Matrix Metalloproteinase-1 (MMP-1) Promoter Polymorphisms are Well Linked with Lower Stomach Tumor Formation in Eastern Indian Population

Expression of matrix metalloproteinase-1 (MMP-1), an interstitial collagenase, plays a major role in cellular invasion during development of gastric cancer, a leading cause of death worldwide. A single-nucleotide polymorphism (SNP) 21607 1G/2G site of the MMP-1 gene promoter has been reported to alter transcription level. While the importance’s of other SNPs in the MMP-1 promoter have not yet been studied in gastric cancer, our aim was to investigate MMP-1 gene promoter polymorphisms and gastric cancer susceptibility in eastern Indian population. A total of 145 gastric cancer patients and 145 healthy controls were genotyped for MMP-1 21607 1G/2G (rs1799750) by PCR-restriction fragment length polymorphism (RFLP), while MMP-1 2519 A/G (rs1144393), MMP-1 2422 T/A (rs475007), MMP-1 2340 T/C (rs514921) and MMP-1 2320 T/C (rs494379) were genotyped by DNA sequencing. A positive association was found with MMP-1 2422 T/A SNP that showed significant risk for regional lymph node metastasis (P = 0.021, Odd’s ratio (OR) = 3.044, Confidence intervals (CI) = 1.187– 7.807). In addition, we found a significant association with lower stomach tumor formation among gastric cancer patients for three adjacent polymorphisms near the transcriptional start sites of [MMP-1 2422 T/A (P = 0.043, OR = 2.182, CI = 1.03– 4.643), MMP-1 2340 T/C (P = 0.075, OR = 1.97, CI = 0.94–4.158) and MMP-1 2320 T/C (P = 0.034, OR = 2.224, CI = 1.064– 40731)]. MMP-1 level in patients’ serum was correlated with MMP-1 promoter haplotypes conferring these three SNPs to evaluate the functional importance of these polymorphisms in lower stomach tumor formation and significant correlation was observed. Furthermore, MMP-1 2519 A/G polymorphism displayed poor cellular differentiation (P = 0.024, OR = 3.8, CI = 1.69–8.56) attributing a higher risk of cancer progression.In conclusion, MMP-1 proximal promoter SNPs are associated with the risk of lower stomach tumor formation and node metastasis in eastern Indian population

Outcomes of Patients Who Have Do Not Resuscitate Status prior to Being Admitted to an Intensive Care Unit

Admission of patients who have do not resuscitate (DNR) status to an intensive care unit (ICU) is potentially a misallocation of limited resources to patients who may neither need nor want intensive care. Yet, patients who have DNR status are often admitted to the ICU. This is a retrospective review of patients who had a valid DNR status at the time that they were admitted to an ICU in a single hospital over an eighteen-month period. Thirty-five patients met the criteria for inclusion in the study. The primary reasons for admission to the ICU were respiratory distress (54.2%) and sepsis (45.7%). Sixteen (45.7%) of the patients died, compared to a 5.4% mortality rate for all patients admitted to our ICU during this period (p<0.001). APACHE II score was a significant predictor of mortality (18.5 ± 1.3 alive and 23.4 ± 1.4 dead; p=0.038). Of the 19 patients discharged alive, 9 were discharged home, 5 to hospice, and 4 to a post-acute care facility. Conclusions. Patients who have DNR status and are admitted to the ICU have a higher mortality than other ICU patients. Those who survive have a high likelihood of being discharged to hospice or a post-acute care facility. The value of intensive intervention for these patients is not supported by these results. Only a minority of patients were seen by palliative care and chaplain teams, services which the literature supports as valuable for DNR patients. Our study supports the need for less expensive and less intensive but more appropriate resources for patients and families who have chosen DNR status

FERMENTABLE CARBOHYDRATES AND ENTERAL NUTRITION INTOLERANCE: A RETROSPECTIVE STUDY IN CRITICALLY ILL PATIENTS

Objective. The aim of our study is to observe whether FODMAP content of EN is associated with either diarrhea, distention or gastric residual volumes in critically ill patients. Background. The role of enteral nutrition (EN) in the critically ill patient has been well established as it maintains gut integrity and is associated with improved outcomes and decreased morbidity. Intolerance to enteral nutrition (EN) is a common problem and is usually manifested as diarrhea, distention and elevated gastric residual volume. When this occurs, EN is often held or infused at a lower rate which causes calorie deficits, further compromising outcomes. Multiple factors including osmolality and ingredients of enteral formula need to be considered when assessing EN intolerance. Recently short chain carbohydrates known as FODMAPs (Fermentable Olgio Di- Mono- Saccharides And Polyols) has been shown to be associated with increased risk of intolerance. In colonic bacterial environment the FODMAPs produce rapidly fermentable substrate generating excessive amount of gas with characteristic symptoms including abdominal pain, discomfort, bloating, distention and altered bowel habits. Hamos et al demonstrated that hospitalized patients receiving Isosource 1.5 (an enteral formula with a lower FODMAP content) had a considerable reduction in risk of developing diarrhea. Methods. This retrospective observational study was approved by the Intstitutional Review Board of Mount Sinai Medical Center, Miami Beach Florida. The electronic health record, of all ICU admissions that were either on Peptamen AF ® or Replete ® from July 2012 through September 2013 were reviewed. Patients on EN for three or more consecutive days were included. Diarrhea was defined as one episode of loose or watery stool and/ or three or more stools within a twenty four hour period regardless of consistency. Distension was defined as a distended and/ or firm abdomen as reported in the nursing or dietitian record. Gastric residual was counted if the volume was greater than 250 cc on at least one occasion. Formulas were assigned to patients based on the preference of the physician or dietitian. Peptamen AF ® contains 5.2 g/ L of FODMAPs which consist of inulin (1.6 g/ L) and fructooligosaccharides (3.6 g/ L), while Replete ® does not contain any. Results. Among 221 patients the incidence of gastric residuals was higher in the Peptamen AF® group (18.9% vs 9.2%, P \u3c 0.05, odds ratio (OR) of 2.31). There was no significant difference in the occurrence of either diarrhea (P=0.847) or distension (P=0.087). We observed increased occurrence of diarrhea with longer duration of EN (P\u3c0.05, OR 1.05). Abdominal distension was associated with renal replacement therapy (RRT) (P\u3c0.05, OR 2.906), and gastric residuals was predicted by inotropes (P\u3c0.05, OR 4.047) and RRT (P=0.05, OR 3.014). Logistic regression failed to show any significant differences in diarrhea, distension, or gastric residuals between the two groups. Conclusion. Duration of enteral nutrition, RRT and inotropes were significant independent predictors of EN intolerance. Although FODMAPs have been associated with diarrhea, it does not influence EN intolerance in critically ill patients. This observation may be influenced by multiple variables increasing the risk for gastric intolerance. Further prospective studies are warranted in this unique population to evaluate the causes of intolerance. Grants. No grants to disclos

Doxycycline blocks gastric ulcer by regulating matrix metalloproteinase-2 activity and oxidative stress

AIM: To examine the effect of doxycycline on the activity of matrix metalloproteinases (MMPs) and oxidative stress in gastric tissues of rats following gastric injury

Haplotype effect on serum MMP-1 concentration.

<p>Serum MMP-1 level in patients with lower stomach cancer with risk haplotypes (n = 54), and upper stomach cancer with non risk haplotypes (n = 15) were compared by ELISA. Results showed patients with lower stomach cancer exhibit a 1.43 fold higher MMP-1 level than in upper stomach cancer patients (p<0.05 by t-test) (box whisker diagram).</p

PCR primers used for polymorphism analysis.

<p>PCR primers used for polymorphism analysis.</p

Association between the genotypes of MMP-1 SNPs and clinicopathological characteristics of gastric cancer patients.

<p>P value, ORs and 95% CIs were calculated by unconditional binary logistic regression (using SPSS v16 software) with respective reference genotypes. (a) Adjusted with Sex. (b) Adjusted with Age. (c) Adjusted with Age, Sex, and Addiction. Values in bold indicate positive significance (P<0.05). (*) Histological classification is dependent on the basis of glandular architecture of adenocarcinoma. WD = Well differentiated, MD = Moderately differentiated, PD = poorly differentiated. (¥) Tumor stage is classified according to the criterion of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) TNM stage grouping <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088040#pone.0088040-Inoue1" target="_blank">[25]</a>. (#) Depth of tumor defined according to the criterion of AJCC.</p

Association of increasing order of MMP-1 polymorphic variant alleles in haplotypes with Lower stomach gastric cancer risk.

<p>Haplotypes order as MMP-1.1-MMP-1.2-MMP-1.3-MMP-1.4-MMP-1.5.</p><p>(a) two sided χ² Association P value, OR = Odds ratio, CI = Confidence Interval, Ref = Reference haplotype to calculate OR. Other possible combinations of linked loci are omitted because of null frequency in the population. Haplotype frequency and haplotype association test performed using Haploview4.2 software. Haplotype numbers denote the number of risk allele(s) present in the haplotypes.</p