COVID-19 severity is associated with the risk of gastrointestinal bleeding.

OBJECTIVE: The association between the severity of COVID-19 and gastrointestinal (GI) bleeding is unknown. This study aimed to determine whether the severity of COVID-19 is a risk factor for GI bleeding. DESIGN: A multicentre, retrospective cohort study was conducted on hospitalised patients with COVID-19 between January 2020 and December 2021. The severity of COVID-19 was classified according to the National Institute of Health severity classification. The primary outcome was the occurrence of GI bleeding during hospitalisation. The main analysis compared the relationship between the severity of COVID-19 and the occurrence of GI bleeding. Multivariable logistic regression analysis was performed to evaluate the association between the severity of COVID-19 and the occurrence of GI bleeding. RESULTS: 12 044 patients were included. 4165 (34.6%) and 1257 (10.4%) patients had severe and critical COVID-19, respectively, and 55 (0.5%) experienced GI bleeding. Multivariable analysis showed that patients with severe COVID-19 had a significantly higher risk of GI bleeding than patients with non-severe COVID-19 (OR: 3.013, 95% CI: 1.222 to 7.427). Patients with critical COVID-19 also had a significantly higher risk of GI bleeding (OR: 15.632, 95% CI: 6.581 to 37.130). Patients with severe COVID-19 had a significantly increased risk of lower GI bleeding (OR: 10.349, 95% CI: 1.253 to 85.463), but the risk of upper GI bleeding was unchanged (OR: 1.875, 95% CI: 0.658 to 5.342). CONCLUSION: The severity of COVID-19 is associated with GI bleeding, and especially lower GI bleeding was associated with the severity of COVID-19. Patients with severe or critical COVID-19 should be treated with caution as they are at higher risk for GI bleeding.

[Multimodal therapy improved carcinoid syndrome secondary to liver metastases of an atypical lung carcinoid tumor:a case report].

A 69-year-old male presented for an annual medical examination, and his chest X-ray showed an abnormal shadow. He presented to our hospital, and was diagnosed with typical carcinoid tumor of the lung by bronchoscopy. We recommended surgery, however the patient did not agree to the operation. One year later, two masses were detected in the liver. Ultrasound guided biopsy revealed that they were metastases from the atypical carcinoid tumor of the lung. We recommended chemotherapy, but he refused. Six months later, he was admitted to our hospital for symptoms of flushing, fever, watery diarrhea, and palpitations. We diagnosed this combination of symptoms as carcinoid syndrome, and started the administration of a long acting release (LAR) octreotide. The patient's symptoms improved, but did not resolve completely. We then performed a hepatic artery embolization for the liver metastases, and the symptoms resolved. However, viable lesions of the liver metastases slowly grew and caused a carcinoid crisis. By increasing the dosage of octreotide up to a continuous intravenous infusion of 1500µg/day, as well as LAR 30mg/4weeks, the patient recovered from the crisis. Hepatic artery embolization was performed shortly afterward. Because it was difficult to control the carcinoid syndrome by hepatic artery embolization alone, he underwent a resection of the liver metastases. After the hepatic resection, he has had no recurrence of carcinoid syndrome while still being treated with octreotide LAR.

Pressure accelerates the circadian clock of cyanobacteria.

Although organisms are exposed to various pressure and temperature conditions, information remains limited on how pressure affects biological rhythms. This study investigated how hydrostatic pressure affects the circadian clock (KaiA, KaiB, and KaiC) of cyanobacteria. While the circadian rhythm is inherently robust to temperature change, KaiC phosphorylation cycles that were accelerated from 22 h at 1 bar to 14 h at 200 bars caused the circadian-period length to decline. This decline was caused by the pressure-induced enhancement of KaiC ATPase activity and allosteric effects. Because ATPase activity was elevated in the CI and CII domains of KaiC, while ATP hydrolysis had negative activation volumes (ΔV≠), both domains played key roles in determining the period length of the KaiC phosphorylation cycle. The thermodynamic contraction of the structure of the active site during the transition state might have positioned catalytic residues and lytic water molecules favourably to facilitate ATP hydrolysis. Internal cavities might represent sources of compaction and structural rearrangement in the active site. Overall, the data indicate that pressure differences could alter the circadian rhythms of diverse organisms with evolved thermotolerance, as long as enzymatic reactions defining period length have a specific activation volume.

Funding map using paragraph embedding based on semantic diversity.

Maps of science representing the structure of science can help us understand science and technology (S&T) development. Studies have thus developed techniques for analyzing research activities' relationships; however, ongoing research projects and recently published papers have difficulty in applying inter-citation and co-citation analysis. Therefore, in order to characterize what is currently being attempted in the scientific landscape, this paper proposes a new content-based method of locating research projects in a multi-dimensional space using the recent word/paragraph embedding techniques. Specifically, for addressing an unclustered problem associated with the original paragraph vectors, we introduce paragraph vectors based on the information entropies of concepts in an S&T thesaurus. The experimental results show that the proposed method successfully formed a clustered map from 25,607 project descriptions of the 7th Framework Programme of EU from 2006 to 2016 and 34,192 project descriptions of the National Science Foundation from 2012 to 2016.

Analysis of O2-binding Sites in Proteins Using Gas-Pressure NMR Spectroscopy: Outer Surface Protein A.

Internal cavities in proteins produce conformational fluctuations and enable the binding of small ligands. Here, we report a NMR analysis of O2-binding sites by O2-induced paramagnetic relaxation enhancements (PREs) on amide groups of proteins in solution. Outer surface protein A contains a nonglobular single-layer ß-sheet that connects the N- and C-terminal globular domains. Several cavities have been observed in both domains of the crystallized protein structure. The receptor-binding sites are occluded and line the largest cavity of the C-terminal domain. We observed significant O2-induced PREs for amide protons located around the largest cavity and at the central ß-sheet. We suggested three potential O2-accessible sites in the protein based on the 1/r6 distance dependence of the PRE. Two sites were in or close to the largest cavity and the third site was in the surface crevice of the central ß-sheet. These results provide, to our knowledge, the first evidence of ligand binding to the surface crevice and cavity of the protein in solution. Because O2 generally binds more specifically to hydrophobic rather than hydrophilic cavities within a protein, the results also indicated that the receptor-binding sites lining the largest cavity were in the hydrophobic environment in the ground-state conformation. Molecular dynamics simulations permitted the visualization of the rotational and translational motions of O2 within the largest cavity, egress of O2 from the cavity, and ingress of O2 in the surface crevice of the ß-sheet. These molecular dynamics simulation results qualitatively explained the O2-induced changes in NMR observations. Exploring cavities that are sufficiently dynamic to enable access by small molecules can be a useful strategy for the design of stable proteins and their ligands.

Effect of water impurity in CsLiB6O10 crystals on bulk laser-induced damage threshold and transmittance in the ultraviolet region.

We investigate the effect of water impurity in a CsLiB(6)O(10) (CLBO) crystal on the ultraviolet properties of the bulk laser-induced damage threshold (LIDT) and transmittance. The water impurity was eliminated by heating the CLBO sample with dimensions of 5 mm x 5 mm x 10 mm at 150 degrees C in an ambient atmosphere and subsequently in a dry atmosphere. The bulk LIDT of the sample after heat treatment improved by about 1.6-fold compared with that before heat treatment.

Extracorporeal elimination of TNF-alpha-producing CD14(dull)CD16(+) monocytes in leukocytapheresis therapy for ulcerative colitis.

BACKGROUND: In recent years leukocytapheresis using a leukocyte removal filter (known as lymphocytapheresis, LCAP) has been applied to the treatment of various autoimmune diseases including ulcerative colitis (UC). In the present study we aimed to clarify how LCAP therapy modifies inflammatory responses by modulating circulating TNF-alpha-producing monocytes. METHODS: Mononuclear cells were obtained from blood before and after the first treatment, and the expression profiles of various immune cells (naive versus. memory, regulatory CD4(+)CD25(bright) versus non-regulatory CD4(+)CD25(-) T cells, and CD14(+)CD16(-) versus CD14(dull)CD16(+) monocytes) were assessed. To evaluate immunological differences between CD14(+)CD16(-) and CD14(dull)CD16(+) monocytes, the expression of TNF-alpha, IL-6, IL-12, IL-10, IL-18, surface toll-like receptor 2 (TLR2), TLR4, and other activation markers including HLA-DR, CD80 and CD86, as well as cytokine profiles, were analyzed. RESULTS: LCAP treatment selectively removed CD14(dull)CD16(+) monocytes, which preferentially produce TNF-alpha and IL-12 and express HLA-DR, CD80, CD86, and TLR2, compared with the major fraction of CD14(+)CD16(-) monocytes, which conversely produce a higher amount of IL-10. In addition, the CD4(+)CD45RO(+)CD62L(-)/CD4(+)CD45RO(+)CD62L(+) ratio was significantly lower after LCAP therapy. However, the CD4(+)CD25(bright)/total CD4(+) ratio did not change. CONCLUSIONS: The present findings revealed the real target of proinflammatory CD14(dull)CD16(+) monocytes removed during LCAP treatment of UC and that LCAP might be used as an extracorporeal anti-TNF-alpha therapy, expanding the clinical applications of this procedure to include the treatment of Crohn's disease.

[Case of severe ulcerative colitis successfully treated with intravenous cyclosporine without high dose corticosteroid].

A 44-year-old women developed marked myopathy one year earlier, when she was treated with intravenous prednisolone for acute severe exacerbation of ulcerative colitis. When she was admitted to our hospital for another severe exacerbation, intravenous cyclosporine A was administered as monotherapy because she could not tolerate corticosteroid. The treatment was successful and she obtained complete remission. Cyclosporine A monotherapy is considered to be a valuable alternative to proctocolectomy for severe ulcerative colitis patients who cannot tolerate corticosteroid.

[A case report: Severe bone marrow suppression caused by 6-mercaptopurin in Crohn's disease patient].

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/microl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.

[A case of sacroiliitis complicated by ulcerative colitis that was successfully treated with steroid].

A 23-year-old woman was admitted in November, 2002, complaining pain of the left side and buttock. She had ulcerative colitis when she was 16 and received medical treatment. Based on physical examination and findings of magnetic resonance imaging and bone scintigrapy, as sacroiliitis complicated by ulcerative colitis. was diagnosed Reports on sacroiliitis and ankylosing spondylitis complicated by inflammatory bowel diseases (IBD) are relatively rare in Japan, whereas they are common complications of IBD in Western countries. The efficacy of steroids on pain relief of sacroiliitis and ankylosing spondylitis is unclear.

Ameliorating effect of saporin-conjugated anti-CD11b monoclonal antibody in a murine T-cell-mediated chronic colitis.

BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease that is associated with several changes in the immune system, including an increased number of infiltrating macrophages. These macrophages release a variety of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) which are critically involved in the onset and the development of CD. The present study was performed to explore the initial involvement of macrophages in the development of T-cell-mediated chronic colitis. METHODS: The effects were evaluated of saporin-conjugated anti-CD11b monoclonal antibody (mAb) on the development of chronic colitis in severe combined immunodeficiency (SCID) mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells as an animal model of CD. RESULTS: Significantly increased CD11b-expressing macrophages as well as CD4(+) T cells were found in inflamed colon from colitic mice. Administration of saporin-conjugated anti-CD11b mAb markedly ameliorated the clinical and histopathological disease. In vivo treatment with saporin-conjugated anti-CD11b mAb decreased CD4(+) T-cell infiltration in the colon and suppressed interferon-gamma (IFN-gamma) and TNF-alpha production by lamina propria CD4(+) T cells. CONCLUSIONS: Collectively, the present results suggest an initial role of macrophages in the pathogenesis of T-cell-mediated chronic colitis. Furthermore, the macrophage-specific targeting may be a promising strategy for therapeutic intervention in CD.

TH1/TH2-mediated colitis induced by adoptive transfer of CD4+CD45RBhigh T lymphocytes into nude mice.

BACKGROUND: Transfer of CD4CD45RB T cells from normal donors to SCID/Rag-1, 2-deficient mice, which lack T and B cells, leads to the development of a TH1-mediated inflammatory bowel disease (IBD)-like syndrome characterized by extensive mononuclear cell infiltrates and epithelial cell hyperplasia. Because it is well known that B cells are also involved in a multitude of mechanistic pathways in human IBD, this study attempts to establish a new model of colitis in nude mice. METHODS: We transferred CD4CD45RB T cells into athymic nude mice, which lack thymus-dependent T cells but retain normal B cells, to establish and investigate a B cell-involving chronic colitis model. As a control, CD4CD25 T cells were also used. RESULTS: Mice reconstituted with CD4CD45RB but not CD4CD25 T cells developed a wasting disease, with severe infiltrates of B cell aggregates as well as T cells, macrophages, and dendritic cells into the colon and elevated levels of interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-4, IL-5, and IL-10, by 7 weeks after T cell transfer. Furthermore, the infiltrated lamina propria B cells in colitic nude mice consisted predominantly of massive aggregated immunoglobulin (Ig) M- and scattered IgG-positive cells, but not IgA-positive cells. In contrast, mice reconstituted with CD4CD45RB and CD4CD45RB did not develop wasting disease or colitis. CONCLUSIONS: Collectively, the power of the colitis model induced by the adoptive transfer of CD4CD45RB T cells into nude mice is that one can investigate the roles of TH2-type cells and B cells in a regulatory T cell-depleted condition.

Ectopic CD40 ligand expression on B cells triggers intestinal inflammation.

Several studies indicate that CD4(+) T cells, macrophages, and dendritic cells initially mediate intestinal inflammation in murine models of human inflammatory bowel disease. However, the initial role of B cells in the development of intestinal inflammation remains unclear. In this study we present evidence that B cells can trigger intestinal inflammation using transgenic (Tg) mice expressing CD40 ligand (CD40L) ectopically on B cells (CD40L/B Tg). We demonstrated that CD40L/B Tg mice spontaneously developed severe transmural intestinal inflammation in both colon and ileum at 8-15 wk of age. In contrast, CD40L/B TgxCD40(-/-) double-mutant mice did not develop colitis, indicating the direct involvement of CD40-CD40L interaction in the development of intestinal inflammation. The inflammatory infiltrates consisted predominantly of massive aggregated, IgM-positive B cells. These mice were also characterized by the presence of anti-colon autoantibodies and elevated IFN-gamma production. Furthermore, although mice transferred with CD4(+) T cells alone or with both CD4(+) T and B220(+) B cells, but not B220(+) cells alone, from diseased CD40L/B Tg mice, develop colitis, mice transferred with B220(+) B cells from diseased CD40L/B Tg mice and CD4(+) T cells from wild-type mice also develop colitis, indicating that the Tg B cells should be a trigger for this colitis model, whereas T cells are involved as effectors. As it has been demonstrated that CD40L is ectopically expressed on B cells in some autoimmune diseases, the present study suggests the possible contribution of B cells in triggering intestinal inflammation in human inflammatory bowel disease.