hypothalamic phosphorylated AMP-activated protein kinase (pAMPK) increased by 3 µg with metformin treatment, but there was no further increase in pAMPK with increases in metformin dosage. The hypothalamic phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased by 3 µg with metformin treatment, but, there was no further increase in pSTAT3 level following increases of metformin dosage. Hypothalamic proopiomelanocortin was elevated with metformin treatment, while neuropeptide Y was not significantly changed.
Our results suggest that metformin induces anorexia via direct action in the hypothalamus and the increase in pSTAT3, at least in part, is involved in the process. However, hypothalamic pAMPK appears not to contribute to metformin-induced appetite reduction in normal rats. Further studies exploring new pathways connecting metformin and feeding regulation are needed.
Appetite; Hypothalamus; Metformin; Pro-opiomelanocortin
Symptomatic pulmonary arterial hypertension (PAH) in patients with isolated atrial septal defect (ASD) is rare during infancy. We report a case of isolated ASD with severe PAH in an infant who developed airway obstruction as cardiomegaly progressed. The patient presented with recurrent severe respiratory insufficiency and failure to thrive before the repair of the ASD. Echocardiography confirmed volume overload on the right side of heart and severe PAH (tricuspid regurgitation [TR] with a peak pressure gradient of 55 to 60 mmHg). The chest radiographs demonstrated severe collapse of both lung fields, and a computed tomography scan showed narrowing of the main bronchus because of an intrinsic cause, as well as a dilated pulmonary artery compressing the main bronchus on the left and the intermediate bronchus on the right. ASD patch closure was performed when the infant was 8 months old. After the repair of the ASD, echocardiography showed improvement of PAH (TR with a peak pressure gradient of 22 to 26 mmHg), and the patient has not developed recurrent respiratory infections while showing successful catch-up growth. In infants with symptomatic isolated ASD, especially in those with respiratory insufficiency associated with severe PAH, extrinsic airway compression should be considered. Correcting any congenital heart diseases in these patients may improve their symptoms.
Secundum atrial septal defect; Pulmonary arterial hypertension; Airway obstruction; Infant
Fenofibrate is a selective peroxisome proliferator-activated receptor α (PPARα) activator and is prescribed to treat hyperlipidemia. The mechanism through which PPARα agonists reduce food intake, body weight, and adiposity remains unclear. One explanation for the reduction of food intake is that fenofibrate promotes fatty acid oxidation and increases the production of ketone bodies upon a standard experimental dose of the drug (100~300 mg/kg/day). We observed that low-dose treatment of fenofibrate (30 mg/kg/day), which does not cause significant changes in ketone body synthesis, reduced food intake in Long-Evans Tokushima (LETO) rats. LETO rats are the physiologically normal controls for Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are obese and cholecystokinin (CCK)-A receptor deficient. We hypothesized that the reduced food intake by fenofibrate-treated LETO rats may be associated with CCK production. To investigate the anorexic effects of fenofibrate in vivo and to determine whether CCK production may be involved, we examined the amount of food intake and CCK production. Fenofibrate-treated OLETF rats did not significantly change their food intake while LETO rats decreased their food intake. Treatment of fenofibrate increased CCK synthesis in the duodenal epithelial cells of both LETO and OLETF rats. The absence of a change in the food intake of OLETF rats, despite the increase in CCK production, may be explained by the absence of CCK-A receptors. Contrary to the OLETF rats, LETO rats, which have normal CCK receptors, presented a decrease in food intake and an increase in CCK production. These results suggest that reduced food intake by fenofibrate treatment may be associated with CCK production.
Fenofibrate; Cholecystokinin; Food intake; LETO rat; OLETF rat
Activation of innate immunity (natural killer cell/interferon-γ: NK cell/IFN-γ) has been shown to play an important role in anti-viral and anti-tumor defenses as well as anti-fibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10 week-carbon tetrachloride (CCl4) challenge, respectively. Injection of poly I:C or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl4 model. Such activation was diminished in the 10-week CCl4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week vs. the 2-week CCl4 model. In vitro co-culture experiments demonstrated that 4-day cultured (early-activated) HSCs induce NK cell activation via an NKG2D-retinoic acid-induced early gene 1 (RAE1)-dependent mechanism. Such activation was reduced when co-cultured with 8-day cultured (intermediately-activated) HSCs due to the production of transforming growth factor-β (TGF-β) by HSCs. Moreover, early-activated HSCs were sensitive, while intermediately-activated HSCs were resistant to IFN-γ mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately-activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, while production of TGF-β by HSCs inhibited NK cell function and cytotoxicity against HSCs.
The anti-fibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to the increased production of TGF-β and expression of SOCS1 in intermediately-activated HSCs.
hepatic stellate cell; STAT1; SOCS1; TGF-β; retinol
The present study elucidated the effect of the selective inducible nitric oxide synthase (iNOS) inhibitor N6-(1-iminoethyl)-L-lysine (L-NIL) on monosodium urate (MSU) crystal-induced inflammation and edema in mice feet. L-NIL (5 or 10 mg/kg/day) was administered intraperitoneally 4 h before injection of MSU (4 mg) into the soles of mice hindlimb feet. Twenty-four hours after MSU injection, foot thickness was increased by 160% and L-NIL pretreatment reduced food pad swelling in a dose dependent manner. Pretreatment of 10 mg/kg/day L-NIL significantly suppressed the foot pad swelling by MSU. Plasma level of nitric oxide (NO) metabolites and gene expression and protein level of iNOS in feet were increased by MSU, which was suppressed by L-NIL pretreatment. Similar pattern of change was observed in nitrotyrosine level. MSU increased the gene expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β and L-NIL pretreatment suppressed MSU-induced cytokines expression. The mRNA levels of superoxide dismutase and glutathione peroxidase1 were increased by MSU and L-NIL pretreatment normalized the gene expression. Phosphorylation of extracellular signal-regulated kinase 1/2 and p38 was increased by MSU, which was suppressed by L-NIL pretreatment. The mRNA levels of iNOS, TNF-α, and IL-1β were increased by MSU in human dermal fibroblasts, C2C12 myoblasts, and human fetal osteoblasts in vitro, which was attenuated by L-NIL in a dose dependent manner. This study shows that L-NIL inhibits MSU-induced inflammation and edema in mice feet suggesting that iNOS might be involved in MSU-induced inflammation.
Uric acid; Gout; iNOS
This study was conducted to assess the exposure risk through inhalation to baby powder for babies and adults under simulated conditions. Baby powder was applied to a baby doll and the amount of baby powder consumed per application was estimated. The airborne exposure to baby powder during application was then evaluated by sampling the airborne baby powder near the breathing zones of both the baby doll and the person applying the powder (the applicator). The average amount of baby powder consumed was 100 mg/application, and the average exposure concentration of airborne baby powder for the applicator and baby doll was 0.00527 mg/m3 (range 0.00157~0.01579 mg/m3) and 0.02207 mg/m3 (range 0.00780~ 0.04173 mg/m3), respectively. When compared with the Occupational Exposure Limit of 2 mg/m3 set by the Korean Ministry of Labor and the Threshold Limit Value (TLV) of 2 mg/m3 set by the ACGIH (American Conference of Governmental Industrial Hygienists), the exposure concentrations were much lower. Next, the exposure to asbestos-containing baby powder was estimated and the exposure risk was assessed based on the lung asbestos contents in normal humans. As a result, the estimated lung asbestos content resulting from exposure to asbestos-containing baby powder was found to be much lower than that of a normal Korean with no asbestos-related occupational history.
Talc; Asbestos; Baby powder; Exposure assessment; Risk assessment