Background: Chronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population. Methods: We analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis. Results: For CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR?=?1.93, P?=?4.99???10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR?=?1.88, P?=?4.99???10-7). Conclusions: We found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.Trial registrationClinicalTrials.gov NCT00608764, NCT00292552
Chimeric antigen receptors (CARs) are recombinant receptors that combine the specificity of an antigen-specific antibody with the T-cell's activating functions. Initial clinical trials of genetically engineered CAR T cells have significantly raised the profile of T cell therapy, and great efforts have been made to improve this approach. In this review, we provide a structural overview of the development of CAR technology and highlight areas that require further refinement. We also discuss critical issues related to CAR therapy, including the optimization of CAR T cells, the route of administration, CAR toxicity and the blocking of inhibitory molecules.
Background: Hyperoxia triggers the release of toxic reactive oxygen species (ROS). Pomegranate Juice (PJ) is a rich source of potent antioxidants. We assessed the effects of PJ supplementation on Acute Lung Injury (ALI) in adult rats exposed to hyperoxia for 5 days. Methods: Adult rats were divided into four different groups: control, hyperoxia, hyperoxia + PJ and PJ. Animals were placed in chambers containing either room air or oxygen above 95% for a total of 5 days. Two different PJ concentrations were utilized and the control group received placebo water. Animals were euthanized and their lungs were excised. Assessment of lung injury was accomplished by: a) wet to dry ratio (W/D) method, b) measurement of albumin concentration in the bronchoalveolar lavage fluid (BALF), c) oxidative stress, d) histological evaluation of the lung e) apoptosis and f) transcriptional expression levels of the inflammatory mediators IL-1beta, IL-6 and TNF-alpha. Adult rats were divided into; Control, Hyperoxia, Hyperoxia + PJ and PJ. Animals were placed in either room air or oxygen above 95% for a total of 5 days. Results: An increase in the W/D and albumin leak was noted in Hyperoxia (p < 0.05). Those findings were attenuated by the higher dose of PJ supplementation. Hyperoxia increased ROS production. Again PJ significantly reduced oxidative stress. Lung sections showed significant reduction in inflammation, edema, and infiltrating neutrophils in Hyperoxia + 80 mumol/kg when compared with Hyperoxia. TUNEL demonstrated significant apoptosis in the Hyperoxia, which was diminished in the Hyperoxia + 80 mumol/kg. Furthermore, increase in IL-1beta and IL-6 was noted in Hyperoxia. Again, 80 mumol/kg of PJ significantly reduced the expression of inflammatory mediators. Conclusion: In this animal model, PJ supplementation attenuated ALI associated with hyperoxia.
Background: This study aimed to evaluate the prophylactic effect of goshajinkigan (GJG) on paclitaxel (PTX)-induced neuropathy and to elucidate the mechanism of action. Results: There was a time-dependent irreversible decrease in pain threshold in PTX group. In PTX/GJG group, pain threshold showed changes in the same level as control. Electron microscope showed that although the ganglion cells of control and PTX/GJG groups were normal, degeneration of the nucleus and swelling of the mitochondria were observed in PTX group. Expression of transient receptor potential vanilloid 4 (TRPV4) gene in PTX group significantly increased compared with that in control and PTX/GJG groups. In TRPV4 knock-out mice, no PTX-induced hyperalgesia was observed, and there was no significant difference in pain threshold between the 3 groups. Conclusions: These results showed that PTX induced hyperalgesia by enhancing TRPV4 expression, and suggested that GJG might alleviate hyperalgesia by preventing degeneration of the ganglion cells and suppressing TRPV4 expression.
Background: Topiramate is a drug which emerged from its anticonvulsant properties and now over the years is used for a wider range of indications, including migraine prophylaxis. We described a very rare case of topiramate induced acute onset myopia during use for migraine. It is the first reported case of its kind from Sri Lanka with only a handful of reported cases in world literature.Case presentationA 35-year-old Sri Lankan female presented with long standing history of intermittent headache with recent worsening. A diagnosis of migraine was made and due to poor response to other medication was initiated on topiramate. Two weeks later patient developed visual impairment which was finally attributed to topiramate. Following discontinuation of the drug, within 3 days the symptoms started to improve with full recovery in 10 days. Conclusion: All clinicians should be aware of the potential ocular side effects of topiramate. Although relatively rare, prompt recognition is key to appropriate management.
Background: Cancer stem cells (CSCs) have been reported to play an important role in chemoradiation resistance. Although the association of CSC markers with clinicopathological outcomes after neoadjuvant chemoradiotherapy (NACRT) has been reported in various types of cancers, there have been no such reports for pancreatic cancer. Here we examined the sequential changes in CSC marker expressions after NACRT in patients with pancreatic adenocarcinoma (PA) and the impact of these changes on the prognosis. Methods: We used immunohistochemistry to evaluate the expressions of the CSC markers epithelial cell adhesion molecule (EpCAM), CD24, CD44, CD133, CXCR4 and Aldehyde dehydrogenase 1 (ALDH1) in resected specimens obtained from 28 PA patients, and we compared these expressions with the patients' clinicopathological parameters and survival data. Results: The expression frequencies of CD44 and ALDH1 were significantly higher in the NACRT group (n = 17) compared to the non-NACRT group (n = 11), but the CD133 expression was significantly lower in the NACRT group. In the NACRT group, the expression of CD133 was inversely correlated with that of ALDH1, and CD133+/ALDH1- expression was associated with an unfavorable patient outcome. Conclusion: This is the first report showing that NACRT may influence the expression frequencies of CD44, CD133 and ALDH1 in PA patients. Moreover, CD133 and ALDH1 expressions may be useful predictors of prognosis in PA patients who have received NACRT.
Background: Health-related millennium development goals are off track in most of the countries in the sub-Saharan African region. Lack of access to, and low utilization of essential services and high-impact interventions, together with poor quality of health services, may be partially responsible for this lack of progress. We explored whether improvement approaches can be applied to increase utilization of antenatal care (ANC), health facility deliveries, prevention of mother-to-child transmission services and adherence to ANC standards of care in a rural district in Kenya. We targeted improvement of ANC services because ANC is a vital point of entry for most high-impact interventions targeting the pregnant mother. Methods: Healthcare workers in 21 public health facilities in Kwale District, Kenya formed improvement teams that met regularly to examine performance gaps in service delivery, identify root causes of such gaps, then develop and implement change ideas to address the gaps. Data were collected and entered into routine government registers by the teams on a daily basis. Data were abstracted from the government registers monthly to evaluate 20 indicators of care quality for improvement activities. For the purposes of this study, aggregate data for the district were collected from the District Health Management Office. Results: The number of pregnant mothers starting ANC within the first trimester and those completing at least four ANC checkups increased significantly (from 41 (8%) to 118 (24%) p=0.002 and from 186 (37%) to 316 (64%) p<0.001, respectively). The proportions of ANC visits in which provision of care adhered to the required standards increased from <40% to 80-100% within three to six months (X2 for trend 4.07, p<0.001). There was also a significant increase in the number of pregnant women delivering in health facilities each month from 164 (33%) to 259 (52%) (p=0.012). Conclusion: Improvement approaches can be applied in rural health care facilities in low-income settings to increase utilization of services and adherence to standards of care. Using the quality improvement methodology to target integrated health services feasible. Longer follow-up periods are needed to gather more evidence on the sustainability of quality improvement initiatives in low-income countries.
Background: Adhesion and migration are relevant physiological functions that must be regulated by the cell under both normal and pathological conditions. The dioxin receptor (AhR) has emerged as a transcription factor regulating both processes in mesenchymal, epithelial and endothelial cells. Indirect results suggest that AhR could cooperate not only with additional transcription factors but also with membrane-associated proteins to drive such processes. Results: In this study, we have used immortalized and primary dermal fibroblasts from wild type (AhR+/+) and AhR-null (AhR?/?) mice to show that AhR modulates membrane distribution and mobilization of caveolin-1 (Cav-1) during directional cell migration. AhR co-immunoprecipitated with Cav-1 and a fraction of both proteins co-localized to detergent-resistant membrane microdomains (DRM). Consistent with a role of AhR in the process, AhR?/?cells had a significant reduction in Cav-1 in DRMs. Moreover, high cell density reduced AhR nuclear levels and moved Cav-1 from DRMs to the soluble membrane in AhR+/+but not in AhR?/?cells. Tyrosine-14 phosphorylation had a complex role in the mechanism since its upregulation reduced Cav-1 in DRMs in both AhR+/+and AhR?/?cells, despite the lower basal levels of Y14-Cav-1 in the null cells. Fluorescence recovery after photobleaching revealed that AhR knock-down blocked Cav-1 transport to the plasma membrane, a deficit possibly influencing its depleted levels in DRMs. Membrane distribution of Cav-1 in AhR-null fibroblasts correlated with higher levels of cholesterol and with disrupted membrane microdomains, whereas addition of exogenous cholesterol changed the Cav-1 distribution of AhR+/+cells to the null phenotype. Consistently, higher cholesterol levels enhanced caveolae-dependent endocytosis in AhR-null cells. Conclusions: These results suggest that AhR modulates Cav-1 distribution in migrating cells through the control of cholesterol-enriched membrane microdomains. Our study also supports the likely possibility of membrane-related, transcription factor independent, functions of AhR.
Two haloalkane dehalogenases, LinBUT and LinBMI, each with 296 amino acid residues, exhibit only seven amino acid residue differences between them, but LinBMI’s catalytic performance towards β-hexachlorocyclohexane (β-HCH) is considerably higher than LinBUT’s. To elucidate the molecular basis governing this difference, intermediate mutants between LinBUT and LinBMI were constructed and kinetically characterized. The activities of LinBUT-based mutants gradually increased by cumulative mutations into LinBUT, and the effects of the individual amino acid substitutions depended on combination with other mutations. These results indicated that LinBUT’s β-HCH degradation activity can be enhanced in a stepwise manner by the accumulation of point mutations.
Background: We examined the effects of the unilateral cortical stimulation on the survival of neurons showing degenerative changes and compared those in delaying the progression of amyotrophic lateral sclerosis (ALS) between the unilateral cortical stimulation and the bilateral one in an animal experimental model using mice. Methods: We used 19 G93A transgenic mice and randomly divided into three groups: the control group (n = 6) (the implantation of electrodes in the bilateral motor cortex without electrical stimulation), the unilateral stimulation group (n = 7) (the implantation of electrodes in the unilateral motor cortex with a 24-hour cortical stimulation) and the bilateral stimulation group (n = 6) (the implantation of electrodes in the bilateral motor cortex with a 24-hour cortical stimulation). Results: The mean survival period was significantly longer in the bilateral stimulation group as compared with the control group (124.33 +/- 11.00 days vs. 109.50 +/- 10.41 days) (P < 0.05). In addition, on postoperative weeks 11, 12, 13, 14 and 15, the mean Rota-rod score was significantly higher in the unilateral stimulation group as compared with the control group (P < 0.05). Furthermore, despite a lack of statistical significance, it was the lowest in the bilateral stimulation group on postoperative weeks 13, 14, 15 and 17. On postoperative weeks 11, 12, 13, 14 and 16, the mean score of paw-grip endurance was significantly higher in the unilateral stimulation group as compared with the control group (P < 0.05). Furthermore, despite a lack of statistical significance, it was the lowest in the bilateral stimulation group on postoperative weeks 13, 14, 15 and 17. Conclusions: In conclusion, our results indicate that the bilateral epidural cortical stimulation might have a treatment effect in a murine model of ALS. But it is the limitation that we examined a small number of experimental animals. Further studies are therefore warranted to establish our results and to identify the optimal parameters of the epidural cortical stimulation in a larger number of experimental animals.