The Hedgehog (Hh) genes play a key role in the regulation of embryonic development and govern processes such as cell differentiation, cell proliferation, and tissue patterning. In vertebrate embryos, Hh gene expression regulates correct formation of limbs, skeleton, muscles, and organs including stomach. In the adult, the Hh pathway functions in tissue repair and regeneration, along with maintenance of stem cells. Sonic Hedgehog (Shh) signaling has been extensively studied for its role in developmental and cancer biology. Recent advances in the field of gastroenterology show that in the stomach, Shh is responsible for proper differentiation of the gastric glands. The aberrant activity of the Shh signaling pathway leads to an altered gastric differentiation program and loss of gastric acid secretion that is the predominant function of the stomach. In this chapter, we review the most recent findings that reveal the role of Shh as a regulator of gastric function and differentiation and how this signaling is dysregulated during the development of gastric cancer in response bacterial infection.
The anti-inflammatory activity of the essential oil from C. longepaniculatum was evaluated by three experimental models including the dimethyl benzene-induced ear edema in mice, the carrageenan-induced paw edema in rat and the acetic acid-induced vascular permeability in mice. The influence of the essential oil on histological changes and prostaglandin E2 (PGE2), histamine and 5-hydroxytryptamine (5-HT) production associated with carrageenan-induced rat paw edema was also investigated. The essential oil (0.5, 0.25, 0.13 ml/kg b.w.) showed significantly inhibition of inflammation along with a dose-dependent manner in the three experimental models. The anti-inflammatory activity of essential oil was occurred both in early and late phase and peaked at 4 h after carrageenan injection. The essential oil resulted in a dose dependent reduction of the paw thickness, connective tissue injury and the infiltration of inflammatory cell. The essential oil also significantly reduced the production of PGE2, histamine and 5-HT in the exudates of edema paw induced by carrageenan. Both the essential oil and indomethacin resulted relative lower percentage inhibition of histamine and 5-HT than that of PGE2 at 4 h after carrageenan injection.
Cinnamomum longepaniculatum; essential oil; anti-inflammatory activity
The optimal timing of stabilization in patients with traumatic thoracolumbar fractures remains controversial. There is currently a lack of consensus on the timing of surgical stabilization, which is limited by the reality that a randomized controlled trial to evaluate early versus late stabilization is difficult to perform. Therefore, the objective of this study was to determine the benefits, safety and costs of early stabilization compared with late stabilization using data available in the current literature.
An electronic literature search was performed in Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for relevant studies evaluating the timing of surgery in patients with thoracolumbar fractures. Two reviewers independently analyzed and selected each study on the basis of the eligibility criteria. The quality of the included studies was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE). Any disagreements were resolved by consensus.
Ten studies involving 2,512 subjects were identified. These studies demonstrated that early stabilization shortened the hospital length of stay, intensive care unit length of stay, ventilator days and reduced morbidity and hospital expenses for patients with thoracic fractures. However, reduced morbidity and hospital expenses were not observed with stabilization of lumbar fractures. Owing to the very low level of evidence, no conclusion could be made regarding the effect of early stabilization on mortality.
We could adhere to the recommendation that patients with traumatic thoracolumbar fractures should undergo early stabilization, which may reduce the hospital length of stay, intensive care unit length of stay, ventilator days, morbidity and hospital expenses, particularly when the thoracic spine is involved. Individual patient characteristics should be concerned carefully. However, the definite conclusion cannot be made due to the heterogeneity of the included studies and low level of evidence. Further prospective studies are required to confirm whether there are benefits to early stabilization compared with late stabilization.
Thoracolumbar; Fracture; Spine; Timing of surgery; Systematic review
To investigate the effect of γ-terpineol on cell proliferation and apoptosis of human hepatoma BEL-7402 cells to elucidate its molecular mechanism. Here, BEL-7402 cells were treated with various concentrations (40, 80, 160, 320 and 640 μg/ml) of γ-terpineol for 48 h, cell proliferation was determined by 3-(4,5-dimethyl-thiazolyl-2)-2,5-diphenyl tetrazolium bromides (MTT) assay. Cell colony inhibition was determined by soft agar assay. Apoptosis and possible molecular mechanisms were evaluated by morphological observation, flow cytometry analysis, and DNA fragmentation assay. The γ-terpineol significantly suppressed BEL-7402 cell proliferation in a dose-dependent manner. Characteristic morphological and biochemical changes associated with apoptosis such as cells shrinkage, deformation and vacuolization of mitochondria, nuclear chromatin condensation and fragmentation, formation of apoptotic bodies were observed after BEL-7402 cells treated with γ-terpineol for 24 h and 48 h. Cell cycle were displayed by flow cytometry analysis, the γ-terpineol treatment resulted in accumulation of cells at G1 or S phase and a blockade of cell proliferation compared to control group. Treating BEL-7402 cells with 320 μg/ml of γ-terpineol for 36 h and 48 h, a typical apoptotic “DNA ladder” was observed using DNA fragmentation assay. The present study demonstrated that possible anti-cancer mechanism of γ-terpineol on human hematomas cells is through inducing cell apoptosis to suppress tumor cell growth.
γ-terpineol; human hepatoma; BEL-7402; cell proliferation; apoptosis
Neoadjuvant chemoradiotherapy (nCRT) combined with surgery has been implemented as a standard treatment strategy in locally advanced rectal cancer (LARC). However, there is a wide spectrum of response to nCRT. The aim of this study was to determine whether enhancer of zeste homologue 2 (EZH2 ) expression could predict response to nCRT and outcomes for patients in LARC.
The study examined the EZH2 expression in 112 biopsies by immohistochemistry. The associations between EZH2 and clinical characters were analyzed.
EZH2 expression in biopsy tissue was significantly related to increased tumor cell proliferation, as assessed by Ki-67 expression with a cutoff value of 37% (p <0.001). High EZH2 expression was correlated closely with low differentiation (p = 0.029), high CEA level (p = 0.041), T4 status (p = 0.011) and node metastasis (p =0.045). By univariate and multivariate analysis, we observed low EZH2 expression could reliably and independently predict the good response to nCRT ( p = 0.026 and p = 0.023) and down-staging ( p = 0.021 and p = 0.027). In univariate analysis, high EZH2 expression was significantly associated with poor 5-year disease-free survival (p = 0.025) and 5-year overall survival (p = 0.032). In multivariate analysis, EZH2 was a prognostic factor for 5-year DFS (HR = 2.287; 95% CI 1.137-4.602, p = 0.020) but not for 5-year OS (HR = 2.182; 95% CI 0.940-5.364, p = 0.069).
Our study revealed that low EZH2 expression in biopsy tissue might be a useful predictive factor of good tumor response to nCRT and longer 5-year DFS in patients with LARC. However this is a relatively small retrospective study, to further validate the role of EZH2 in rectal cancer, large consistent cohort studies are needed.
Rectal cancer; EZH2; Neoadjuvant chemoradiotherapy; Tumor response; Prognosis
The detection of γ-glutamyl transferase (GGT) has previously been reported to be useful in the diagnosis in hepatocellular carcinoma (HCC). The aim of the present study was to investigate the baseline serum GGT levels in patients with intermediate HCC (Barcelona Clinic Liver Cancer stage B) following treatment with transcatheter arterial chemoembolization (TACE) combined with three-dimensional conformal radiotherapy (3DCRT). A total of 154 intermediate HCC patients with Child-Pugh grade A were retrospectively investigated. Receiver operating characteristic (ROC) analysis was used to determine the optimal threshold for the GGT serum levels, and univariate and multivariate analyses were used to establish the prognostic factors. The median overall survival (OS) time was 24.3 months. The optimal threshold for GGT was 85 U/L (sensitivity, 75.13%; specificity, 69.81%; and area under the ROC curve, 0.763). The one-, three- and five-year OS rates were 79.9, 49.7 and 17.2%, respectively, for patients with low GGT levels (≤85 U/l) and 52.3, 22.1 and 8.5%, respectively, for patients with high GGT levels (>85 U/l) (P=0.007). The results indicated that the serum GGT level was an independent prognostic factor (hazard ratio=2.32; P=0.007) for OS. Furthermore, in subgroups stratified according to serum α-fetoprotein, gross tumor volume and radiation dose, serum GGT was also found to correlate with OS (P<0.05). Therefore, the baseline GGT level may be a significant prognostic factor for intermediate HCC patients with Child-Pugh grade A following TACE combined with 3DCRT.
prognostic value; serum γ-glutamyl transferase; hepatocellular carcinoma; transcatheter arterial chemoembolization; embolization; three-dimensional conformal radiotherapy
Physical exercise has been proved to be neuroprotective in clinical trials and animal experiments. However, the exact mechanism underlying this neuroprotective effect remains unclear. The aim of the present study was to explore whether pre-ischemic treadmill training could act as a form of ischemic preconditioning in a rat following ischemic stroke by reducing oxidative damage. Fifty-four rats were randomly divided into three groups (n=18 per group): Sham surgery, middle cerebral artery occlusion (MCAO) without exercise and MCAO with exercise. Subsequent to treadmill training, ischemic stroke was induced by occluding the MCA for 1.5 h, followed by reperfusion. Six rats in each group were evaluated for neurological deficits and then sacrificed by decapitation to calculate the infarct volume. The remaining rats in each group were sacrificed to detect the level of superoxide dismutase (SOD) activity (n=6) and malondialdehyde (MDA) concentration (n=6). The results indicated that pre-ischemic exercise training reduced brain infarct volume and neurological deficits, increased SOD activity and decreased the concentration of MDA following ischemic stroke. In conclusion, treadmill exercise training prior to MCAO/reperfusion increased the antioxidant ability and decreased the oxidative damage in the brain subsequent to ischemic stroke.
pre-ischemic exercise; oxidative damage; ischemic stroke; malondialdehyde; superoxide dismutase
Single Nucleotide Polymorphisms (SNPs) between microarray probes and RNA targets can affect the performance of expression array by weakening the hybridization. In this paper, we examined the effect of the SNPs on Affymetrix GeneChip probe set summaries and the expression quantitative trait loci (eQTL) mapping results in two eQTL datasets, one from mouse and one from human. We showed that removing SNP-containing probes significantly changed the probe set summaries and the more SNP-containing probes we removed the greater the change. Comparison of the eQTL mapping results between with and without SNP-containing probes showed that less than 70% of the significant eQTL peaks were concordant regardless of the significance threshold. These results indicate that SNPs do affect both probe set summaries and eQTLs (both cis and trans), thus SNP-containing probes should be filtered out to improve the performance of eQTL mapping.
microarray; SNP; eQTL; cis-eQTL; trans-eQTL; mouse; human
Rationale: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete.
Objectives: To identify genetic risk variants for ARDS using large scale genotyping.
Methods: A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n = 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P < 5 × 10−4 for replication in stage II, a trauma case–control population (n = 778). SNPs replicating their association in stage II (P < 0.005) were tested in a stage III nested case–control population of mixed subjects in the intensive care unit (n = 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDS-associated genotype and plasma protein levels.
Measurements and Main Results: A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P < 0.004) and III (P < 0.02), and was robust to clinical adjustment (combined odds ratio = 0.81; P = 4.2 × 10−5). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN.
Conclusions: The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk.
functional genetic polymorphism; acute lung injury; acute respiratory distress syndrome; IL-1 receptor antagonist; replication
Increasing cases of diabetes, a general lack of routinely operational prevention, and a long history of separating disease prevention and treatment call for immediate engagement of frontier clinicians. This applies especially to village doctors who work in rural China where the majority of the nation’s vast population lives.
This study aims to develop and test an online Smart Web Aid for Preventing Type 2 Diabetes (SWAP-DM2) capable of addressing major barriers to applying proven interventions and integrating diabetes prevention into routine medical care.
Development of SWAP-DM2 used evolutionary prototyping. The design of the initial system was followed by refinement cycles featuring dynamic interaction between development of practical and effective standardized operation procedures (SOPs) for diabetes prevention and Web-based assistance for implementing the SOPs. The resulting SOPs incorporated proven diabetes prevention practices in a synergetic way. SWAP-DM2 provided support to village doctors ranging from simple educational webpages and record maintenance to relatively sophisticated risk scoring and personalized counseling. Evaluation of SWAP-DM2 used data collected at baseline and 6-month follow-up assessment: (1) audio recordings of service encounters; (2) structured exit surveys of patients’ knowledge, self-efficacy, and satisfaction; (3) measurement of fasting glucose, body mass index, and blood pressure; and (4) qualitative interviews with doctors and patients. Data analysis included (1) descriptive statistics of patients who received SWAP-DM2–assisted prevention and those newly diagnosed with prediabetes and diabetes; (2) comparison of the variables assessed between baseline and follow-up assessment; and (3) narratives of qualitative data.
The 17 participating village doctors identified 2219 patients with elevated diabetes risk. Of these, 84.85% (1885/2219) consented to a fasting glucose test with 1022 new prediabetes and 113 new diabetes diagnoses made within 6 months. The prediabetic patients showed substantial improvement from baseline to 6-month follow-up in vegetable intake (17.0%, 43/253 vs 88.7%, 205/231), calorie intake (1.6%, 4/253 vs 71.4%, 165/231), leisure-time exercises (6.3%, 16/253 vs 21.2%, 49/231), body weight (mean 62.12 kg, SD 9.85 vs mean 58.33 kg, SD 9.18), and body mass index (mean 24.80 kg/m2, SD 3.21 vs mean 23.36 kg/m2, SD 2.95). The prediabetic patients showed improvement in self-efficacy for modifying diet (mean 5.31, SD 2.81 vs mean 8.53, SD 2.25), increasing physical activities (mean 4.52, SD 3.35 vs mean 8.06, SD 2.38), engaging relatives (mean 3.93, SD 3.54 vs mean 6.93, SD 2.67), and knowledge about diabetes and risks of an imbalanced diet and inadequate physical activity. Most participating doctors and patients viewed SWAP-DM2 as useful and effective.
SWAP-DM2 is helpful to village doctors, acceptable to patients, and effective in modifying immediate determinants of diabetes at least in the short term, and may provide a useful solution to the general lack of participation in diabetes prevention by frontier clinicians in rural China.
International Standard Randomized Controlled Trial Number (ISRCTN): 66772711; http://www.controlled-trials.com/ISRCTN66772711 (Archived by WebCite at http://www.webcitation.org/6OMkAqyEy).
diabetes mellitus; prediabetic state; Internet; prevention; evaluation; eHealth
To identify the independent risk factors, based on available evidence in the literature, for patients developing surgical site infections (SSI) after spinal surgery.
Non-interventional studies evaluating the independent risk factors for patients developing SSI following spinal surgery were searched in Medline, Embase, Sciencedirect and OVID. The quality of the included studies was assessed by a modified quality assessment tool that had been previously designed for observational studies. The effects of studies were combined with the study quality score using a best-evidence synthesis model.
Thirty-six observational studies involving 2,439 patients with SSI after spinal surgery were identified. The included studies covered a wide range of indications and surgical procedures. These articles were published between 1998 and 2012. According to the quality assessment criteria for included studies, 15 studies were deemed to be high-quality studies, 5 were moderate-quality studies, and 16 were low-quality studies. A total of 46 independent factors were evaluated for risk of SSI. There was strong evidence for six factors, including obesity/BMI, longer operation times, diabetes, smoking, history of previous SSI and type of surgical procedure. We also identified 8 moderate-evidence, 31 limited-evidence and 1 conflicting-evidence factors.
Although there is no conclusive evidence for why postoperative SSI occurs, these data provide evidence to guide clinicians in admitting patients who will have spinal operations and to choose an optimal prophylactic strategy. Further research is still required to evaluate the effects of these above risk factors.
Surgical site infection; Spinal surgery; Postoperative infection; Risk factors; Systematic review
The analysis was designed to compare dosimetric parameters among 3-D conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) and RapidArc (RA) to identify which can achieve the lowest risk of radiation-induced liver disease (RILD) for hepatocellular carcinoma (HCC).
Twenty patients with HCC were enrolled in this study. Dosimetric values for 3DCRT, IMRT, and RA were calculated for total dose of 50 Gy/25f. The percentage of the normal liver volume receiving >40, >30, >20, >10, and >5 Gy (V40, V30, V20, V10 and V5) were evaluated to determine liver toxicity. V5, V10, V20, V30 and Dmean of liver were compared as predicting parameters for RILD. Other parameters included the conformal index (CI), homogeneity index (HI), and hot spot (V110%) for the planned target volume (PTV) as well as the monitor units (MUs) for plan efficiency, the mean dose (Dmean) for the organs at risk (OARs) and the maximal dose at 1% volume (D1%) for the spinal cord.
The Dmean of IMRT was higher than 3DCRT (p = 0.045). For V5, there was a significant difference: RA > IMRT >3DCRT (p <0.05). 3DCRT had a lower V10 and higher V20, V30 values for liver than RA (p <0.05). RA and IMRT achieved significantly better CI and lower V110% values than 3DCRT (p <0.05). RA had better HI, lower MUs and shorter delivery time than 3DCRT or IMRT (p <0.05).
For right lobe tumors, RapidArc may have the lowest risk of RILD with the lowest V20 and V30 compared with 3DCRT or IMRT. For diameters of tumors >8 cm in our study, the value of Dmean for 3DCRT was lower than IMRT or RapidArc. This may indicate that 3DCRT is more suitable for larger tumors.
Hepatocellular carcinoma; Radiotherapy; Dosimetry; Radiation-induced liver disease; Liver protection
We report surgical treatment and radiotherapy of an extremely rare case of malignant epidermoid cyst located in cerebellopontine angle. MRI and CT demonstrated the lesion with partial enhancement and calcification. During operation, we found the tumor attached tightly to surrounding tissue. Finally we achieved near total resection of it. Histopathology confirmed the diagnosis of epidermoid cyst with malignant transformation. With adjuvant radiotherapy, the patient underwent excellent recovery, and follow-up MRI demonstrated no obvious residue or recurrence of the tumor. Malignant epidermoid cyst can be diagnosed radiologically in combination with clinical presentation. Maximal removal plus adjuvant radiotherapy is the treatment of choice, although the general prognosis of it is poor.
Intracranial epidermoid cyst (IEC); malignant epidermoid cyst (MEC); surgical treatment; intensity-modulated radiotherapy (IMRT)
Although cystitis glandularis (CG) is a common benign urinary bladder epithelial abnormality, it remains unclear whether CG is a premalignant lesion. Cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) overexpression has recently been reported as a potential tumor initiator or promoter. We evaluated and compared COX-2 and Bcl-2 expression in CG, chronic cystitis (CC), and primary vesicle adenocarcinoma (ADC) tissues.
We conducted a retrospective study to investigate COX-2 and Bcl-2 levels in CG and ADC. We obtained tissue samples from 75 patients (including 11 cases of CC, 30 typical cases of CG (CGTP), 30 cases of intestinal CG (CGIT), and 4 cases of ADC) between 1989 and 2009 from the Surgical Pathology Archives of the No. 2 People’s Hospital of Zhenjiang, affiliated with Jiangsu University. COX-2 and Bcl-2 immunohistochemical staining was performed on all tissues. Nine normal bladder epithelial specimens were evaluated as control samples. Correlations between COX-2 and Bcl-2 expression in CG were also analyzed.
COX-2 and Bcl-2 expression was higher in the ADC group compared to other groups (p < 0.05). COX-2 and Bcl-2 levels were higher in the CGIT group compared to the CGTP group (p = 0.000 for both). The CGIT and CGTP groups both showed higher COX-2 expression compared to the CC group (p = 0.000 for both). There was no difference in Bcl-2 expression between the CGTP and CC groups (p = 0.452). Additionally, the difference in COX-2 and Bcl-2 expression between the control and CC groups was also insignificant (p = 0.668 and p = 0.097, respectively). Finally, we found that COX-2 and Bcl-2 levels were positively related (r = 0.648, p = 0.000).
COX-2 and Bcl-2 overexpression in the CG group suggests that CG, particularly the intestinal type, may be a premalignant lesion that converts into a tumor in the presence of carcinogens.
Cyclooxygenase-2; Bcl-2; Cystitis
Despite the high incidence and the economic impact of the common cold, there are still no effective therapeutic options available. Although traditional Chinese medicine (TCM) is widely used in China to treat the common cold, there is still a lack of high-quality clinical trials. This article sets forth the protocol for a high-quality trial of a new TCM drug, Baoji Tablets, which is designed to treat the common cold with summer-heat and dampness syndrome (CCSDS). The trial is evaluating both the efficacy and safety of Baoji Tablets.
This study is designed as a multicenter, phase II, parallel-group, double-blind, double-dummy, randomized and placebo-controlled trial. A total of 288 patients will be recruited from four centers. The new tablets group are administered Baoji Tablets 0.9 g and dummy Baoji Pills 3.7 g. The old pills group are administered dummy Baoji Tablets 0.9 g and Baoji Pills 3.7 g. The placebo control group are administered dummy Baoji Tablets 0.9 g and dummy Baoji Pills 3.7 g. All drugs are taken three times daily for 3 days. The primary outcome is the duration of all symptoms. Secondary outcomes include the duration of primary and secondary symptoms, changes in primary and secondary symptom scores and cumulative symptom score at day 4, as well as an evaluation of treatment efficacy.
This is the first multicenter, double-blind, double-dummy, randomized and placebo-controlled trial designated to treat CCSDS in an adult population from China. It will establish the basis for a scientific and objective assessment of the efficacy and safety of Baoji Tablets for treating CCSDS, and provide evidence for a phase III clinical trial.
This study is registered with the Chinese Clinical Trial Registry. The registration number is ChiCTR-TRC-13003197.
Common cold; Summer-heat and dampness syndrome; Baoji Tablets; Traditional Chinese medicine; Randomized controlled trial
There is a debate regarding the choice of operative intervention in humeral shaft fractures that require surgical intervention. The choices for operative interventions include intramedullary nailing (IMN) and dynamic compression plate (DCP). This meta-analysis was performed to compare fracture union, functional outcomes, and complication rates in patients treated with IMN or DCP for humeral shaft fractures and to develop GRADE (Grading of Recommendations, Assessment, Development, and Evaluation)-based recommendations for using the procedures to treat humeral shaft fractures. A systematic search of all the studies published through December 2012 was conducted using the Medline, Embase, Sciencedirect, OVID and Cochrane Central databases. The randomized controlled trials (RCTs) and quasi-RCTs that compared IMN with DCP in treating adult patients with humeral shaft fractures and provided data regarding the safety and clinical effects were identified. The demographic characteristics, adverse events and clinical outcomes were manually extracted from all of the selected studies. Ten studies that included a total of 448 patients met the inclusion criteria. The results of a meta-analysis indicated that both IMN and DCP can achieve similar fracture union with a similar incidence of radial nerve injury and infection. IMN was associated with an increased risk of shoulder impingement, more restriction of shoulder movement, an increased risk of intraoperative fracture comminution, a higher incidence of implant failure, and an increased risk of re-operation. The overall GRADE system evidence quality was very low, which reduces our confidence in the recommendations of this system. DCP may be superior to IMN in the treatment of humeral shaft fractures. Because of the low quality evidence currently available, high-quality RCTs are required.
Antibiotics are often given for inflammatory bowel disease (IBD) exacerbations, but their use among pediatric inpatients has not been assessed. We aimed to validate administrative data for identifying hospitalizations for IBD exacerbation and to characterize antibiotic use for IBD exacerbations across children's hospitals.
To validate administrative data for identifying IBD exacerbation, we reviewed charts of 409 patients with IBD at 3 US tertiary care children's hospitals. Using the case definition with optimal test characteristics, we identified 3450 children with 5063 hospitalizations for IBD exacerbation at 36 children's hospitals between January 1, 2007 and December 31, 2009, excluding those with diagnosis codes for specific bacterial infections. We estimated predicted and expected hospital-specific antibiotic utilization rates using mixed-effects logistic regression, adjusting for patient- and hospital-level factors.
Administrative codes for receipt of intravenous steroids or endoscopy provided 79% positive predictive value and 71% sensitivity for identifying hospitalizations for IBD exacerbation. Antibiotics were administered for ≥2 of the first 3 hospital days during 40.7% of IBD exacerbations in US children's hospitals; however, the proportion of patients receiving antibiotics varied significantly across hospitals from 27% to 71% (P < .001), despite adjustment for several patient- and hospital-level variables. Among those given antibiotics, the 3 most common regimens were metronidazole alone (26.9%), metronidazole with ciprofloxacin (10.3%), and ampicillin with gentamicin and metronidazole (7.0%).
Significant variability exists in antibiotic use for children hospitalized with IBD exacerbation, which is unexplained by disease severity or hospital volume. Further study should determine the optimal antibiotic therapy for this condition.
Epidemiology; Antibiotics; Variation; Inflammatory Bowel Disease
The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been investigated specifically. The aim of this study was to identify genetic variants contributing to ARDS from pulmonary or extrapulmonary causes.
We conducted a multi-stage genetic association study. We first performed a large-scale genotyping (50K IBC Chip) in 1,717 Caucasian critically ill patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p ≤ 0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n = 765) and pneumonia/pulmonary sepsis (Population II; n = 838), as causes for ARDS/ALI. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n = 224, Stage III).
In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p < 0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p < 0.007, Stage II; p < 0.05, Stage III). Meta-analysis confirmed these associations.
Different genetic variants may influence ARDS susceptibility depending on direct vs indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI, respectively.
acute respiratory distress syndrome; acute lung injury; pulmonary/extrapulmonary injury; single-nucleotide polymorphism; genetic susceptibility profile; large scale genomic association study; replication
Familial transmission of stroke and myocardial infarction (MI) is partially mediated by transmission of cerebrovascular and cardiovascular risk factors. We examined relationships between family risk of stroke and MI with risk factors for these phenotypes.
Cross-sectional association between the stratified log-rank family score (SLFS) for stroke and MI with prevalent risk factors was assessed in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.
Individuals in the 4th quartile of SLFS scores for stroke were more likely to have prevalent risk factors including hypertension (OR: 1.43; 95% CI: [1.30, 1.58]), left ventricular hypertrophy (OR 1.42; 95% CI: [1.16, 1.42]), diabetes (OR: 1.26; 95% CI: [1.12, 1.43]) and atrial fibrillation (OR 1.23; 95% CI: [1.03, 1.45]) compared to individuals in the 1st quartile. Likewise, individuals in the 4th quartile of SLFS scores for MI were more likely to have prevalent risk factors including hypertension (OR 1.57; 95% CI: [1.27, 1.94]) and diabetes (OR 1.29; 95% CI: [1.12, 1.43]) than the 1st quartile. In contrast to stroke, the family risk score for MI was associated with dyslipidemia (OR 1.38; 95% CI: [1.23, 1.55]) and overweight/obesity (OR 1.22; 95% CI: [1.10, 1.37]).
Family risk of stroke and MI are strongly associated with the majority of risk factors associated with each disease. Family history and genetic studies separating nonspecific contributions of intermediate phenotypes from specific contributions to the disease phenotype may lead to more thorough understanding of transmission for these complex disorders.
stroke; myocardial infarction; cohort studies; family risk; REGARDS
To determine whether childhood antianaerobic antibiotic exposure is associated with the development of inflammatory bowel disease (IBD).
This retrospective cohort study employed data from 464 UK ambulatory practices participating in The Health Improvement Network. All children with ≥2 years of follow-up from 1994 to 2009 were followed between practice enrollment and IBD development, practice deregistration, 19 years of age, or death; those with previous IBD were excluded. All antibiotic prescriptions were captured. Antianaerobic antibiotic agents were defined as penicillin, amoxicillin, ampicillin, penicillin/β-lactamase inhibitor combinations, tetracyclines, clindamycin, metronidazole, cefoxitin, carbapenems, and oral vancomycin.
A total of 1 072 426 subjects contributed 6.6 million person-years of follow-up; 748 developed IBD. IBD incidence rates among antianaerobic antibiotic unexposed and exposed subjects were 0.83 and 1.52/10 000 person-years, respectively, for an 84% relative risk increase. Exposure throughout childhood was associated with developing IBD, but this relationship decreased with increasing age at exposure. Exposure before 1 year of age had an adjusted hazard ratio of 5.51 (95% confidence interval [CI]: 1.66–18.28) but decreased to 2.62 (95% CI: 1.61–4.25) and 1.57 (95% CI: 1.35–1.84) by 5 and 15 years, respectively. Each antibiotic course increased the IBD hazard by 6% (4%–8%). A dose-response effect existed, with receipt of >2 antibiotic courses more highly associated with IBD development than receipt of 1 to 2 courses, with adjusted hazard ratios of 4.77 (95% CI: 2.13–10.68) versus 3.33 (95% CI: 1.69–6.58).
Childhood antianaerobic antibiotic exposure is associated with IBD development.
antimicrobials; epidemiology; inflammatory bowel disease; pediatric; population-based studies
Multiple SDAVFs are quite rare. We present two cases with double synchronous shunts and both were treated during one-stage interventional or surgical procedure. Unique images of the multiple SDAVFs as a PMAVF-like fistula were obtained. These interesting findings suggest the presence of multiple fistulas must be considered in patients being evaluated for SDAVF. A multidisciplinary approach to the management of multiple SDAVFs should depend on the anatomic location and angioarchitecture.
Multiple spinal dural arteriovenous fistulae; perimedullary arteriovenous fistula; multidisciplinary management
Single nucleotide polymorphism (SNP) and copy number variation (CNV) are both widespread characteristic of the human genome, but are often called separately on common genotyping platforms. To capture integrated SNP and CNV information, methods have been developed for calling allelic specific copy numbers or so called copy number polymorphism (CNP), using limited inter-marker correlation. In this paper, we proposed a haplotype-based maximum likelihood method to call CNP, which takes advantage of the valuable multi-locus linkage disequilibrium (LD) information in the population. We also developed a computationally efficient algorithm to estimate haplotype frequencies and optimize individual CNP calls iteratively, even at presence of missing data. Through simulations, we demonstrated our model is more sensitive and accurate in detecting various CNV regions, compared with commonly-used CNV calling methods including PennCNV, another hidden Markov model (HMM) using CNP, a scan statistic, segCNV, and cnvHap. Our method often performs better in the regions with higher LD, in longer CNV regions, and in common CNV than the opposite. We implemented our method on the genotypes of 90 HapMap CEU samples and 23 patients with acute lung injury (ALI). For each ALI patient the genotyping was performed twice. The CNPs from our method show good consistency and accuracy comparable to others.
CNV; CNP; GWAS; haplotype; joint SNP and CNV calling; integrated SNP and CNV
Rationale: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis.
Objectives: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD.
Methods: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis.
Measurements and Main Results: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5′ region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis.
Conclusions: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.
primary graft dysfunction; single-nucleotide polymorphism; long pentraxin 3; lung transplantation
AIM: To explore the protective effect and the relevant mechanisms of Fufang Biejia Ruangan Pills (FFBJRGP) on hepatic fibrosis in vivo and in vitro.
METHODS: Hepatic fibrosis was induced by carbon tetrachloride composite factors. Adult Wistar rats were randomly divided into four groups: normal control group; hepatic fibrosis model group; FFBJRGP-treated group at a daily dose of 0.55 g/kg; and colchicine-treated group at a daily dose of 0.1 g/kg. The effects of FFBJRGP on liver function, serum levels of hyaluronic acid (HA), type IV collagen (CIV), type III procollagen (PC III), laminin (LN), histopathology, and expression of transforming growth factor (TGF-β1) and Smad3 in hepatic fibrosis were evaluated in vivo. The effects of FFBJRGP on survival rate, hydroxyproline content and cell cycle distribution were further detected in vitro.
RESULTS: Compared with the hepatic fibrosis model group, rats treated with FFBJRGP showed a reduction in hepatic collagen deposition and improvement in hepatic lesions. Compared with those of the model group, the activities of alanine aminotransferase (62.0 ± 23.7 U/L) and aspartate aminotransferase (98.8 ± 40.0 U/L) in the FFBJRGP-treated group were decreased (50.02 ± 3.7 U/L and 57.2 ± 30.0 U/L, respectively, P < 0.01). Compared with those in the model group, the levels of PCIII (35.73 ± 17.90 μg/mL), HA (563.82 ± 335.54 ng/mL), LN (89.57 ± 7.59 ng/mL) and CIV (29.20 ± 6.17 ng/mL) were decreased to 30.18 ± 9.41, 456.18 ± 410.83, 85.46 ± 7.51 and 28.02 ± 9.45 ng/mL, respectively. Reverse-transcriptase polymerase chain reaction and Western blotting also revealed that expression of TGF-β1 and Smad3 were down-regulated in vivo. Cell proliferation was inhibited, the level of hydroxyproline was decreased compared with the control group (P < 0.01), and the cell cycle was redistributed when exposed to FFBJRGP in vitro.
CONCLUSION: FFBJRGP inhibits hepatic fibrosis in vivo and in vitro, which is probably associated with downregulation of fibrogenic signal transduction of the TGF-β-Smad pathway.
Fufang Biejia Ruangan Pill; Hepatic fibrosis; Transforming growth factor-Smad signaling
To properly evaluate therapies for cutaneous dermatomyositis (DM), it is essential to administer an outcome instrument that is reliable, valid, and responsive to clinical change, particularly when measuring disease activity.
The purpose of this study is to compare two skin-severity DM outcome measures, the Cutaneous Disease and Activity Severity Index (CDASI) and the Cutaneous Assessment Tool-Binary Method (CAT-BM), with the physician global assessment (PGA) as the ‘gold standard’.
Ten dermatologists evaluated fourteen patients with DM using the CDASI, CAT-BM, and PGA scales. Inter-, intra-rater reliability, validity, responsiveness, and completion time were compared for each outcome instrument. Responsiveness was assessed from a different study population, where one physician evaluated 35 patients with 110 visits.
The CDASI was found to have a higher inter- and intra-rater reliability. Regarding construct validity, both the CDASI and the CAT-BM were significant predictors of the PGA scales. The CDASI had the best responsiveness among the three outcome instruments examined. The CDASI had a statistically longer completion time than the CAT-BM by about 1.5 minutes.
The small patient population may limit the external validity of the findings observed.
The CDASI is a better clinical tool to assess skin severity in DM.
Dermatomyositis; CDASI; CAT-BM; Autoimmune Disease; Outcome Instrument; Reliability; Validity; Responsiveness