Expression and activities of three inducible enzymes in the healing of gastric ulcers in rats

Aim: To explore the roles of nitric oxide synthase (NOS), heme oxygenase (HO) and cyclooxygenase (COX) in gastric ulceration and to investigate the relationships of the expression and activities of these enzymes at different stages of gastric ulceration. Methods: Gastric ulcers (kissing ulcers) were induced by luminal application of acetic acid. Gastric tissue samples were obtained from the ulcer base, ulcer margin, and non-ulcerated area around the ulcer margin at different time intervals after ulcer induction. The mRNA expression and protein levels of inducible and constitutive isoforms of NOS, HO and COX were analyzed with RT-PCR and Western blotting methods. The activities of the total NOS, inducible NOS (iNOS), HO, and COX were also determined. Results: Differential expression of inducible iNOS, HO-1 and COX-2 and enzyme activities of NOS, HO and COX were found in the gastric ulcer base. High iNOS expression and activity were observed on day 1 to day 3 in severely inflamed ulcer tissues. Maximum expressions of HO-1 and COX-2 and enzyme activities of HO and COX lagged behind that of iNOS, and remained at high levels during the healing phase. Conclusion: The expression and activities of inducible NOS, HO-1 and COX-2 are found to be correlated to different stages of gastric ulceration. Inducible NOS may contribute to ulcer formation while HO-1 and COX-2 may promote ulcer healing.published_or_final_versio

Colored Motifs Reveal Computational Building Blocks in the C. elegans Brain

Background: Complex networks can often be decomposed into less complex sub-networks whose structures can give hints about the functional organization of the network as a whole. However, these structural motifs can only tell one part of the functional story because in this analysis each node and edge is treated on an equal footing. In real networks, two motifs that are topologically identical but whose nodes perform very different functions will play very different roles in the network. Methodology/Principal Findings: Here, we combine structural information derived from the topology of the neuronal network of the nematode C. elegans with information about the biological function of these nodes, thus coloring nodes by function. We discover that particular colorations of motifs are significantly more abundant in the worm brain than expected by chance, and have particular computational functions that emphasize the feed-forward structure of information processing in the network, while evading feedback loops. Interneurons are strongly over-represented among the common motifs, supporting the notion that these motifs process and transduce the information from the sensor neurons towards the muscles. Some of the most common motifs identified in the search for significant colored motifs play a crucial role in the system of neurons controlling the worm's locomotion. Conclusions/Significance: The analysis of complex networks in terms of colored motifs combines two independent data sets to generate insight about these networks that cannot be obtained with either data set alone. The method is general and should allow a decomposition of any complex networks into its functional (rather than topological) motifs as long as both wiring and functional information is available

Polymorphisms in Nucleotide Excision Repair Genes, Arsenic Exposure, and Non-Melanoma Skin Cancer in New Hampshire

Background: Arsenic exposure may alter the efficiency of DNA repair. UV damage is specifically repaired by nucleotide excision repair (NER), and common genetic variants in NER may increase risk for non-melanoma skin cancer (NMSC). Objective: We tested whether polymorphisms in the NER genes XPA (A23G) and XPD (Asp312Asn and Lys751Gln) modify the association between arsenic and NMSC. Methods: Incident cases of basal and squamous cell carcinoma (BCC and SCC, respectively) were identified through a network of dermatologists and pathology laboratories across New Hampshire. Population-based controls were frequency matched to cases on age and sex. Arsenic exposure was assessed in toenail clippings. The analysis included 880 cases of BCC, 666 cases of SCC, and 780 controls. Results: There was an increased BCC risk associated with high arsenic exposure among those homozygous variant for XPA [odds ratio (OR) = 1.8; 95% confidence interval (CI), 0.9–3.7]. For XPD, having variation at both loci (312Asn and 751Gln) occurred less frequently among BCC and SCC cases compared with controls (OR = 0.8; 95% CI, 0.6–1.0) for both case groups. In the stratum of subjects who have variant for both XPD polymorphisms, there was a 2-fold increased risk of SCC associated with elevated arsenic (OR = 2.2; 95% CI, 1.0–5.0). The test for interaction between XPD and arsenic in SCC was of borderline significance (p < 0.07, 3 degrees of freedom). Conclusions: Our findings indicate a reduced NMSC risk in relation to XPD Asp312Asn and Lys751Gln variants. Further, these data support the hypothesis that NER polymorphisms may modify the association between NMSC and arsenic

Essential Roles of BCCIP in Mouse Embryonic Development and Structural Stability of Chromosomes

BCCIP is a BRCA2- and CDKN1A(p21)-interacting protein that has been implicated in the maintenance of genomic integrity. To understand the in vivo functions of BCCIP, we generated a conditional BCCIP knockdown transgenic mouse model using Cre-LoxP mediated RNA interference. The BCCIP knockdown embryos displayed impaired cellular proliferation and apoptosis at day E7.5. Consistent with these results, the in vitro proliferation of blastocysts and mouse embryonic fibroblasts (MEFs) of BCCIP knockdown mice were impaired considerably. The BCCIP deficient mouse embryos die before E11.5 day. Deletion of the p53 gene could not rescue the embryonic lethality due to BCCIP deficiency, but partially rescues the growth delay of mouse embryonic fibroblasts in vitro. To further understand the cause of development and proliferation defects in BCCIP-deficient mice, MEFs were subjected to chromosome stability analysis. The BCCIP-deficient MEFs displayed significant spontaneous chromosome structural alterations associated with replication stress, including a 3.5-fold induction of chromatid breaks. Remarkably, the BCCIP-deficient MEFs had a ∼20-fold increase in sister chromatid union (SCU), yet the induction of sister chromatid exchanges (SCE) was modestly at 1.5 fold. SCU is a unique type of chromatid aberration that may give rise to chromatin bridges between daughter nuclei in anaphase. In addition, the BCCIP-deficient MEFs have reduced repair of irradiation-induced DNA damage and reductions of Rad51 protein and nuclear foci. Our data suggest a unique function of BCCIP, not only in repair of DNA damage, but also in resolving stalled replication forks and prevention of replication stress. In addition, BCCIP deficiency causes excessive spontaneous chromatin bridges via the formation of SCU, which can subsequently impair chromosome segregations in mitosis and cell division

Exclusion of PINK1 as candidate gene for the late-onset form of Parkinson's disease in two European populations

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recently, mutations in the PINK1 (PARK6) gene were shown to rarely cause autosomal-recessively transmitted, early-onset parkinsonism. In order to evaluate whether PINK1 contributes to the risk of common late-onset PD we analysed PINK1 sequence variations. A German (85 patients) and a Norwegian cohort (90 patients) suffering from late-onset PD were screened for mutations and single nucleotide polymorphisms (SNPs) in the PINK1 gene. Both cohorts consist of well-characterized patients presenting a positive family history of PD in ~17%. Investigations were performed by single strand conformation polymorphism (SSCP), denaturating high performance liquid chromatography (DHPLC) and sequencing analyses. SNP frequencies were compared by the χ(2 )test RESULTS: Several common SNPs were identified in our cohorts, including a recently identified coding variant (Q115L) in exon 1. Genotyping of the Q115L variation did not reveal significant frequency differences between patients and controls. Pathogenic mutations in the PINK1 gene were not identified, neither in the German nor in the Norwegian cohort. CONCLUSION: Sequence variation in the PINK1 gene appears to play a marginal quantitative role in the pathogenesis of the late-onset form of PD, in German and Norwegian cohorts, if at all

Skin and soft tissue infections in hospitalized and critically ill patients: a nationwide population-based study

<p>Abstract</p> <p>Background</p> <p>The proportional distributions of various skin and soft tissue infections (SSTIs) with/without intensive care are unclear. Among SSTI patients, the prevalence and significance of complicating factors, such as comorbidities and infections other than skin/soft tissue (non-SST infections), remain poorly understood. We conducted this population-based study to characterize hospitalized SSTI patients with/without intensive care and to identify factors associated with patient outcome.</p> <p>Methods</p> <p>We analyzed first-episode SSTIs between January 1, 2005 and December 31, 2007 from the hospitalized claims data of a nationally representative sample of 1,000,000 people, about 5% of the population, enrolled in the Taiwan National Health Insurance program. We classified 18 groups of SSTIs into three major categories: 1) superficial; 2) deeper or healthcare-associated; and 3) gangrenous or necrotizing infections. Multivariate logistic regression models were applied to identify factors associated with intensive care unit (ICU) admission and hospital mortality.</p> <p>Results</p> <p>Of 146,686 patients ever hospitalized during the 3-year study period, we identified 11,390 (7.7%) patients having 12,030 SSTIs. Among these SSTI patients, 1,033 (9.1%) had ICU admission and 306 (2.7%) died at hospital discharge. The most common categories of SSTIs in ICU and non-ICU patients were "deeper or healthcare-associated" (62%) and "superficial" (60%) infections, respectively. Of all SSTI patients, 45.3% had comorbidities and 31.3% had non-SST infections. In the multivariate analyses adjusting for demographics and hospital levels, the presence of several comorbid conditions was associated with ICU admission or hospital mortality, but the results were inconsistent across most common SSTIs. In the same analyses, the presence of non-SST infections was consistently associated with increased risk of ICU admission (adjusted odds ratios [OR] 3.34, 95% confidence interval [CI] 2.91-3.83) and hospital mortality (adjusted OR 5.93, 95% CI 4.57-7.71).</p> <p>Conclusions</p> <p>The proportional distributions of various SSTIs differed between ICU and non-ICU patients. Nearly one-third of hospitalized SSTI patients had non-SST infections, and the presence of which predicted ICU admission and hospital mortality.</p

Increase in mammography detected breast cancer over time at a community based regional cancer center: a longitudinal cohort study 1990–2005

Background: Coincident with the advent of mammography screening, breast carcinoma in situ has increased in the US population. Methods: We conducted a prospective cohort study of all women presenting with primary breast cancer, aged 21-94, and biopsy confirmed Stage 0-IV from 1990-2005 identified and tracked by our registry. Clinical presentation characteristics including age, race, TNM stage, family and pregnancy history, histologic type and method of detection by patient (PtD), physician (PhysD) or mammography (MgD) were chart abstracted at time of diagnosis. Cases with unknown or other method of detection (n = 84), or unusual cell types (n = 26) were removed (n = 6074). Results: From 1990 to 1998 the percentage of PtD and MgD cases was roughly equivalent. In 1999 the percentage of MgD cases increased to 56% and PtD dropped to 37%, a significant 20% differential, constant to 2005 (Pearson chi square = 120.99, p less than .001). Overall, percent TNM stage 0 (breast carcinoma in situ) cases increased after 1990, percent stage I and III cases declined, and stage II and IV cases remained constant (Pearson chi square = 218.36, p less than .001). Increase in MgD over time differed by age group with an 8.5% increase among women age 40-49 and 12% increase among women age 50-95. Women age 21-39 rarely had MgD BC. In forward stepwise logistic regression modeling, significant predictors of MgD BC by order of entry were TNM stage, age at diagnosis, diagnosis year, and race (chi square = 1867.56, p less than .001). Conclusion: In our cohort the relative proportion of mammography detected breast cancer increased over time with a higher increase among women age 50+ and an increase of breast carcinoma in situ exclusively among MgD cases. The increase among women currently targeted by mammography screening programs (age = 50) combined with an increase of breast carcinoma in situ most often detected by mammography screening indicates a possible incidence shift to lower stage breast cancer as a result of mammographic detection.Kaplan Research Fun

Subgroup Economic Analysis for Glioblastoma in a Health Resource-Limited Setting

BACKGROUND: The aim of this research was to evaluate the economic outcomes of radiotherapy (RT), temozolomide (TMZ) and nitrosourea (NT) strategies for glioblastoma patients with different prognostic factors. METHODOLOGY/PRINCIPAL FINDINGS: A Markov model was developed to track monthly patient transitions. Transition probabilities and utilities were derived primarily from published reports. Costs were estimated from the perspective of the Chinese healthcare system. The survival data with different prognostic factors were simulated using Weibull survival models. Costs over a 5-year period and quality-adjusted life years (QALYs) were estimated. Probabilistic sensitivity and one-way analyses were performed. The baseline analysis in the overall cohort showed that the TMZ strategy increased the cost and QALY relative to the RT strategy by $25,328.4 and 0.29, respectively; and the TMZ strategy increased the cost and QALY relative to the NT strategy by$23,906.5 and 0.25, respectively. Therefore, the incremental cost effectiveness ratio (ICER) per additional QALY of the TMZ strategy, relative to the RT strategy and the NT strategy, amounts to $87,940.6 and$94,968.3, respectively. Subgroups with more favorable prognostic factors achieved more health benefits with improved ICERs. Probabilistic sensitivity analyses confirmed that the TMZ strategy was not cost-effective. In general, the results were most sensitive to the cost of TMZ, which indicates that better outcomes could be achieved by decreasing the cost of TMZ. CONCLUSIONS/SIGNIFICANCE: In health resource-limited settings, TMZ is not a cost-effective option for glioblastoma patients. Selecting patients with more favorable prognostic factors increases the likelihood of cost-effectiveness

Primary Phacoemulsification and Intraocular Lens Implantation for Acute Primary Angle-Closure

Background: To investigate the effect of primary phacoemulsification on intraocular pressure (IOP) in patients with acute primary angle-closure (PAC) and coexisting cataract. Methodology: Sixteen eyes of 14 patients with acute PAC received phacoemulsification and intraocular lens implantation as initial management for medically uncontrolled IOP in a retrospective chart review. The effects on IOP, vision, anterior chamber depth (ACD), and number of antiglaucoma medications were evaluated. Principal Findings: The postoperative IOP was reduced in 16 eyes (100%). The mean 6 standard deviation preoperative IOP was 48.81616.83 mm Hg, which decreased postoperatively to 16.46610.67 mm Hg at 1 day, 9.4363.03 mm Hg at 1 week

Health Effects of Exposure to Natural Arsenic in Groundwater and Coal in China: An Overview of Occurrence

Between 2001 and 2005, 21,155 of 445,638 wells in 20,517 villages in 292 counties in 16 provinces from China, or 5% of wells, were found to contain > 50 μg/L arsenic (As) by field testing with the Merck As kit. We achieved quality assurance of analysis of at least 10% of the wells containing > 50 μg/L As using hydride generation atomic fluorescence spectrometry and silver dithiodicarbomate spectrometry. Our best estimate of the population exposed to > 50 μg/L As in drinking water was 582,769. This is probably an underestimate for China because of the limited area surveyed. In a survey of 135,492 individuals in eight provinces, we used the National Diagnosis Standard for Endemic Arsenicosis and identified 10,096 cases of arsenicosis with various degrees of skin lesions. The arsenicosis occurrence rate of 7.5% is likely an overestimate, because the survey focused more on known and suspected endemic areas of arsenicosis. The occurrence of arsenicosis correlates positively with the percentage of wells containing > 50 μg/L As, or at a ratio of 1 to 5%. Based on both the amount of As in well water and the rate of occurrence of arsenicosis, Shanxi province, Inner Mongolia autonomous region, and Jilin province are the top three areas in China as of 2005 for exposure to endemic As from drinking water. Our survey also identified exposure to high levels of As from wells in several provinces and from the indoor burning of coal containing high levels of As in Shaanxi province. These areas, however, have not had any reports of previous arsenicosis endemics. In the endemic areas, the average rate of occurrence of arsenicosis at advanced stages was 1.2%, possibly because of a long exposure time of > 20 years; the rate of occurrence increased to 2.7% when we included a high dose of As exposure from the indoor burning of coal. Mitigation to reduce As exposure remains a challenge in rural China