The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is critical for both normal mammary gland development and malignant transformation. It has been reported that the IGF-1 stimulates breast cancer cell proliferation and is upregulated in tumors with BRCA1/2 mutations. We report here that IGF-1 is negatively regulated by BRCA1 at the transcriptional level in human breast cancer cells. BRCA1 knockdown (BRCA1-KD) induces the expression of IGF-1 mRNA in MCF7 cells in an estrogen receptor α (ERα)-dependent manner. We found that both BRCA1 and ERα bind to the endogenous IGF-1 promoter region containing an estrogen-responsive element-like (EREL) site. BRCA1-KD does not significantly affect ERα binding on the IGF-1 promoter. Reporter analysis demonstrates that BRCA1 could regulate IGF-1 transcripts via this EREL site. In addition, enzyme-linked immunosorbent assay revealed that de-repression of IGF-1 transcription by BRCA1-KD increases the level of extracellular IGF-1 protein, and secreted IGF-1 seems to increase the phospho-IGF-1Rβ and activate its downstream signaling pathway. Blocking the IGF-1/IGF-1R/phosphoinositide 3-kinase (PI3K)/AKT pathway either by a neutralizing antibody or by small-molecule inhibitors preferentially reduces the proliferation of BRCA1-KD cells. Furthermore, the IGF-1-EREL-Luc reporter assay demonstrates that various inhibitors, which can inhibit the IGF-1R pathway, can suppress this reporter activity. These findings suggest that BRCA1 defectiveness keeps turning on IGF-1/PI3K/AKT signaling, which significantly contributes to increase cell survival and proliferation.
BRCA1; IGF-1; negative regulation; ERα; positive-feedback activation
We underwent protein assay for Myc expression in 76 human gastric cancer tissues using immunohistochemistry. Expression of Myc protein was analyzed according to proliferative indices measured by flow cytometry. Levels of Myc protein expression was evaluated by correlating with biologic and clinical parameters. In 36 (47.4%) of 76 primary gastric cancers, overexpression of Myc was observed. We could observe expression of Myc protein in a significant portion of early gastric cancer (42.9%). Expression of Myc protein was demonstrated to be more frequent in poorly differentiated cancer cells (p=0.043). However, expression of Myc protein had little influence over progress or extent of the disease. Expression of Myc protein was significantly correlated with increased proliferative activity (p=0.032) and patients with high levels of Myc expression had poor disease-free survival. In a certain proportion of human gastric cancer, Myc protein may function as a regulator of cancer cell growth and expression of Myc may represent an aggressive phenotype of gastric cancer.
Coccidioidomycosis is an endemic disease found in the southwestern part of North America. Travellers who visit the endemic area may carry the infection. We report a case of pulmonary coccidioidomycosis in a 74-year-old woman. She was healthy before visiting Arizona, U.S.A twice. After returning home, she began to complain of intermittent dry coughing. The symptom was mild, however, and she was treated symptomatically. Later a chest radiograph, which was taken 4 years after the onset of the symptom, showed a solitary pulmonary nodule in the right upper lobe. By percutaneous needle aspiration, a few clusters of atypical cells were noted in the necrotic background. A right upper and middle lobectomy was done. A 1.5 x 1.5 x 1.2 cm sized tan nodule was present in otherwise normal lung parenchyma. Microscopically, the nodule consisted of aggregates of multiple solid granulomas inside of which was mostly necrotic. Neutrophils and nuclear debris were scattered along the periphery of the necrotic foci. Numerous multinucleated giant cells were associated with the granulomas. In the necrotic area, mature spherules of Coccidioides immitis, which were 30-100 microm in diameter, were present. They contained numerous endospores which ranged from 5 to 15 microm and were also noted in multinucleated giant cells. The diagnosis of coccidioidomycosis was made. She is doing well after the resection.
Hepatoblastoma is thought to originate from embryonal hepatic tissue, and most of these tumors occur in children under the age of 2 years. Hepatoblastoma in adults is extremely rare, and the prognosis is much worse than the mixed hepatoblastoma of childhood. We experienced a case of mixed hepatoblastoma in a 51 year old female patient. She had been suffering from a mild pain and a palpable lump in the epigastric area. Serum AFP was 43,850 ng/ml. Computerized tomography and selective abdominal angiography showed a large low-density mass. With a suspicion of hepatocellular carcinoma of the left lobe, a left lateral segmentectomy was performed. The external surface showed a huge protruding mass and the capsule was previously ruptured. On section, the tumor was a 11 x 7 cm sized expanding mass which had a variegated surface composed of yellow-white friable tissue with multifocal hemorrhagic areas. Microscopic examination revealed a tumor consisted of epithelial and mesenchymal elements. The mesenchymal cells were spindle in shape and proliferated over the whole tumor with focal osteosarcomatous differentiation. The epithelial components showed well-differentiated hepatocellular carcinoma-like areas, poorly differentiated acinar or tubular structures.
Spinal congenital dermal sinus (CDS) is a rare entity which supposedly results from the failure of the neuroectoderm to separate from the cutaneous ectoderm during the process of neurulation. The lesions are most frequent at the lumbosacral followed by the occipital region. CDS of the thoracic region is very rare. The patients with spinal CDS present with meningitis and/or mass effect from the associated inclusion tumor. They are usually dermoid or epidermoid cysts. Teratoma is rarely associated. The authors experienced 5 cases of spinal CDS over a 10 year period. Of the 5 cases, 2 were at thoracic and 3 were at lumbosacral levels. Dermoid cyst, epidermoid cyst and teratoma were associated in one case each. Two cases presented with neurological deficit and meningitis while an additional case presented with neurological deficit and a history of probable meningitis. Pain was present in 2 cases. Magnetic resonance imaging played an important role in the diagnosis of the lesion and planning of surgery. All the cases showed a good response to surgery even though one patient had persistent neurological deficit.
c-Jun N-terminal kinase (JNK) is activated by dual phosphorylation of both threonine and tyrosine residues in the phosphorylation loop of the protein in response to several stress factors. However, the precise molecular mechanisms for activation after phosphorylation remain elusive. Here we show that Pin1, a peptidyl-prolyl isomerase, has a key role in the JNK1 activation process by modulating a phospho-Thr-Pro motif in the phosphorylation loop. Pin1 overexpression in human breast cancer cell lines correlates with increased JNK activity. In addition, small interfering RNA (siRNA) analyses showed that knockdown of Pin1 in a human breast cancer cell line decreased JNK1 activity. Pin1 associates with JNK1, and then catalyzes prolyl isomerization of the phospho-Thr-Pro motif in JNK1 from trans- to cis-conformation. Furthermore, Pin1 enhances the association of JNK1 with its substrates. As a result, Pin1−/− cells are defective in JNK activation and resistant to oxidative stress. These results provide novel insights that, following stress-induced phosphorylation of Thr in the Thr-Pro motif of JNK1, JNK1 associates with Pin1 and undergoes conformational changes to promote the binding of JNK1 to its substrates, resulting in cellular responses from extracellular signals.
c-Jun N-terminal kinase; peptidyl-prolyl cis/trans-isomerase; apoptosis
We report our experience with endovascular treatment of supra-aortic arteries and follow-up results in patients with Takayasu’s arteritis (TA) presenting with neurological symptoms. Of the 20 patients with TA who underwent cerebral angiography for neurological manifestations between May 2002 and May 2009, 12 (11 females, one male; mean age, 39 years; range 31-56 years) underwent endovascular treatment and evaluated outcome for 21 lesions, including nine common carotid arteries, four vertebral arteries, four subclavian arteries, two internal carotid arteries, and one brachiocephalic artery. Eight patients underwent multiple endovascular procedures for different lesions in single or multiple stages. Mean angiographic and clinical follow-up durations were 34 months (range, 11-79 months) and 39 months (range 11-91 months), respectively.
Technical success was achieved for 20 procedures in 11 patients. One procedure failed, with 50% residual stenosis after stenting due to dense calcification of vessel walls. There were no procedure-related complications. Restenosis occurred at two lesions in two patients were treated by re-stenting. Asymptomatic occlusion occurred at two lesions in one patient. Ten patients remained in 0-1 on the modified Rankin scale (mRs) during mean 39 months. One patient, however, had a score of 3 on mRs due to a traumatic contusion during follow-up. One patient died from cardiac failure 36 months after successful angioplasty.
Our data suggest that endovascular treatment of symptomatic supra-aortic lesions of TA is effective and durable in selected patients with neurologic symptoms.
Takayasu’s arteritis, angiography, stroke, stenosis, angioplasty
We sought the long-term efficacy of traditionally used antidiabetic herbs in controlling blood glucose homeostasis and low-grade inflammation. Ninety-four subjects with either impaired glucose tolerance or mild T2D were randomized either to treatment arm or placebo arm and received 1 : 1 : 1 mixture of ginseng roots, mulberry leaf water extract, and banaba leaf water extract (6 g/d) for 24 weeks. Oral 75 g glucose tolerance test was performed to measure glucose and insulin responses. Blood biomarkers of low-grade inflammation were also determined. Results found no significant difference in glucose homeostasis control measure changes. However, plasma intracellular adhesion molecule-1 (ICAM-1) concentration was decreased showing a significant between-treatment changes (P = 0.037). The concentrations of vascular cell adhesion molecule-1 (VCAM-1) (P = 0.014) and ICAM-1 (P = 0.048) were decreased in the treatment group at week 24, and the oxidized low-density lipoprotein (ox-LDL) concentration was reduced at week 24 compared to the baseline value in the treatment group (P = 0.003). These results indicate a long-term supplementation of ginseng, mulberry leaf, and banaba leaf suppresses inflammatory responses in T2D.
Detection of aquaporin-4–specific immunoglobulin G (IgG) has expanded the spectrum of neuromyelitis optica (NMO). Rare reports of familial aggregation have suggested a component of genetic susceptibility but these reports mostly antedated the discovery of the NMO-IgG biomarker and recently updated diagnostic criteria.
We report a case series describing the demographic, clinical, neuroimaging, and NMO-IgG serologic status of 12 multiplex NMO pedigrees with a total of 25 affected individuals.
Twenty-one patients (84%) were women. Families were Asian (n = 5), Latino (n = 4), white (n = 1), or African (n = 2). Apparent transmission was either maternal (n = 5) or paternal (n = 2). In 1 family, 3 individuals had NMO; in the others, 2 individuals were affected. Sibling pairs (n = 6), parent-child (n = 4), and aunt-niece (n = 3) pairs were observed. Nineteen patients (76%) were NMO-IgG positive. Twelve (48%) had clinical or serologic evidence of another autoimmune disease. Familial occurrence of NMO occurs in approximately 3% of patients with well-established diagnosis of NMO.
A small proportion of patients with NMO have relatives with this condition, but familial occurrence is more common than would be expected from its frequency in the general population. Familial NMO is indistinguishable from sporadic NMO based on clinical symptoms, age at onset, sex distribution, and frequency of NMO-IgG detection. One or 2 generations were affected and affected individuals represented a small fraction of family members. Taken together, these data suggest complex genetic susceptibility in NMO.
= confidence interval;
= human leukocyte antigen;
= immunoglobulin G;
= longitudinally extensive transverse myelitis;
= multiple sclerosis;
= neuromyelitis optica;
= optic neuritis;
= odds ratio.
The main determinant of muscle carnosine (M-Carn) content is undoubtedly species, with, for example, aerobically trained female vegetarian athletes [with circa 13 mmol/kg dry muscle (dm)] having just 1/10th of that found in trained thoroughbred horses. Muscle fibre type is another key determinant, as type II fibres have a higher M-Carn or muscle histidine containing dipeptide (M-HCD) content than type I fibres. In vegetarians, M-Carn is limited by hepatic synthesis of β-alanine, whereas in omnivores this is augmented by the hydrolysis of dietary supplied HCD’s resulting in muscle levels two or more times higher. β-alanine supplementation will increase M-Carn. The same increase in M-Carn occurs with administration of an equal molar quantity of carnosine as an alternative source of β-alanine. Following the cessation of supplementation, M-Carn returns to pre-supplementation levels, with an estimated t1/2 of 5–9 weeks. Higher than normal M-Carn contents have been noted in some chronically weight-trained subjects, but it is unclear if this is due to the training per se, or secondary to changes in muscle fibre composition, an increase in β-alanine intake or even anabolic steroid use. There is no measureable loss of M-Carn with acute exercise, although exercise-induced muscle damage may result in raised plasma concentrations in equines. Animal studies indicate effects of gender and age, but human studies lack sufficient control of the effects of diet and changes in muscle fibre composition.
Muscle carnosine; β-alanine; Species; Diet; Exercise and training; Age and gender
A uterus-like mass is a rare, benign extra-uterine tumour composed of smooth muscle and endometrium. The majority of uterus-like masses occur in the ovary. Rarely, uterus-like masses occur in the broad ligament, small bowel, small bowel mesentery or uterine cervix. Here, we report a case of a uterus-like mass in the sigmoid mesocolon. A well-defined, markedly enhanced soft-tissue mass with central cystic change and haemorrhage was observed on CT. The current report describes the CT characteristics of this sigmoid mesocolon uterus-like mass together with the differential diagnoses.
To evaluate an improved quantitative lung fibrosis score based on a computer-aided diagnosis (CAD) system that classifies CT pixels with the visual semi-quantitative pulmonary fibrosis score in patients with sclero-derma-related interstitial lung disease (SSc-ILD).
High-resolution, thin-section CT images were obtained and analysed on 129 subjects with SSc-ILD (36 men, 93 women; mean age 48.8±12.1 years) who underwent baseline CT in the prone position at full inspiration. The CAD system segmented each lung of each patient into 3 zones. A quantitative lung fibrosis (QLF) score was established via 5 steps: 1) images were denoised; 2) images were grid sampled; 3) the characteristics of grid intensities were converted into texture features; 4) texture features classified pixels as fibrotic or non-fibrotic, with fibrosis defined by a reticular pattern with architectural distortion; and 5) fibrotic pixels were reported as percentages. Quantitative scores were obtained from 709 zones with complete data and then compared with ordinal scores from two independent expert radiologists. ROC curve analyses were used to measure performance.
When the two radiologists agreed that fibrosis affected more than 1% or 25% of a zone or zones, the areas under the ROC curves for QLF score were 0.86 and 0.96, respectively.
Our technique exhibited good accuracy for detecting fibrosis at a threshold of both 1% (i.e. presence or absence of pulmonary fibrosis) and a clinically meaningful threshold of 25% extent of fibrosis in patients with SSc-ILD.
texture feature; classification; scleroderma; interstitial lung disease; CAD
Management of symptomatic carotid near occlusion especially in high-risk patients is different from outcome analysis of NASCET. We evaluated outcome in high-risk patients with symptomatic near occlusion.
For 48 patients with near occlusion out of 166 symptomatic high-risk patients who underwent carotid stenting, we assessed the procedural success defined as residual stenosis <30%, modified Rankin Scale (mRS) at one and six months following stenting, and the 13 cerebrovascular factors related to the outcome. Initial National Institutes of Health Stroke Scale (NIHSS) ≥4,1-3 and 0 were 13,14 and 21 patients each. We compared the outcome with patients who underwent CAS (n=118) due to symptomatic stenosis without near occlusion during the same period.
Our procedural success rate was 98%. A good outcome (mRS ≥2) was achieved in 44 patients (92%) at six months. There were five events (10%) within six months, i.e. three minor strokes, one major stroke caused by hemorrhage, and one death excluding two deaths not related to stroke. Hyperperfusion (n=4) was the most common cause of events leading to two minor strokes and a major stroke. Although initial NIHSS (P = .012) was related to poor outcome (mRS >2) compared to the CAS group, there was no statistical significance between two groups in the event rate of stroke, death or restenosis.
The outcome of carotid stenting in high-risk patients with symptomatic near occlusion did not reveal any difference compared with CAS. Poor outcome was related to the initial NIHSS (>4). Hyperperfusion tended to be more commonly related to an event occurring after stenting.
carotid arteries, stenosis or obstruction, stenting, outcome
The aim of this study is to compare blinded with partially blinded detection of gastric cancer with multidetector (MD) CT by using surgery and endoscopic submucosal dissection (ESD) as reference standards. 44 patients with gastric cancer underwent MDCT with air as an oral contrast agent. Surgery was performed on 37 patients, ESD on six and surgery after ESD on one. To provide comparison cases of blinded evaluation, 38 MDCT examinations were added for cases where no focal gastric lesion was seen on endoscopy. Two radiologists, blinded to the presence, number and location of the tumours, evaluated axial and axial plus multiplanar reformation (MPR) images of 82 MDCT examinations with or without gastric cancer. For partially blinded evaluation, the same radiologists, blinded to the location and number of tumours, evaluated axial and axial plus MPR images of 44 MDCT examinations of gastric cancer. Differences in assessment were resolved by consensus. 45 gastric cancers were found in surgical and ESD specimens. Detection rates of gastric cancer from axial and axial plus MPR images during blinded evaluation and from axial and axial plus MPR images during partially blinded evaluation were 62% (28/45), 64% (29/45), 64% (29/45) and 71% (32/45), respectively. There was no statistical significance for the comparison between blinded and partially blinded detection rates of gastric cancer. The detection rate of gastric cancer with MDCT during blinded evaluation showed no specific difference compared with the detection rate of gastric cancer with MDCT during partially blinded evaluation.
To study cross‐national inequalities in mortality of adults and of children aged <5 years using a novel approach, with clustering techniques to stratify countries into mortality groups (better‐off, worse‐off, mid‐level) and to examine risk factors associated with inequality.
Design, setting and participants
Analysis of data from the World Development Indicators 2003 database, compiled by the World Bank.
Main outcome measures
Adult and child mortality among countries placed into distinct mortality categories by cluster analysis.
29 countries had a high adult mortality (mean 584/1000; range 460/1000 to 725/1000) and 23 had a high child mortality (mean 207/1000, range 160/1000 to 316/1000). All these countries were in western and sub‐Saharan Africa and Afghanistan. Bivariate analyses showed that relative to countries with low child mortality, those with high child mortality had significantly higher rates of extreme poverty (p<0.001), populations living in rural areas (p<0.001) and female illiteracy (p<0.001), significantly lower per capita expenditure on healthcare (p<0.001), outpatient visits, hospital beds and doctors, and lower rates of access to improved water (p<0.001), sanitation (p<0.001) and immunisations. In multivariate analyses, countries with high adult mortality had a higher prevalence of HIV infection (odds ratio per 1% increase 18.6; 95% CI 0.3 to 1135.5). Between 1960 and 2000, adult male mortality in countries with high mortality increased at >4 times the rate in countries with low mortality. For child mortality, the worse‐off group made slower progress in reducing <5 mortality than the better‐off group.
Inequalities in child and adult mortality are large, are growing, and are related to several economic, social and health sector variables. Global efforts to deal with this problem require attention to the worse‐off countries, geographic concentrations, and adopt a multidimensional approaches to development.
An experimental study of picosecond pulse amplification in a gyrotron-traveling wave tube (gyro-TWT) has been carried out. The gyro-TWT operates with 30 dB of small signal gain near 140 GHz in the HE06 mode of a confocal waveguide. Picosecond pulses show broadening and transit time delay due to two distinct effects: the frequency dependence of the group velocity near cutoff and gain narrowing by the finite gain bandwidth of 1.2 GHz. Experimental results taken over a wide range of parameters show good agreement with a theoretical model in the small signal gain regime. These results show that in order to limit the pulse broadening effect in gyrotron amplifiers, it is crucial to both choose an operating frequency at least several percent above the cutoff of the waveguide circuit and operate at the center of the gain spectrum with sufficient gain bandwidth.
The purpose of this study was to evaluate intratumoral cystic lesions of pancreatic ductal adenocarcinoma (PDAC) depicted on MRI, and to correlate these cystic lesions with their histopathological findings. This study included 12 patients (7 males and 5 females; mean age, 59 years) with intratumoral cystic lesions of PDAC detected on a retrospective MRI review. We reviewed the histopathological findings of the cystic lesions within PDACs and analysed the MRI findings, focusing on the appearance of the intratumoral cystic lesions, i.e. the size, number, margin and intratumoral location, and on the ancillary findings of PDAC, i.e. peripancreatic infiltration, upstream pancreatic duct dilatation and distal parenchymal atrophy. Intratumoral cystic lesions were classified as neoplastic mucin cysts (n = 7, 58%) or cystic necrosis (n = 5, 42%) according to the histopathological findings; they ranged in greatest dimension from 0.5 cm to 3.4 cm (mean, 1.7 cm). Seven patients had only one cystic lesion each, while the remaining five had multiple cystic lesions. Most of the neoplastic mucin cysts had smooth margins (n = 6, 86%) and eccentric locations (n = 6), whereas most cystic necroses had irregular margins (n = 4, 80%) and centric locations (n = 4). The most common ancillary findings of PDAC were peripancreatic infiltration, distal pancreatic atrophy and upstream pancreatic duct dilatation (92%, 75% and 58%, respectively). The intratumoral cystic lesions of PDACs on MRI were classified as either neoplastic mucin cysts with smooth margins and eccentric locations or cystic necroses with irregular margins and centric locations.
Stathmin1 is a microtubule-regulating protein that has an important role in the assembly and disassembly of the mitotic spindle. The roles of stathmin1 in carcinogenesis of various cancers, including prostate and breast cancer, have been explored. However, its expression and roles in gastric cancer have not yet been described.
Stathmin1 expression in paraffin-embedded tissue sections from 226 patients was analysed by immunohistochemistry. Roles of stathmin1 were studied using a specific small interfering RNA (siRNA).
The expression of stathmin1 was positively correlated with lymph node metastasis, TNM stages and vascular invasion, and negatively with recurrence-free survival, in the diffuse type of gastric cancer. The median recurrence-free survival in patients with a negative and positive expression of stathmin1 was 17.0 and 7.0 months, respectively (P=0.009). When the expression of stathmin1 was knocked down using siRNA, the proliferation, migration and invasion of poorly differentiated gastric cancer cells in vitro were significantly inhibited. Moreover, stathmin1 siRNA transfection significantly slowed the growth of xenografts in nude mice.
These results suggest that stathmin1 can be a good prognostic factor for recurrence-free survival rate and is a therapeutic target in diffuse-type gastric cancer.
stathmin1; gastric cancer; proliferation; migration
Objective and methods:
Given the profound weight loss after gastric banding and bypass we compared fat compartmentalization by whole body magnetic resonance imaging in women and men after these procedures to two groups of non-surgical controls who were either matched for age, weight and height or were of lower body mass index (BMI).
In women post-surgery (n=17; BMI 31.7 kg/m2) there was lower visceral adipose tissue (VAT) (1.4 vs 2.5 kg; P<0.01) compared with matched controls (n=59; BMI 32.1 kg/m2). In contrast, VAT (5.3 vs 5.4 kg) was nearly identical in men post-surgery (n=10; BMI 34.1 kg/m2) compared with matched controls (n=10; BMI 32.1 kg/m2) even though the degree of weight reduction was not significantly different from women (27.4 vs 32.6%). Furthermore, VAT when adjusted for total adipose tissue (TAT) was 43% less in women post-surgery (1.2 vs 2.1 kg; P=0.03) than in controls with lower BMI (25.1 kg/m2). After adjustment for TAT, subcutaneous adipose tissue in women post-surgery was significantly greater than matched controls (35.1 vs 34.2 kg; P=0.03). There was a significant negative correlation of VAT and the degree of weight loss in women (r=−0.57; P=0.018) but this relationship was not significant in men (r=−0.39; P=0.27). Skeletal muscle was lower in both sexes compared with matched controls (women, 21.8 vs 23.1 kg; men, 32.5 vs 35.5 kg).
Prospective studies are necessary to confirm if there is a sexual dimorphism in the effects of bariatric surgery on body composition.
adjustable gastric banding; Roux-en-Y gastric bypass; body composition; magnetic resonance imaging; leptin; obesity
We assessed the efficacy and safety of solifenacin compared with tolterodine for treatment of overactive bladder (OAB) in Korean patients.
Materials and methods:
The study was randomised, double-blind, tolterodine-controlled trial in Korea. Patients had average frequency of ≥ 8 voids per 24 h and episodes of urgency or urgency incontinence ≥ 3 during 3-day voiding diary period. Patients were randomised to 12-week double-blind treatment with either tolterodine immediate release (IR) 2 mg twice daily (TOL4) or solifenacin 5 mg (SOL5) or 10 mg (SOL10) once daily. The outcome measure was mean change in daily micturition frequency, volume, daily frequency of urgency incontinence, urgency and nocturia from baseline to week 12. Quality of life was assessed using the King’s Health Questionnaire.
A total of 357 were randomised and 329 were evaluated for efficacy. All voiding parameters recorded in micturition diary improved after treatment in all three groups. Mean changes in volume voided were 19.30 ml (26.69%) in TOL4, 30.37 ml (25.89%) in SOL5 and 37.12 ml (33.36%) in SOL10 group (p = 0.03). Speed of onset of SOL10 efficacy on urgency incontinence was faster than that of SOL5 and TOL4. Quality of life improved in all three groups. Dry mouth was the most common adverse event; its incidence was the lowest in SOL5 group (7.63%, compared with 19.49% and 18.64% in SOL10 and TOL4 groups respectively).
Solifenacin succinate 5 and 10 mg once daily improve OAB symptoms with acceptable tolerability levels compared with tolterodine IR 4 mg. Solifenacin 5 mg is a recommended starting dose in Korean patients with OAB.
To date, there are a few technologies for the development of noncompetitive immunoassays for small molecules; the most common of which relies on the use of anti-immunocomplex antibodies. This approach is laborious, case specific and relies upon monoclonal antibody technology for its implementation. We recently demonstrated that, in the case of monoclonal antibody-based immunoassays, short peptide loops isolated from phage display libraries can be used as substitutes of the anti-immunocomplex antibodies for noncompetitive immunodetection of small molecules. The aim of this work was to demonstrate that such phage ligands can be isolated even when the selector antibodies are polyclonal in nature. Using phenoxibenzoic acid (PBA), a major pyrethroid metabolite, as a model system, we isolated the CFNGKDWLYC peptide after panning a cyclic peptide library on the PBA/anti-PBA immunocomplex. The sensitivity of the noncompetitive ELISA set up with this peptide was 5-fold (heterologous) or 400-fold (homologous) higher than that of the competitive assay set up with the same antibody. PHAIA was also easily adapted into a rapid and highly sensitive dipstick assay. The method not only provides a positive readout, but also constitutes a major shortcut in the development of sensitive polyclonal-based assays, avoiding the need of synthesizing heterologous competing haptens.
polyclonal antibodies; anti-immunocomplexn assay; dipstick
There is no optimal treatment for symptomatic degenerative disc disease which affects millions of people worldwide. One novel approach would be to form a patch or tissue replacement to repair the annulus fibrosus (AF) through which the NP herniates. As the optimal scaffold for this has not been defined the purpose of this study was to determine if porous silk scaffolds would support AF cell attachment and extracellular matrix accumulation and whether chemically decorating the scaffold with RGD peptide, which has been shown to enhance attachment for other cell types, would further improve AF cell attachment and tissue formation. Annulus fibrosus cells were isolated from bovine caudal discs and seeded into porous silk scaffolds. The percent cell attachment was quantified and the cell morphology and distribution within the scaffold was evaluated using scanning electron microscopy. The cell-seeded scaffolds were grown for up to 8 weeks and evaluated for gene expression, histological appearance and matrix accumulation. AF cells attach to porous silk scaffolds, proliferate and synthesize and accumulate extracellular matrix as demonstrated biochemically and histologically. Coupling the silk scaffold with RGD-peptides did not enhance cell attachment nor tissue formation but did affect cell morphology. As well, the cells had higher levels of type II collagen and aggrecan gene expression when compared to cells grown on the non-modified scaffold, a feature more in keeping with cells of the inner annulus. Porous silk is an appropriate scaffold on which to grow AF cells. Coupling RGD peptide to the scaffold appears to influence AF cell phenotype suggesting that it may be possible to select an appropriate scaffold that favours inner annulus versus outer annulus differentiation which will be important for tissue engineering an intervertebral disc.
Annulus fibrosus; Tissue engineering; Silk biomaterial; Scaffold
To evaluate the role of preoperative bone scintigraphy in determining the operative treatment method for femoral neck fracture, we reviewed the data of 83 patients who underwent preoperative bone scanning after femoral neck fracture. Fractures were classified using the Garden staging system. Radioisotope uptake in femoral heads was evaluated visually. Of 28 patients with Garden stage I or II, radioactivity of the femoral head was normal in 26, partially reduced in one, and generally reduced in one patient. Twenty-seven patients were treated by closed reduction and multiple pinning, and one patient was treated by bipolar hemiarthroplasty. Of 55 patients with Garden stage III or IV, femoral-head radioactivity was normal in three, partially reduced in seven and generally reduced in 45 patients. Fifty-four patients were treated by bipolar hemiarthroplasty or total hip arthroplasty, and one patient was treated by closed reduction and multiple pinning. In only one of the 83 cases was the operative method changed because of bone scan findings. Isotope uptake of the femoral head after femoral neck fracture generally corresponded with the degree of fracture displacement. Preoperative bone scans appear to have no significant role to play in determining the operative treatment method for femoral neck fracture.
N-(4-hydroxyphenyl)retinamide (4HPR), a synthetic retinoid effective in cancer chemoprevention and therapy, is thought to act via apoptosis induction resulting from increased reactive oxygen species (ROS) generation. As ROS can activate MAP kinases and protein kinase C (PKC), we examined the role of such enzymes in 4HPR-induced apoptosis in HNSCC UMSCC22B cells. 4HPR increased ROS level within 1 h and induced activation of caspase 3 and PARP cleavage within 24 h. Activation of MKK3/6 and MKK4, JNK, p38 and ERK was detected between 6 and 12 h, increased up to 24 h and preceded apoptosis. 4HPR-induced activation of these kinases was abrogated by the antioxidants BHA and vitamin C. SP600125, a JNK inhibitor, suppressed 4HPR-induced c-Jun phosphorylation, cytochrome c release from mitochondria and apoptosis. Suppression of JNK1 and JNK2 using siRNA decreased, whereas overexpression of wild type-JNK1 enhanced 4HPR-induced apoptosis. PD169316, a p38, inhibitor suppressed phosphorylation of Hsp27 and apoptosis. PD98059, an MEK1/2 inhibitor, also suppressed ERK1/2 activation and apoptosis induced by 4HPR. Likewise, PKC inhibitor GF109203X suppressed ERK and p38 phosphorylation and PARP cleavage. These data indicate that 4HPR-induced apoptosis is triggered by ROS increase, leading to the activation of the mitogen-activated protein serine/threonine kinases JNK, p38, PKC and ERK, and subsequent apoptosis.
4HPR; apoptosis; ROS; MAPK; HNSCC