Several genomic regions are reported to be associated with the development of asthma and allergy, including chromosome 2q33. This region harbors the candidate gene cytotoxic T-lymphocyte antigen 4 ...(CTLA-4), an important regulator of T-cell activation and differentiation.
We sought to explore possible associations between CTLA-4 polymorphisms and allergy and asthma.
Seven single nucleotide polymorphisms (SNPs; MH30, -1147CT, +49AG, CT60, JO31, JO30, JO27_1) in CTLA-4 were analyzed for associations with total serum IgE, allergic sensitization (positive skin prick test to common allergens), bronchial hyperresponsiveness (BHR) to methacholine, asthma, and lung function (FEV1 % of predicted) in 364 asthmatic families from 3 European countries.
Transmission disequilibrium test analysis showed that several SNPs were significantly associated with serum IgE levels, allergy, asthma, and FEV1 % predicted below 80%, but not with BHR, and CTLA-4 polymorphisms of potentially direct pathogenic significance in atopic disorders were identified.
We identified associations between 4 newly discovered SNPs in the CTLA-4 gene and serum IgE levels, allergy, asthma, and reduced lung function, but not BHR, suggesting an important role for CTLA-4 in atopy and reduced lung function in asthmatic subjects rather than asthma per se. The particular SNP alleles found positively associated with our phenotypes were recently shown to be associated negatively with autoimmune disorders. Although a skewing toward a TH1 reactivity pattern is believed to characterize autoimmune diseases, atopic diseases are considered TH2-mediated. Hence, our data suggest a role for CTLA-4 polymorphisms in determining the TH1/TH2 balance and identify CTLA-4 signaling as a potential therapeutic target in atopic disease.
Background
Pharyngo-laryngo-esophagectomy (PLE) has been regarded as a standard treatment for cervical esophageal cancer, but the morbidity and mortality rates associated with PLE are substantial. ...Chemoradiation (CTRT) is widely used to treat esophageal cancer; however, its role in managing cervical esophageal cancer has not been fully elucidated. It was hypothesized that up-front CTRT could be an effective alternative treatment option to PLE. The purpose of this study was to compare the outcomes of patients with cervical esophageal cancer treated with these two methods.
Methods
Patients with cervical esophageal cancer from 1995 to 2008 were studied. Three main groups were identified: those treated with PLE, those managed with up-front concurrent chemoradiation, and those not suitable for either PLE or chemoradiation but to whom palliative treatment was offered. The demographics, management strategies, and outcomes of these patients were studied and analyzed.
Results
A total of 107 patients were studied: 87 (81.3%) were men, and the median age was 64 years (range 17–92 years). There were 62 patients who underwent PLE as the primary treatment, 21 had up-front chemoradiation, and the others had palliative treatment. In the PLE group, curative resection was achieved in 37 (59.7%) patients, 20 of whom had either adjuvant chemoradiation or radiotherapy. The hospital mortality rate was 7.1%. In the chemoradiation group, 10 (47.6%) had tumor down-staging, 6 of whom achieved a clinically complete response. Among the 11 patients with poor response, 5 required salvage PLE for palliation. Chemoradiation-associated morbidities included oral mucositis, bilateral vocal cord palsy, esophageal stricture, carotid artery blowout, and permanent hypothyroidism and hypoparathyroidism. The median survival durations of patients in the PLE and chemoradiation groups were 20 and 25 months respectively (
P
= 0.39).
Conclusions
Up-front chemoradiation can be an alternative therapeutic strategy to PLE. However, this method is not without drawbacks. A significant proportion also requires salvage surgery. Both PLE and chemoradiation have significant curative as well as palliative role in the management of cervical esophageal cancer and treatment should be individualized.
Frailty and obesity contribute to the adverse clinical outcome of peritoneal dialysis (PD) patients, but the interaction between frailty and obesity remains uncertain.
To examine the interaction ...between frailty and obesity on the clinical outcome of PD patients.
Single centre prospective observational cohort study.
267 prevalent Chinese PD patients were recruited.
Frailty was identified by a standard score. General and central obesity were determined by body mass index (BMI) and waist-hip ratio (WHR), respectively. Body composition was assessed by bioimpedance spectroscopy. All patients were followed for two years. Outcome measures included all-cause as well as cardiovascular mortality and hospitalization.
Of the 267 patients, 120 (44.9%) were frail. Frail individuals were more likely to have central obesity (p < 0.001) but not general obesity. Although WHR did not predict patient survival, there was a significant interaction between WHR and frailty on patient survival and cardiovascular survival (p = 0.002 and p = 0.038, respectively). For patients without frailty, the two-year cardiovascular survival was 91.3% and 74.4% for those with and without central obesity, respectively (p = 0.002). For patients with frailty, however, the two-year cardiovascular survival was 64.6% and 66.7% for those with and without central obesity, respectively (p = 0.6). For patients without frailty, the number of hospital admission for cardiovascular disease over 2 years were 0.12 ± 0.37 and 0.34 ± 0.72 for those with and without central obesity, respectively (p = 0.03). For frail patients, however, the number of hospital admission was similar between those with and without central obesity.
There is a significant interaction between frailty and central obesity on the outcome of PD patients. The protective role of central obesity is only apparent in PD patients without frailty but not the frail ones, and there is a little prognostic value of general (non-central) obesity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionFear of cancer recurrence (FCR) is a prevalent and frequently debilitating response to a cancer diagnosis, affecting a substantial proportion of cancer survivors. Approximately 30% of ...local Hong Kong Chinese cancer survivors in a recent survey reportedly experienced persistent high FCR over the first-year post-surgery. This was associated with lower levels of psychological well-being and quality of life. A manualised intervention (ConquerFear) developed primarily based on the Self-Regulatory Executive Function Model and the Rational Frame Theory, has been found to reduce FCR effectively among Caucasian cancer survivors. The intervention now has been adapted to a Chinese context; ConquerFear-HK. The primary aim of this study is to evaluate its efficacy vs a standard-survivorship-care control (BasicCancerCare) in FCR improvement in a randomised control trial (RCT).Methods and analysisIn this RCT, using the sealed envelope method, 174 eligible Chinese cancer survivors will be randomised to either the ConquerFear-HK or BasicCancerCare intervention. Both interventions include six sessions over 10 weeks, which will be delivered via face to face or online by trained therapists. The ConquerFear-HK intervention incorporates value classification, metacognitive therapy, attentional training, detached mindfulness and psychoeducation; BasicCancerCare includes relaxation training, dietary and physical activity consultations. Participants will be assessed at prior randomisation (baseline; T0), immediately postintervention (T1), 3 months (T2) and 6 months postintervention (T3) on the measures of FCR (Fear of Cancer Recurrence Inventory) as a primary outcome; metacognition (30-item Metacognitions Quesionnaire) and cognitive attentional syndrome (Cognitive-attentional Syndrome Questionnaire) as process outcomes; psychological distress (Hospital Anxiety and Depression Scale), cancer-related distress (Chinese Impact of Events Scale), quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire) and treatment satisfaction are secondary outcomes.Ethics and disseminationEthics approval has been obtained from HKU/HA HKW Institutional Review Board (ref: UW19-183). The patients/participants provide their written informed consent to participate in this study. The study results will be disseminated through international peer-review publications and conference presentations.Trial registration numberNCT04568226.
The peptidyl-proplyl-isomerase, PIN1, upregulates beta-catenin by inhibiting its interaction with APC. beta-catenin accumulation occurs in about 70% of hepatocellular carcinoma (HCC), of which only ...20% are due to beta-catenin mutations. The role of PIN1 in beta-catenin upregulation in HCC was investigated. PIN1 was shown to be overexpressed in more than 50% of HCC. All cases with PIN1 overexpression also showed beta-catenin accumulation, with 68% of cases showing concomitant beta-catenin and cyclin D1 accumulation. PIN1 was shown to contribute to beta-catenin and cyclin D1 overexpression directly by in vitro cell-line transfection experiments. Finally, we showed that PIN1 overexpression and beta-catenin gene mutations appeared to be mutually exclusive events, leading to beta-catenin accumulation in HCC. These results showed that PIN1 overexpression leading to beta-catenin accumulation might be a critical event in hepatocarcinogenesis, and that PIN1 is a potential target for therapeutic intervention in HCC.
This was a cross-sectional study.
The present study aimed to explore the differences in leptin bioavailability between adolescent idiopathic scoliosis (AIS) and healthy age-matched girls in a Chinese ...Han population.
AIS is a common spinal deformity mainly occurring in girls during the peripubertal period. The development of scoliosis is related to relative anterior spinal overgrowth. AIS girls also have associated lower body mass index (BMI) and lower bone mineral status. Leptin, together with soluble leptin receptor (sOB-R), was shown to play an important role in the regulation of bone and energy metabolism in children. It was hypothesized that leptin and sOB-R are abnormal and associated with deranged growth and anthropometric phenotypes in AIS girls.
Serum leptin and sOB-R were measured together with documentation of anthropometric parameters and clinical data in 95 AIS girls and 46 healthy matched controls (age 11-16 years). Serum leptin and sOB-R concentrations were measured by enzyme-linked immunosorbent assay and correlated with the different measured parameters.
AIS girls had significantly lower BMI and longer arm span than healthy controls. AIS girls were found to have significantly higher sOB-R levels and lower free leptin index (FLI) after adjusting for age and body weight in multivariate regression analysis. Significant correlation was found between sOB-R, FLI, and curve severity in AIS girls.
This is the first study demonstrating the presence of abnormal leptin bioavailability in AIS girls that might play an important role in the etiopathogenesis of AIS. Further investigation is required to provide a better understanding of the underlying mechanisms, with the aim to explore the potential clinical application as a biomarker for predicting curve initiation or progression in AIS.
Magnetic resonance (MR) imaging and multiplanar reconstruction was used to evaluate the morphology and relative position of the spinal cord in adolescent idiopathic scoliosis (AIS).
To determine the ...longitudinal and cross-sectional morphology of spinal cord in AIS subjects versus normal controls and their correlation with relative position of cerebellar tonsils and somatosensory cortical evoked potentials (SSEP).
Our previous studies revealed significantly reduced spinal cord to vertebral column length ratios in AIS patients with severe scoliotic curves suggesting the presence of disproportional growth between the neural and skeletal system. A possible neural origin of etiopathogenesis of AIS is suggested.
MR multiplanar reconstruction was performed in 97 adolescent girls (35 moderate, 26 severe AIS with right-sided thoracic/thoracolumbar curve, and 36 age-matched controls). Measurements of the ratio of anteroposterior (AP) and transverse (TS) diameter of the cord, the concave and convex lateral cord space (LCS) were obtained at the apical level in AIS subjects. Same parameters were obtained in normal controls at matched vertebral levels. Correlations were made with cord to vertebral column length ratio, cerebellar tonsil position and SSEP findings.
AP/TS cord ratio and LCS ratio were increased in AIS subjects in the presence of reduced spinal cord to vertebral length ratio when compared with normal controls (P < 0.05). The above ratios were exaggerated in AIS subjects with abnormal SSEP findings. The AP/TS cord ratio and LCS ratio were negatively correlated with the cord to vertebral column length ratio (rho = -0.410 and -0.313, P < 0.01) and cerebellar tonsillar level (rho = -0.309 and -0.432, P < 0.01).
Our study suggests presence of tethering and increased tension along the longitudinal axis of spinal cord with associated morphologic changes of cross-sectional shape and relative position of the cord.
A case-control study comparing bone quality in Adolescent Idiopathic Scoliosis (AIS) with normal controls.
To evaluate bone quality with quantitative ultrasound (QUS) in AIS and normal controls so as ...to detect any derangement in bone quality among AIS subjects.
AIS is characterized by complex spinal deformities. Despite its high prevalence and clinical impact in adolescents, etiology of AIS remains unknown but one possible mechanism is related to derangement of bony mechanical stability, as quantified by bone mineral density (BMD) and bone quality. AIS is known for its association with osteopenia, but little is known about the bone quality in AIS. With technological advancement, QUS can provide objective measurement of bone quality. In this study, we sought to compare bone quality in AIS with normal controls using QUS in addition to the conventional BMD measurement.
Six hundred thirty-five AIS girls and 269 age-matched normal girls were investigated. Broadband ultrasound attenuation (BUA), velocity of sound (VOS), and stiffness index (SI) were measured over the nondominant calcaneus using QUS. The results were correlated with anthropometric measurement, radiologic assessment, and BMD of both hips.
The z-score of BMD at the femoral neck of AIS subjects (-0.47 ± 0.97) was significantly lower than that of normal controls (-0.12 ± 1.01, P < 0.001). Crude comparison showed that BUA, VOS, and SI of AIS group were 3.8% (P < 0.01), 0.5% (P = 0.042), and 6.9% (P < 0.01) lower than controls, respectively. After controlling confounding from maturity, body weight, body height, and BMD with multiple linear regression analysis for both mild (Cobb's angle ≤ 25°) and severe (Cobb's angle > 25°) curves, BUA and SI were found to be statistically significantly lower in AIS as compared with controls (P < 0.05).
In addition to higher prevalence of osteopenia, AIS patients were also found to have deranged bone quality. These might contribute to the etiopathogenesis of spinal deformities in AIS.
A genetic association study to comprehensively investigate variations of melatonin receptor 1B gene polymorphism by a set of tagging single nucleotide polymorphisms (tagSNPs) derived from the ...International Hapmap project.
To determine whether melatonin receptor 1B (MTNR1B) gene polymorphisms are associated with the predisposition and/or disease severity of adolescent idiopathic scoliosis (AIS).
Linkage studies suggested a genetic predisposition for AIS. In addition, evidence showed that AIS might be related to melatonin deficiency and dysfunction of melatonin signaling pathway. Locating in one of the chromosomal regions linked to AIS, MTNR1B gene is a potential candidate gene for AIS.
This study was carried out in 2-stage case-control analysis: 1) initial screening (472 cases and 304 controls) and 2) separate replication test (342 cases and 347 controls) to confirm results in the screening. In the first screening stage, 5 tagSNPs were selected to cover most of the genetic variation in the MTNR1B gene. In the second stage, SNPs showing association in the screening stage were studied in a separate replication sample set to confirm the association. Genotyping was performed by PCR-RFLP.
The first stage showed a putative association between rs4753426 and AIS, which was confirmed in the replication sample set. By meta-analysis, the frequency of C allele of this SNP locating in the promoter was significantly higher in the cases than controls (P = 0.006 aftermeta-analysis). Subjects with the CC genotype had an odds ratio of 1.29 for AIS. Another SNP rs741837 in promoter region, being moderate linkage disequilibrium with rs4753426, was also marginally associated with AIS.
Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene.
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