Abstract Objectives Classical methods for combining summary data from genome-wide association studies (GWAS) only use marginal genetic effects and power can be compromised in the presence of heterogeneity. We aim to enhance the discovery of novel associated loci in the presence of heterogeneity of genetic effects in sub-groups defined by an environmental factor. Methods We present a p-value Assisted Subset Testing for Associations (pASTA) framework that generalizes the previously proposed as sociation analysis based on sub set s (ASSET) method by incorporating gene-environment (G-E) interactions into the testing procedure. We conduct simulation studies and provide two data examples. Results Simulation studies show that our proposal is more powerful than methods based on marginal associations in the presence of G-E interactions and maintains comparable power even in their absence. Both data examples demonstrate that our method can increase power to detect overall genetic associations and identify novel studies/phenotypes that contribute to the association. Conclusions Our proposed method can be a useful screening tool to identify candidate single nucleotide polymorphisms (SNPs) that are potentially associated with the trait(s) of interest for further validation. It also allows researchers to determine the most probable subset of traits that exhibit genetic associations in addition to the enhancement of power.
Activation of proinflammatory cytokines in seizures has been well characterized. However, role of cytokines in epilepsy and association with different clinical phenotype has not been well investigated. Reports on possible link between proinflammatory molecules and epilepsy are very limited. In this study, we performed a hospital-based case control study to investigate the association of plasma cytokines and their expression with different clinical categories of epilepsy. Patients admitted to Neurology Department of Renmin Hospital were enrolled in this study after clinical investigations. In all, 92 patients with temporal lobe epilepsy (TLE) and 45 with extra-temporal lobe epilepsy (XTLE) were included in this study. Furthermore, we included 86 healthy controls from the similar geographical population. Plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β were quantified by enzyme-linked immunosorbent assay (ELISA). All plasma cytokines were elevated in TLE and XTLE compared to healthy controls ( P < 0.0001). Furthermore, IL-6 and IL-1β were significantly higher in TLE when compared to extra-temporal epilepsy. Incidentally, no difference in mean plasma TNF-α levels was noticed among TLE and XTLE. Positive correlations were observed between all plasma proinflammatory molecules (TNF-α, IL-6, and IL-1β) investigated in this study. Epilepsy patients displayed higher proinflammatory molecules, namely, IL-6, IL-1β, and TNF-α. Plasma IL-6 and IL-1β can be use as biomarkers for differentiation of TLE from XTLE.
To investigate the correlation between initial response to antiepileptic drugs (AEDs) and long-term outcomes after 3 years in patients with newly diagnosed epilepsy.This prospective study included 204 patients with newly diagnosed epilepsy, who were followed-up for at least 36 months. The long-term seizure freedom at 36 months (36MSF) was evaluated in patients with seizure freedom 6 months (6MSF) or 12 months (12MSF) after initial treatment vs those with no seizure freedom after the initial 6 months (6MNSF) or 12 months (12MNSF). Univariate analysis and a multiple logistic regression model were used to analyze the association of potential confounding variables with the initial response to AEDs.The number of patients with 36MSF was significantly higher for patients that had 6MSF (94/131, 71.8%) than those that had 6MNSF [16/73, 21.9%; χ2 = 46.862, p < 0.0001, odd ratio (OR) = 9.051]. The number of patients with 36MSF was significantly higher in patients that had 12MSF (94/118 79.7%) than those that had 12MNSF (19/86, 22.1%; χ2 = 66.720, p < 0.0001, OR = 13.811). The numbers of patients that had 36MSF were not significantly different between patients that experienced 6MSF and 12MSF or between patients that had 6MNSF and 12MNSF. Abnormalities observed in magnetic resonance imaging or computed tomography and the number of seizures before treatment correlated with poor initial 6-month response to AEDs.The initial 6-month response to AEDs is a valuable predictor of long-term response in patients with newly diagnosed epilepsy. The number of seizures before treatment and brain-imaging abnormalities are two prognostic predictors of initial 6-month seizure freedom.
The Scientific Registry of Transplant Recipients (SRTR) system has become a rich resource for understanding the complex mechanisms of graft failure after kidney transplant, a crucial step for allocating organs effectively and implementing appropriate care. As transplant centers that treated patients might strongly confound graft failures, Cox models stratified by centers can eliminate their confounding effects. Also, since recipient age is a proven non-modifiable risk factor, a common practice is to fit models separately by recipient age groups. The moderate sample sizes, relative to the number of covariates, in some age groups may lead to biased maximum stratified partial likelihood estimates and unreliable confidence intervals even when samples still outnumber covariates. To draw reliable inference on a comprehensive list of risk factors measured from both donors and recipients in SRTR, we propose a de-biased lasso approach via quadratic programming for fitting stratified Cox models. We establish asymptotic properties and verify via simulations that our method produces consistent estimates and confidence intervals with nominal coverage probabilities. Accounting for nearly 100 confounders in SRTR, the de-biased method detects that the graft failure hazard nonlinearly increases with donor's age among all recipient age groups, and that organs from older donors more adversely impact the younger recipients. Our method also delineates the associations between graft failure and many risk factors such as recipients' primary diagnoses (e.g. polycystic disease, glomerular disease, and diabetes) and donor-recipient mismatches for human leukocyte antigen loci across recipient age groups. These results may inform the refinement of donor-recipient matching criteria for stakeholders.
<b><i>Objectives:</i></b> Classical methods for combining summary data from genome-wide association studies only use marginal genetic effects, and power can be compromised in the presence of heterogeneity. We aim to enhance the discovery of novel associated loci in the presence of heterogeneity of genetic effects in subgroups defined by an environmental factor. <b><i>Methods:</i></b> We present a <i>p</i>value-assisted subset testing for associations (pASTA) framework that generalizes the previously proposed association analysis based on subsets (ASSET) method by incorporating gene-environment (G-E) interactions into the testing procedure. We conduct simulation studies and provide two data examples. <b><i>Results:</i></b> Simulation studies show that our proposal is more powerful than methods based on marginal associations in the presence of G-E interactions and maintains comparable power even in their absence. Both data examples demonstrate that our method can increase power to detect overall genetic associations and identify novel studies/phenotypes that contribute to the association. <b><i>Conclusions:</i></b> Our proposed method can be a useful screening tool to identify candidate single nucleotide polymorphisms that are potentially associated with the trait(s) of interest for further validation. It also allows researchers to determine the most probable subset of traits that exhibit genetic associations in addition to the enhancement of power.
Objective To assess the role of endoscopic ultrasound guided fine needle aspiration (EUS-FNA)for diagnosis of gastrointestinal tract lesions.Methods Sixty-eight patients underwent endoscopic uhrasonagraphy and EUS-FNA between May 2007 and Dec.2008.The result of cytology and/or pathology was compared with that of surgical finding and follow-up study.Results EUS-FNA was successfully performed on 62 patients with lesiorm in oesophagus(4 eases),stomach(19 case),rectum(19 cases),liver(3 case),mediastinum(4 cases)and lymph node(13 cases),and had a successful rate of 91.18%(62/68).Among them,the lesions in 40 patients(64.52%)were cytologically confirmed.The lesions in 10 out of 22 patients(35.48%)were pathologically confirmed.Compared with the results of pathology and long-term followe-up study,the sensitivity,specificity and positive predictive value of EUSFNA in diagnosis of lesions in gastrointestinal tract was 85.48%,100.00%and 90.91%,respectively,The positive predictive value and negative predictive value was100.00%and 57.14%,respectively.Conclusion EUS-FNA is a safe,effective and accurate method for diagnosis of lesions in gastrointestinal tract,and has an important role in cytological diagnosis.
Key words:
Digestive diseases; Endoscopic ultrasonography; Biopsy,fine needle; Diagnosis
Apoptosis signal-regulating kinase 1 (ASK1) not only causes neuronal programmed cell death via the mitochondrial pathway but also is an essential component of the signalling cascade during microglial activation. We hypothesize that ASK1 selective deletion modulates inflammatory responses in microglia/macrophages(Mi/Mϕ) and attenuates seizure severity and long-term cognitive impairments in an epileptic mouse model.Mi/Mϕ-specific ASK1 conditional knockout (ASK1 cKO) mice were obtained for experiments by mating ASK1flox/flox mice with CX3CR1creER mice with tamoxifen induction. Epileptic seizures were induced by intrahippocampal injection of kainic acid (KA). ASK1 expression and distribution were detected by western blotting and immunofluorescence staining. Seizures were monitored for 24 h per day with video recordings. Cognition, social and stress related activities were assessed with the Y maze test and the three-chamber social novelty preference test. The heterogeneous Mi/Mϕ status and inflammatory profiles were assessed with immunofluorescence staining and real-time polymerase chain reaction (q-PCR). Immunofluorescence staining was used to detect the proportion of Mi/Mϕ in contact with apoptotic neurons, as well as neuronal damage.ASK1 was highly expressed in Mi/Mϕ during the acute phase of epilepsy. Conditional knockout of ASK1 in Mi/Mϕ markedly reduced the frequency of seizures in the acute phase and the frequency of spontaneous recurrent seizures (SRSs) in the chronic phase. In addition, ASK1 conditional knockout mice displayed long-term neurobehavioral improvements during the Y maze test and the three-chamber social novelty preference test. ASK1 selective knockout mitigated neuroinflammation, as evidenced by lower levels of Iba1+/CD16+ proinflammatory Mi/Mϕ. Conditional knockout of ASK1 increased Mi/Mϕ proportion in contact with apoptotic neurons. Neuronal loss was partially restored by ASK1 selective knockout.Conditional knockout of ASK1 in Mi/Mϕ reduced seizure severity, neurobehavioral impairments, and histological damage, at least via inhibiting proinflammatory microglia/macrophages responses. ASK1 in microglia/macrophages is a potential therapeutic target for inflammatory responses in epilepsy.
To help in diagnosis and treatment of adult-onset Mendelian Susceptibility to Mycobacterial Disease (MSMD).We reported a 27-year-old man who had disease onset at 18 years. Then we reviewed previous reports of adult-onset MSMD patients, and summarized their clinical characteristics.The case was diagnosed as MSMD with tyrosine kinase 2 (TYK2) mutation and had dramatic improvement after treatment. In addition to our presented case and through a review of the literature, 12 cases in total were included in our study. Average age of disease onset was 29.4 years. Medium delay of diagnosis was 2.5 years. Four were with IFN-γR1 deficiency, four with IL-12β1 deficiency, two with NEMO deficiency, one with TYK2 deficiency and one with STAT1 deficiency. Common symptoms were lymphadenopathy (6/12, 50.0 %), weight loss (6/12, 50.0 %), bone/joint pain (5/12, 41.7 %), fever (4/12, 33.3 %) and gastrointestinal symptoms (4/12, 33.3 %). Mycobacteria caused infections in lymph nodes (7/12, 58.3 %), bone/joint (5/12, 41.7 %) and skin (5/12, 41.7 %). After treatment, eight (66.7 %) got favorable prognosis, two (16.7 %) died and one (16.7 %) was unknown.Adult-onset MSMD have complex clinical presentations and are difficult to recognize, which results in delayed diagnosis. However, once identified, antibiotics and IFN-γ might have good efficacy. Therefore, when encountering adult patients with recurrent and refractory mycobacterial infections, especially in lymph nodes, bone/joints, and skin, MSMD should be considered.
In contrast to the later stages of follicle development, little is known about the characteristics and mechanisms associated with early folliculogenesis in avian species. The objectives of the present study were to examine and compare the histomorphological and molecular changes of primordial, primary, and secondary follicles from duck and goose ovaries during the first 6 post-hatching week. Morphological analysis showed that the length and width of both duck and goose ovaries increased steadily during weeks 1 to 5 but increased acutely at week 6, whereas a greater increment was observed in the ovarian length of ducks than that of geese during weeks 4 to 5. Furthermore, smaller diameters of the 3 categories of follicles were observed in ducks than those in geese at the first appearance, but they reached a similar size at week 6. More importantly, secondary follicles were found in the ovaries of ducks 1 wk earlier than in those of geese. These results indicated a more rapid growth rate for ovarian follicles in ducks than in geese during early post-hatching development. At the molecular level, it was found that the mRNAs encoding follicle stimulating hormone receptor (FSHR), anti-Müllerian hormone (AMH), B-cell leukemia/lymphoma 2, and cysteine-dependent aspartate specific protease 3 (CASPASE3) were ubiquitously expressed in all ovarian follicles of ducks and geese with different expression profiles in each follicular category during the first 6 post-hatching week. Notably, transcript levels of FSHR, AMH, and CASPASE3 changed differently between ducks and geese during weeks 5 to 6, which was postulated to be one of the mechanisms inducing more rapid growth of ovarian follicles in ducks rather than in geese. In conclusion, our results revealed, for the first time, differences in early folliculogenesis, including the rate of growth of each follicular category and the timing of transition of primary to secondary follicles, between ducks and geese, and these differences could result from different expression profiles of FSHR, AMH, and CASPASE3 during early post-hatching development.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
