Gastrointestinal Bleeding and Anticoagulant or Antiplatelet Drugs

Gastrointestinal (GI) bleeding is a frequently encountered and very serious problem in emergency room patients who are currently being treated with anticoagulant or antiplatelet medications. There is, however, a lack of clinical practice guidelines about how to respond to these situations. The goal of this study was to find published articles that contain specific information about how to safely adjust anticoagulant and antiplatelet therapy when GI bleeding occurs.The investigators initiated a global search on the PubMed and Google websites for published information about GI bleeding in the presence of anticoagulant or antiplatelet therapy. After eliminating duplicate entries, the medical articles that remained were screened to narrow the sets of articles to those that met specific criteria. Articles that most closely matched study criteria were analyzed in detail and compared to determine how many actual guidelines exist and are useful.We could provide only minimal information about appropriate therapeutic strategies because no articles provided sufficient specific advice about how to respond to situations involving acute GI bleeding and concurrent use of anticoagulant or antiplatelet drugs. Only 4 articles provided enough detail to be of any use in an emergency situation.Clinical practice guidelines and also clinical trials for GI hemorrhaging should be expanded to state in which situations the use of anticoagulant or antiplatelet drugs should be suspended and the medications should later be resumed, and they should state the level of risk for any particular action

Comparison of the Gut Microbiome between Atopic and Healthy Dogs—Preliminary Data

Human studies show that in addition to skin barrier and immune cell dysfunction, both the cutaneous and the gut microbiota can influence the pathogenesis of atopic diseases. There is currently no data on the gut-skin axis in allergic canines. Therefore, the aim of this study was to assess the bacterial diversity and composition of the gut microbiome in dogs with atopic dermatitis (AD). Stool samples from adult beagle dogs (n = 3) with spontaneous AD and a healthy control group (n = 4) were collected at Days 0 and 30. After the first sampling, allergic dogs were orally dosed on a daily basis with oclacitinib for 30 days, and then re-sampled. Sequencing of the V3–V4 region of the 16S rRNA gene was performed on the Illumina MiSeq platform and the data were analyzed using QIIME2. The atopic dogs had a significantly lower gut microbiota alpha-diversity than healthy dogs (p = 0.033). In healthy dogs, a higher abundance of the families Lachnospiraceae (p = 0.0006), Anaerovoracaceae (p = 0.006) and Oscillospiraceae (p = 0.021) and genera Lachnospira (p = 0.022), Ruminococcustorques group (p = 0.0001), Fusobacterium (p = 0.022) and Fecalibacterium (p = 0.045) was seen, when compared to allergic dogs. The abundance of Conchiformibius (p = 0.01), Catenibacterium spp. (p = 0.007), Ruminococcus gnavus group (p = 0.0574) and Megamonas (p = 0.0102) were higher in allergic dogs. The differences in alpha-diversity and on the compositional level remained the same after 1 month, adding to the robustness of the data. Additionally, we could also show that a 4-week treatment course with oclacitinib was not associated with changes in the gut microbiota diversity and composition in atopic dogs. This study suggests that alterations in the gut microbiota diversity and composition may be associated with canine AD. Large-scale studies preferably associated to a multi-omics approach and interventions targeting the gut microbiota are needed to confirm these results

Physiological concentrations of bile acids down-regulate agonist induced secretion in colonic epithelial cells

In patients with bile acid malabsorption, high concentrations of bile acids enter the colon and stimulate Cl− and fluid secretion, thereby causing diarrhoea. However, deoxycholic acid (DCA), the predominant colonic bile acid, is normally present at lower concentrations where its role in regulating transport is unclear. Thus, the current study set out to investigate the effects of physiologically relevant DCA concentrations on colonic epithelial secretory function. Cl− secretion was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers. At high concentrations (0.5–1 mM), DCA acutely stimulated Cl− secretion but this effect was associated with cell injury, as evidenced by decreased transepithelial resistance (TER) and increased lactate dehydrogenase (LDH) release. In contrast, chronic (24 hrs) exposure to lower DCA concentrations (10–200 μM) inhibited responses to Ca2+ and cAMP-dependent secretagogues without altering TER, LDH release, or secretagogue-induced increases in intracellular second messengers. Other bile acids – taurodeoxycholic acid, chenodeoxycholic acid and cholic acid – had similar antisecretory effects. DCA (50 μM) rapidly stimulated phosphorylation of the epidermal growth factor receptor (EGFr) and both ERK and p38 MAPKs (mitogen-activated protein kinases). The EGFr inhibitor, AG1478, and the protein synthesis inhibitor, cycloheximide, reversed the antisecretory effects of DCA, while the MAPK inhibitors, PD98059 and SB203580, did not. In summary, our studies suggest that, in contrast to its acute prosecretory effects at pathophysiological concentrations, lower, physiologically relevant, levels of DCA chronically down-regulate colonic epithelial secretory function. On the basis of these data, we propose a novel role for bile acids as physiological regulators of colonic secretory capacity

Low serum zinc levels predict presence of depression symptoms, but not overall disease outcome, regardless of ATG16L1 genotype in Crohn's disease patients.

Zinc deficiency (ZD) in Crohn's disease (CD) is considered a frequent finding and may exacerbate CD activity. ZD is associated with depression in non-CD patients. We aimed to assess the prevalence of ZD in CD patients in clinical remission, its association with mood disturbances and to analyze a potential impact on future disease course. Zinc levels from CD patients in clinical remission at baseline and an uncomplicated disease course within the next 3 years ( <i>n</i> = 47) were compared with those from patients developing complications ( <i>n</i> = 50). Baseline symptoms of depression and anxiety were measured with the Hospital Anxiety and Depression scale. Mean zinc level in the 97 patients (40.4 ± 15.7 years, 44.3% males) was 18.0 ± 4.7 μmol/l. While no ZD (<11 μmol/l) was observed, we found low zinc levels (<15.1 μmol/l) in 28 patients (28.9%). Males had higher zinc levels compared with females (19.4 ± 5.7 <i>versus</i> 16.8 ± 3.3, <i>p</i> = 0.006). Patients with low zinc levels more often reported depression symptoms compared with patients with higher levels (27.3 <i>versus</i> 9.4%, <i>p</i> = 0.047). In a multivariate analysis, zinc levels were an independent negative predictor for depression symptoms [odds ratio (OR) 0.727, 95% confidence interval (CI) 0.532-0.993, <i>p</i> = 0.045]. Zinc levels of patients with a complicated disease course were not different from those of patients without (17.7 ± 4.3 <i>versus</i> 18.3 ± 5.1, n.s.). Baseline zinc levels did not predict disease outcome regardless of ATG16L1 genotype. Low-normal zinc levels were an independent predictor for the presence of depression symptoms in CD patients. Zinc levels at baseline did not predict a complicated disease course, neither in CD patients overall, nor ATG16L1 <sup>T300A</sup> carriers

Expression patterns of TNFα, MAdCAM1 and STAT3 in intestinal and skin manifestations of inflammatory bowel disease

Background: Pathogenesis of cutaneous extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics such as anti-integrins or JAK-inhibitors is not yet clear. Methods: We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, Hsp-27/70 on 240 intestinal (55 controls, 185 IBD) and 64 skin biopsies (11 controls, 18 Erythema nodosum (EN), 13 Pyoderma gangenosum (PG), 22 psoriasis). A semiquantitative score (0-100%) was used for evaluation. Results: TNFα was upregulated in intestinal biopsies from active Crohn`s disease (CD) vs. controls (36.2 vs. 12.1, p<0.001), but not ulcerative colitis (UC: 17.9). NFκB however was upregulated in intestinal biopsies from both active CD and UC (43.2 and 34.5 vs. 21.8, p<0.001 and p=0.017). TNFα and NFκB were overexpressed in skin biopsies from EN, PG and psoriasis. No MAdCAM1 overexpression was seen in skin tissues, while it was upregulated in active UC vs. controls (57.5 vs. 35.4, p=0.003). STAT3 was overexpressed in the intestinal mucosa of active and non-active IBD, while a similar upregulation was seen in skin biopsies from EN (84.7 vs. 22.3, p<0.001) and PG (60.5 vs. 22.3, p=0.011), but not in psoriasis. Caspase 3 and CD68 overexpression in skin biopsies distinguished EN/PG from psoriasis and controls. Conclusions: Upregulation of TNFα/NFκB in EN and PG is compatible with the efficacy of anti-TNF in EIM management. Data on overexpressed STAT3, but not MAdCAM1 support a rationale for JAK-inhibitors in EN and PG, while questioning the role of vedolizumab

Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome

OBJECTIVE: Western lifestyle and diet are major environmental factors playing a role in the development of IBD. Titanium dioxide (TiO2) nanoparticles are widely used as food additives or in pharmaceutical formulations and are consumed by millions of people on a daily basis. We investigated the effects of TiO2 in the development of colitis and the role of the nucleotide-binding oligomerisation domain receptor, pyrin domain containing (NLRP)3 inflammasome. DESIGN: Wild-type and NLRP3-deficient mice with dextran sodium sulfate-induced colitis were orally administered with TiO2 nanoparticles. The proinflammatory effects of TiO2 particles in cultured human intestinal epithelial cells (IECs) and macrophages were also studied, as well as the ability of TiO2 crystals to traverse IEC monolayers and accumulate in the blood of patients with IBD using inductively coupled plasma mass spectrometry. RESULTS: Oral administration of TiO2 nanoparticles worsened acute colitis through a mechanism involving the NLRP3 inflammasome. Importantly, crystals were found to accumulate in spleen of TiO2-administered mice. In vitro, TiO2 particles were taken up by IECs and macrophages and triggered NLRP3-ASC-caspase-1 assembly, caspase-1 cleavage and the release of NLRP3-associated interleukin (IL)-1β and IL-18. TiO2 also induced reactive oxygen species generation and increased epithelial permeability in IEC monolayers. Increased levels of titanium were found in blood of patients with UC having active disease. CONCLUSION: These findings indicate that individuals with a defective intestinal barrier function and pre-existing inflammatory condition, such as IBD, might be negatively impacted by the use of TiO2 nanoparticles

Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease: Prevalence, Presentation, and Anti-TNF Treatment.

There is a paucity of data on extraintestinal manifestations (EIM) and their treatment in pediatric patients with inflammatory bowel disease (IBD). Since 2008, the Pediatric Swiss IBD Cohort Study has collected data on the pediatric IBD population in Switzerland. Data on 329 patients were analyzed retrospectively. A total of 55 patients (16.7%) experienced 1-4 EIM (39 Crohn disease, 12 ulcerative colitis, and 4 IBD-unclassified patients). At IBD onset, presence of EIM was more frequent than in the adult population (8.5% vs 5.0%, P = 0.014). EIM were more frequent in Crohn disease when compared to ulcerative colitis/IBD-unclassified (22.5% vs 10.3%, P = 0.003). The most prevalent EIM were peripheral arthritis (26/329, 7.9%) and aphthous stomatitis (24/329, 7.3%). Approximately 27.6% of all EIM appeared before IBD diagnosis. Median time between IBD diagnosis and occurrence of first EIM was 1 month (-37.5-149.0). Thirty-one of the 55 patients (56.4%) were treated with 1 or more anti-tumor necrosis factor (TNF) agents. IBD patients with EIM were more likely to be treated with anti-TNF compared to those without (56.4% vs 35.0%, P = 0.003). Response rates to anti-TNF depended on underlying EIM and were best for peripheral arthritis (61.5%) and uveitis (66.7%). In a cohort of pediatric patients with IBD, EIM were frequently encountered. In up to 30%, EIM appeared before IBD diagnosis. Knowledge of these findings may translate into an increased awareness of underlying IBD, thereby decreasing diagnostic delay. Anti-TNF for the treatment of certain EIM is effective, although a substantial proportion of new EIM may present despite ongoing anti-TNF therapy

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences