Association of interleukin 1 gene family polymorphisms with duodenal ulcer disease

Cytokine genes taking part in the immunological response to Helicobacter pylori infection are good candidates to study for genetic predisposition to duodenal ulcer disease (DU). Among cytokines, interleukin (IL)-1beta and its natural specific inhibitor, the interleukin-1 receptor antagonist, are cytokines that play a key role in regulating gastric acid secretion and modulating the immune response in the gastrointestinal mucosa. We aimed to investigate whether polymorphisms in the IL-1B and IL-1RN genes are involved in the susceptibility to duodenal ulcer. DNA from 131 unrelated Spanish Caucasian patients with DU and 105 ethnically matched healthy controls was typed for the IL-1B-511, IL-1B-31, and IL-1B + 3954 gene polymorphisms, and the VNTR polymorphism in intron 2 of the IL-1RN gene by polymerase chain reaction (PCR)-based methods and TaqMan assays. H. pylori status and non-steroidal anti-inflammatory drugs (NSAIDs) use was determined in all patients and controls. Logistic regression analysis identified H. pylori infection (OR: 9.74; 95%CI = 3.53-26.89) and NSAIDs use (OR: 8.82; 95%CI = 3.51-22.17) as independent risk factors for DU. In addition, the simultaneous carriage of IL-1RN*2, IL-1B-511*C, IL-1B-31*T and IL-1B + 3954*C alleles was a genetic risk factor for DU in patients with H. pylori infection (OR: 3.22; 95%CI = 1.09-9.47). No significant differences in IL-1RN and IL-1B genotypes were found when patients were categorized according to gender, age of onset, smoking habit, NSAIDs use, type of complication and positive family history. Our results provide further evidence that host genetic factors play a key role in the pathogenesis of duodenal ulcer.     

Association between polymorphisms in the human chemokine receptor genes CCR2 and CX3CR1 and rheumatoid arthritis

Cell trafficking into the rheumatoid synovium is thought to play an important role in the inflammation seen in rheumatoid arthritis. Chemokine receptors play a central role in this process, and several common variants are known, including the CCR2 variant, CCR2-64I, and two variants of the CX3CR1 gene, V249I and T280M. All three variants result in functional amino acid substitutions. We studied the association of these chemokine receptor variants with susceptibility to and severity of rheumatoid arthritis in two Dutch patient populations; 282 consecutive rheumatoid arthritis patients from a rheumatology outpatient clinic, and a cohort of 101 female rheumatoid arthritis patients, followed closely for a 12-year period, from whom hand and feet X-rays taken at three year intervals were scored and analyzed in this study. Although there was a trend towards increased severity of disease in patients carrying CX3CR1 variants, this was not independent of known risk factors. We found no evidence for a significant independent role for the CCR2 and CX3CR1 variants in the susceptibility to or severity of rheumatoid arthritis.     

Human papillomavirus type 16 E5 protein (review)

The association of certain human papillomavirus (HPV) types with malignancies of the anogenital tract is well established. The virus type most frequently associated with cellular transformation is HPV 16, as has been shown in epidemiological studies. Its transforming capacity has also been demonstrated in many in vitro cell transformation experiments. The most potent oncogenes of HPV 16 are the E6 and E7 proteins, but the E5 protein, whose homologue is the main oncogene of bovine papillomavirus, has recently been identified as an oncogene also for HPV. On the basis of epidemiological and clinical data from tumor material as well as from in vitro data it has been suggested, that the HPV 16 E5 protein would have a function at the early stages of cervical carcinogenesis. The E5 protein enhances growth factor-mediated signal transduction to the nucleus and consequently augments cellular proliferation. Expression of the E5 protein enables the infected cell to escape growth control provided by surrounding cells by inhibiting gap junctional intercellular communication in epithelial cells. This viral oncogene seems to interfere with the control mechanisms of cellular growth and proliferation and thus facilitate the function of the E6 and E7 proteins and further steps towards epithelial cell transformation.     

Pain and pain management in newborn infants: a survey of physicians and nurses

BACKGROUND: Despite an increased awareness among clinicians regarding pain and pain management for infants undergoing surgery, pain associated with procedures performed outside the operating room may not be adequately managed. PURPOSE: To examine the beliefs and self-described behavior of physicians and nurses regarding the management of procedural pain in newborn infants. METHODS: A survey was distributed to 467 clinicians (nurses and physicians) working in 11 level II and 4 level III nurseries in a large metropolitan area. Respondents were asked to rate the painfulness of 12 common bedside nursery procedures and how often pharmacologic and nonpharmacologic (comfort) measures are currently used and should be used for those procedures. Demographic data were also collected. RESULTS: Surveys were completed by 374 clinicians (80% response rate). Physicians and nurses believe infants feel as much pain as adults and that 9 of the 12 listed procedures are moderately to very painful. Neither pharmacologic nor comfort measures are believed to be used frequently, even for the most painful procedures. Physicians and nurses believe both pharmacologic and comfort measures should be used more frequently, but nurses believe comfort measures should be used more frequently than do physicians. Beliefs about infant pain and procedural pain were related to pain management preferences. Physicians' but not nurses' ratings were associated with significant personal pain. CONCLUSIONS: Despite their beliefs that infants experience significant procedure-related pain, clinicians believe pain management for infants remains below optimal levels. Barriers to more consistent and effective pain management need to be identified and surmounted.     

Bacterial and mammalian DNA alkyltransferases sensitize Escherichia coli to the lethal and mutagenic effects of dibromoalkanes

Here we confirm and extend our previous studies demonstrating that the mutagenic potency of 1,2-dibromoethane (DBE) and dibromomethane (DBM) is markedly enhanced (not prevented) in bacteria expressing the O6- alkylguanine-DNA alkyltransferase (ATase) encoded by the Escherichia coli ogt gene. We demonstrate that, in close parallel with mutagenesis, the Ogt ATase sensitizes the bacteria to the lethal effects of these carcinogens, suggesting that one or more of the potentially mutagenic lesions induced by DBE and DBM in the presence of Ogt has additional lethal capacity. We further demonstrate that the sensitization to both lethality and mutagenesis by DBE and DBM is a property shared by other DNA alkyltransferases. This objective was accomplished by quantifying the induction of mutations and lethal events in ogt- ada- E. coli expressing an exogenous bacterial or mammalian ATase from a multicopy plasmid. Mammalian recombinant ATases enhanced the lethal and mutagenic actions of DBE and suppressed the lack of sensitivity of the vector- transformed bacteria to DBM. In most cases the order of effectiveness of the ATases ranked: murine > human > Ogt > rat. Further comparisons included the full-length Ada ATase from E. coli and a truncated Ada version (T-ada) that retains the O6-methylguanine binding domain of the protein. The full-length Ada ATase was effective in enhancing the lethality but not the mutagenicity induced by DBE and DBM. The T-ada ATase provided less sensitization than Ada to lethality by DBE, but of the three bacterial ATases T-ada yielded the highest sensitization to mutagenesis by this compound. T-ada and Ada ATases were in general less effective than the mammalian versions, with the exception of the rat recombinant ATase. The effectiveness of the different mammalian and bacterial ATases in promoting the deleterious actions of dibromoalkanes was compared with the effectiveness of these proteins in suppressing the lethal and mutagenic effects induced by N-nitroso-N-methylurea. The ability to sensitize E. coli to the lethal and mutagenic effects of DBE and DBM seems restricted to DNA alkyltransferase, since overexpression of thioredoxin (Trx) or glutaredoxin (Grx1) in ogt- ada- cells showed no effect, in spite of the reported potential of bioactive dihaloethane- derived species to alkylate Trx.      

Effects of fibroblast growth factor-4 (k-FGF) on long-term cultures of human bone marrow cells

Fibroblast growth factor-4 (FGF-4), a highly mitogenic protein encoded by the k-fgf/hst oncogene, stimulates the growth of a variety of cells of mesenchymal and neuroectodermal origin. Addition of FGF-4 to human long-term bone marrow cultures increased both the cell density of the stromal layer and the number of hematopoietic colony forming cells in the cultures in a dose-dependent manner. Hematopoiesis in the stromal layer persisted for up to 8 months. Erythropoiesis was maintained for up to 4 weeks, but granulocytes were the predominant nonadherent cell type. Cultures treated with FGF had increased numbers of monocytes compared with control cultures and some CD14+, CD45+ monocytes could still be detected after 8 months of continuous culture. The addition of the growth factor increased the rate of growth of the stromal layer and appeared to delay its senescence. Subcultures made in the presence of FGF-4 had up to 10-fold increases in plating efficiency and grew as relatively uniform monolayers. These subcultures retained the capacity to support hematopoiesis for several months, while untreated subcultures, made without FGF-4, grew erratically and generally lost the capacity to support hematopoiesis within 4 to 6 weeks. The improved growth after subculture greatly enhanced the reliability of limit- dilution assays of multipotential hematopoietic stem cells that use stromal cell monolayers. The primary effect of FGF-4 appeared to be on the stromal cells of the long-term bone marrow cultures, but a direct effect on hematopoietic progenitors could not be ruled out.     

Left-Atrial Appendage Thrombosis in Patients With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation

BackgroundData about the impact of left-atrial appendage thrombosis (LAAT) on early safety and mortality in patients undergoing transfemoral transcatheter aortic valve implantation (TF-TAVI) are scarce. We aimed to investigate the prevalence and predictors of LAAT and the outcome associated with this condition in patients treated by TF-TAVI.MethodsRetrospective data analysis was derived from a prospective single-centre registry comparing patients with and without LAAT regarding early safety at 30 days, according to Valve Academic Research Consortium-2 (VARC-2) and 2-year mortality.ResultsLAAT was found in 7.6% of the whole cohort (n = 2527) and in 16.6% in those patients with known pre-existing atrial fibrillation (AF cohort, n = 1099). Compared with controls, patients with LAAT were sicker, indicated by a higher Society of Thoracic Surgeons (STS) score and burden of comorbidities. Neither VARC-2–defined early safety at 30 days nor the rate of stroke was different between LAAT and controls in both the whole (early safety: 29.2% vs 24.2%, P = 0.123; stroke: 5.9% vs 4.7%, P = 0.495) and AF cohort (early safety: 29.1% vs 22.9%, P = 0.072; stroke: 5.6% vs 3.3%, P = 0.142). Evaluating the whole cohort in a univariate analysis, the 2-year mortality was significantly higher in LAAT compared with controls (hazard ratio, 1.41; 95% confidence interval, 1.07-1.86; P = 0.014). However, multivariate analysis of the whole cohort and the AF cohort revealed no association between LAAT and 2-year mortality.ConclusionsLAAT was frequent in patients undergoing TF-TAVI— in particular, in patients with histories of AF—but it was not associated with an increase in periprocedural complications and did not predict 2-year mortality.     

CTLA4 gene polymorphisms in Dutch and Chinese patients with inflammatory bowel disease

BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by chronic intestinal inflammation as a result of an exaggerated T-cell response. CTLA4, a receptor of activated T cells, has an inhibitory function in regulating T-cell activation. Since CTLA4 gene polymorphisms have been associated with several autoimmune diseases, the aim was to study these gene polymorphisms in patients with IBD in two different populations. METHODS: The C-318T polymorphism in the promoter region and A+49G polymorphism in exon I of the CTLA4 gene were investigated by a PCR-SSP method. We studied 139 unrelated patients with ulcerative colitis (UC), 163 patients with Crohn disease (CD) and 174 healthy controls of Dutch Caucasian origin as well as 35 patients with UC and 62 healthy controls from the Chinese Han population. RESULTS: No significant differences in the distribution of allele, genotype and haplotype frequencies were observed between C-318T and A+49G gene polymorphisms and IBD in Dutch Caucasians and UC in the Chinese Han population. Although the haplotypes of the C-318T and A+49G polymorphisms were distributed differently between Dutch Caucasian and Chinese Han populations, there were no differences in the subgroups of patients with CD classified according to age, localization and behaviour in the Vienna classification and in those with UC classified according to age at onset, disease extension and presence of colectomy in the Dutch patients. However, the CTLA4-318 genotype CC was more frequent in patients with CD over 40 years (93%) than in younger patients (74%) (P = 0.045). CONCLUSION: C-318T and A+49G CTLA4 gene polymorphisms and their haplotypes are not associated in Dutch Caucasian patients with IBD and in Chinese patients with UC.