Treatment of intravenous immunoglobulin-resistant Kawasaki disease with methotrexate

OBJECTIVE: To evaluate the effect of low-dose oral methotrexate (MTX) as treatment for patients with Kawasaki disease (KD) resistant to intravenous immunoglobulin (IVIG). METHODS: The subjects were four patients with KD, aged 8 months to 8 years old, who showed persistent disease after treatment with high-dose IVIG (2 g/kg) and aspirin (100 mg/kg). These patients were re-treated with IVIG and were also treated with IV dexamethasone (0.3 mg/kg). IV dexamethasone induced defervescence in three patients, but fever recurred upon discontinuing the steroid. One patient showed no response to either IVIG or dexamethasone. All patients were subsequently treated weekly with low-dose oral MTX [10 mg/body surface area (BSA)]. RESULTS: MTX treatment resulted in rapid defervescence, improvement in clinical symptoms, and normalization of acute-phase reactants in all patients. There was no progression of coronary artery dilatation and MTX was discontinued with no recurrence of fever. No adverse effects of MTX were observed. CONCLUSION: Low-dose oral MTX is an effective treatment for refractory KD.     

Videocapsule endoscopy versus barium contrast studies for the diagnosis of Crohn's disease recurrence involving the small intestine

OBJECTIVES: Historically, suspected Crohn's disease (CD) has been evaluated with small bowel follow-through (SBFT) or enteroclysis (equally accurate). This study was undertaken to determine the accuracy of videocapsule endoscopy (VCE) in the diagnosis of CD relative to SBFT and clinical/laboratory indices of CD activity. Previous investigations have used VCE for the diagnosis of suspected CD in patients presenting with a variety of gastrointestinal symptoms. This is the first study to evaluate the occurrence of active disease in patients with known CD. METHODS: Thirty subjects (22 female, 8 male, aged 36.9 +/- 14.2 yr); all with prior CD diagnosis made on the basis of standard criteria (5.5 +/- 6.5 yr prior to study), in whom recurrent CD was suspected based on abdominal pain, diarrhea, anemia, and/or arthralgias. Subjects were studied in a prospective, blinded evaluation of VCE versus SBFT. SBFT was performed first; those with stricture and proximal bowel dilation were excluded from further study. For SBFT, studies were graded as grade 0 (normal), grade 1 (minimal nodularity, ulcerations, normal luminal diameter, < 5 cm involved), grade 2 (more extensive ulcers, minimal luminal narrowing, 5-10 cm involved), or grade 3 (fistula, skip areas, extensive ulceration, >10 cm involved). VCE was performed within 1 wk of SBFT. Serum was obtained for ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein), stool was obtained for alpha-1 antitrypsin, and the Harvey Bradshaw index of CD severity was calculated. VCE (digitalized video) was graded as grade 0 (normal), grade 1 (erythema, isolated villi loss), grade 2 (erosion, no ulcer), or grade 3 (ulcers, spontaneous bleeding, and/or stricture). RESULTS: Twelve patients were excluded for small bowel obstruction. VCE and SBFT scores highly correlated (r = 0.65; p= 0.001). Active CD was visualized in 21 of 30 patients with videocapsule endoscopy and in 20 of 30 patients with SBFT. Complete agreement occurred in 13 of 30 studies; 13 of 17 studies differed by one grade. SBFT found mucosal disease in 20 of 30 patients and VCE found mucosal disease in 21 of 30 patients. VCE found mucosal disease in 6 patients (5 in grade 1, 1 in grade 3) with normal SBFT. SBFT showed CD in 5 patients (all grade 1) with normal VCE. Neither VCE nor SBFT scores correlated with biological or clinical indices. Patient satisfaction was superior for VCE. CONCLUSIONS: VCE and SBFT are complementary for the diagnosis of CD. SBFT may be required to detect strictures as the videocapsule may not pass. However, some strictures may also be missed with SBFT. VCE is less invasive, less time-consuming for the patient than SBFT, and avoids radiation exposure, although reading time is greater for the gastroenterologist than the radiologist. Given that patients with clinically suspected CD recurrence may not have active disease, unnecessary and potentially harmful empiric therapy is not warranted without imaging.     

Limitation of the validity of the homeostasis model assessment as an index of insulin resistance in Korea

Homeostasis model assessment of insulin resistance (HOMA-IR) is a less invasive, inexpensive, and less labor-intensive method to measure insulin resistance (IR) as compared with the glucose clamp test. The aim of this study was to evaluate the validity of HOMA-IR by comparing it with the euglycemic clamp test in determining IR. We assessed the validity of HOMA-IR by comparing it with the total glucose disposal rate measured by the 3-hour euglycemic-hyperinsulinemic clamp in subjects with type 2 diabetes (n = 47), impaired glucose tolerance (n = 21), and normal glucose tolerance (n = 22). There was a strong inverse correlation (r = -0.558; P < .001) between the log-transformed HOMA-IR and the total glucose disposal rate. There was moderate agreement between the 2 methods in the categorization according to the IR (weighted kappa = 0.294). The magnitude of the correlation coefficients was smaller in the subjects with a lower body mass index (BMI <25.0 kg/m2 , r = -0.441 vs BMI > or =25.0 kg/m2 , r = -0.615; P = .032), a lower HOMA-beta cell function (HOMA- beta <60.0, r = -0.527 vs HOMA- beta > or =60.0, r = -0.686; P = .016), and higher fasting glucose levels (fasting glucose < or =5.66 mmol/L, r = -0.556 vs fasting glucose >5.66 mmol/L, r = -0.520; P = .039). The limitation of the validity of the HOMA-IR should be carefully considered in subjects with a lower BMI, a lower beta cell function, and high fasting glucose levels such as lean type 2 diabetes mellitus with insulin secretory defects.     

A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial of Retinol Palmitate (Vitamin A) for Symptomatic Chronic Radiation Proctopathy

PURPOSE This study was designed to determine whether oral retinol palmitate (vitamin A) can reduce the symptoms of radiation proctopathy.METHODS A randomized, double-blind trial comparing retinol palmitate (10,000 IU by mouth for 90 days) to placebo was conducted. Eligible patients were more than six months postpelvic radiotherapy and had significant symptoms as measured with the Radiation Proctopathy System Assessments Scale. Nineteen patients were randomized in total: ten to retinol palmitate and nine to placebo. The Radiation Proctopathy System Assessments Scale scores before and every 30 days for 90 days were measured. Five placebo nonresponders were crossed over to the retinol palmitate for another 90 days. Response was defined as a reduction in two or more symptoms by at least two Radiation Proctopathy System Assessments Scale points.RESULTS Seven of ten retinol palmitate patients responded, whereas two of nine responded to placebo (P = 0.057). Mean pre-post-treatment change in Radiation Proctopathy System Assessments Scale ( Radiation Proctopathy System Assessments Scale) in the retinol palmitate group was 11 ± 5, whereas Radiation Proctopathy System Assessments Scale in the placebo group was 2.5 ± 3.6 (P = 0.013, Mann-Whitney U test). Additionally, all five placebo nonresponders who were crossed over to treatment with retinal palmitate responded to treatment.CONCLUSIONS In our trial, retinol palmitate significantly reduced rectal symptoms of radiation proctopathy, perhaps because of wound-healing effects. The current results can serve as the foundation for future trials examining retinol palmitate in the multi-institutional setting.Supported in part by a private grant from Arthur C. Nielsen, Jr.     

Melatonin and verteporfin synergistically suppress the growth and stemness of head and neck squamous cell carcinoma through the regulation of mitochondrial dynamics

The prevalence of head and neck squamous cell carcinoma (HNSCC) has continued to rise for decades. However, drug resistance to chemotherapeutics and relapse, mediated by cancer stem cells (CSCs), remains a significant impediment in clinical oncology to achieve successful treatment. Therefore, we focused on analyzing CSCs in HNSCC and demonstrated the effect of melatonin (Mel) and verteporfin (VP) on SCC-25 cells. HNSCC CSCs were enriched in the reactive oxygen species-low state and in sphere-forming cultures. Combination treatment with Mel and VP decreased HNSCC viability and increased apoptosis without causing significant damage to normal cells. Sphere-forming ability and stem cell population were reduced by co-treatment with Mel and VP, while mitochondrial ROS level was increased by the treatment. Furthermore, the expression of mitophagy markers, parkin and PINK1, was significantly decreased in the co-treated cells. Mel and VP induced mitochondrial depolarization and inhibited mitochondrial function. Parkin/TOM20 was localized near the nucleus and formed clusters of mitochondria in the cells after treatment. Moreover, Mel and VP downregulated the expression of markers involved in epithelial-mesenchymal transition and metastasis. The migration capacity of cells was significantly decreased by co-treatment with Mel and VP, accompanied by the down-regulation of MMP-2 and MMP-9 expression. Taken together, these results indicate that co-treatment with Mel and VP induces mitochondrial dysfunction, resulting in the apoptosis of CSCs. Mel and VP could thus be further investigated as potential therapies for HNSCC through their action on CSCs.     

Interleukin-1beta regulates urokinase plasminogen activator (u-PA), u-PA receptor, soluble u-PA receptor, and plasminogen activator inhibitor-1 messenger ribonucleic acid expression in cultured human endometrial stromal cells

The interleukin-1 (IL-1) system plays an integral role in local intercellular interactions during implantation. In addition, the plasminogen activator system, especially urokinase plasminogen activator (u-PA), plasminogen activator inhibitor (PAI-1), and u-PA receptor (u-PAR), are crucial during embryo implantation. Decidualization and implantation are complex processes dependent upon several proteases, including u-PA, and IL-1 is known to affect PA activity in several cell types. We investigated the role of IL-1beta in regulating u-PA, PAI-1, u-PAR, and soluble u-PAR messenger ribonucleic acid (mRNA) expression in cultured human endometrial stromal cells using quantitative competitive PCR. For confirmation of the mRNA data, we measured PAI-1 and u-PAR protein by enzyme-linked immunosorbent assay. Confluent stromal cell cultures treated with progesterone and estradiol for 9 days were stimulated with IL-1beta, and IL-1beta plus IL-1beta antibody for an additional 24 h. Total RNA was extracted, reverse transcribed, and coamplified using quantitative and competitive PCR with internal standards. IL-1beta increased PAI-1, u-PAR, and soluble u-PAR expression in a dose-dependent manner, and this result was reversed by anti-IL-1beta antibody treatment. u-PA mRNA expression was not dependent on IL-1beta. These results suggest that IL-1 may be important in regulating PAI-1 and u-PAR during stromal cell decidualization before implantation.     

Aortobronchial fistula presenting as recurrent hemoptysis and successfully treated with an endovascular stent graft.

Aortobronchial fistula (ABF) (aortopulmonary fistula) may cause a massive fatal hemoptysis. We have recently seen a patient with ABF presenting with recurrent, massive hemoptysis. She was successfully treated with an endovascular stent graft. The endovascular stent graft may provide an alternative treatment of in patients considered to be poor surgical candidates.     

Platycodon grandiflorum extract represses up-regulated adipocyte fatty acid binding protein triggered by a high fat feeding in obese rats

AIM： To investigate the effect of Platycodon grandiflorum extract （PGE） on lipid metabolism and FABP mRNA expression in subcutaneous adipose tissue of high fat diet-induced obese rats.
METHODS： PGE was treated to investigate the inhibitory effect on the pre-adipocyte 3T3-L1 differentiation and pancreatic lipase activity. Male Sprague-Dawley rats with an average weight of 439.03± 7.61 g were divided into four groups： the control groups that fed an experimental diet alone （C and H group） and PGE treatment groups that administered PGE along with a control diet or HFD at a concentration of 150 mg/kg body weight （C ＋ PGE and H ＋ PGE group, respectively） for 7 wk. Plasma total cholesterol （TC） and triglycerol （TG） concentrations were measured from the tail vein of rats. Adipocyte cell area was measured from subcutaneous adipose tissue and the fatty acid binding protein （FABP） mRNA expression was analyzed by northern blot analysis.
RESULTS： PGE treatment inhibited 3T3-L1 pre-adipocyte differentiation and fat accumulation, and also decreased pancreatic lipase activity. In this experiment, PGE significantly reduced plasma TC and TG concentrations as well as body weight and subcutaneous adipose tissue weight. PGE also significantly decreased the size of subcutaneous adipocytes. Furthermore, it significantly repressed the up-regulation of FABP mRNA expression induced by a high-fat feeding in subcutaneous adipose tissue.
CONCLUSION： PGE has a plasma lipid lowering-effect and anti-obesity effect in obese rats fed a high fat diet.From these results, we can suggest the possibility that PGE can be used as a food ingredient or drug component to therapeutically control obesity.     

Transcription factor decoy for activator protein-1 (AP-1) inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor (PAI-1) gene expression in cultured human vascular smooth muscle cells

AIMS/HYPOTHESIS: Multiple factors, including hyperglycaemia and angiotensin II (Ang II), stimulate plasminogen activator inhibitor-1 (PAI-1) gene expression in human vascular smooth muscle cells. This study tested the hypothesis that hyperglycaemia and Ang II stimulate PAI-1 gene expression through activator protein-1 (AP-1) binding sites. METHODS: We evaluated the role of AP-1 in PAI-1 gene expression in human vascular smooth muscle cells under high D-glucose and Ang II stimulation using a double-stranded cis-element AP-1 oligodeoxynucleotide (decoy ODN). RESULTS: Activator protein 1 activity was stimulated by high glucose and Ang II treatment and the AP-1 decoy ODN, but not a mismatched decoy ODN, competed for AP-1 activity. The increase in PAI-1 expression by high glucose and Ang II was significantly attenuated by the AP-1 decoy ODN (p <0.05 or p < 0.01). The increase in PAI-1 expression by high glucose and Ang II action on AP-1 sites was also confirmed by promoter analysis of PAI-1. Activator protein 1 activation in response to either high glucose or co-stimulation with high glucose and Ang II was inhibited completely by calphostin C (a PKC inhibitor) and partially by genistein (a protein tyrosine kinase inhibitor). CONCLUSION/INTERPRETATION: This study shows that high glucose and Ang II stimulate PAI-1 expression through AP-1 binding sites. Signal transduction after AP-1 activation by both high glucose and Ang II largely depends on PKC activation. These data indicate an important role for AP-1 in PAI-1 expression.