The effect of ITF-1697 on reperfusion in patients undergoing primary angioplasty. Safety and efficacy of a novel tetrapeptide, ITF-1697.

AIM: ITF-1697 is a C-reactive protein-derived tetrapeptide that, based on pre-clinical studies, is thought to reduce reperfusion injury. We performed a dose-finding study to assess safety, preliminary efficacy and clinical outcome of prolonged i.v. infusion of ITF-1697 in patients with an acute myocardial infarction (AMI) who were eligible for percutaneous coronary intervention (PCI). METHODS AND RESULTS: This was a multicentre dose-finding study that was randomised, double blind, and placebo-controlled. Four hundred and two patients were enrolled. Intravenous infusion of four dosages of ITF-1697 (0.1, 0.5, 1.0 or 2.0 microg/kg/min) or placebo was started before PCI and continued for 24 h. After interim analysis of data from 242 patients the study continued with the 0.1 and 1.0 microg/kg/min ITF-1697 regimes. Analysis did not raise any safety concerns. Post-procedure perfusion, assessed by TIMI flow, corrected TIMI frame count, blushgrade and ST-segment resolution, was similar for the placebo, 0.1 and 1.0 microg/kg/min regimes. Furthermore, the results showed no differences between the treatment regimes in enzymatic infarct size or clinical outcome up to 30 days. CONCLUSION: ITF-1697 was well tolerated. However, neither a dose-relation nor improvement of perfusion, clinical outcome or reduction of myocardial damage could be demonstrated with ITF-1697 during and after primary PCI for AMI.     

Dextran Sulfate Sodium-Induced Colitis Is Associated with Enhanced Low Molecular Mass Polypeptide 2 (LMP2) Expression and Is Attenuated in LMP2 Knockout Mice

Low molecular mass polypeptide 2 (LMP2) is an inducible proteasome subunit. Our goals were to examine LMP2 expression in mice with dextran sulfate sodium (DSS)-induced colitis and to evaluate colitis in LMP2 knockout (LMP2-/-) mice. Mice were given 2.5% DSS in the drinking water. On day 0, 2, 4, or 6 after DSS treatment, LMP2 expression was determined in the distal colon by western blot and immunohistochemistry. Parameters of colitis were measured in LMP2-/- mice or wild-type mice. LMP2 expression was enhanced in the colon of DSS-treated mice at all time points. Symptoms of DSS-induced colitis were always lower in LMP2-/- mice. Normalized histology scores and colonic IL-1ss levels increased over the 6-day study period in wild-type mice. These parameters were significantly reduced in LMP2-/- mice that consumed DSS for 6 days. Enhanced LMP2 expression contributes to the pathogenesis of DSS-induced colitis in mice.     

Cap Is the Protease of the Porcine Circovirus 2

Circoviruses are the smallest single-stranded DNA viruses that infect mammalian species, avian species, fish, and insects. The infections of circoviruses are known to be associated with a series of fatal diseases, but the protease of circovirus still remains unknown. In this research, we identified viral capsid protein (Cap) as the protease of porcine circovirus type 2 (PCV2), to our knowledge the first circoviruses protease to be reported. First, we found that the expression of host proteins is affected due to PCV2 infection in the porcine kidney (PK-15) cells. Then, by proteomic analysis, 253 host proteins that were down regulated were identified due to direct or indirect effects of PCV2. Further, Cap expression, but not other ORFs of PCV2, significantly reduced both JMJD6 (bifunctional arginine demethylase and lysyl-hydroxylase) and CCT5 (the chaperonin containing TCP1 subunit 5) in PK-15 cells. Finally, the results in vitro hydrolysis assays demonstrated that Cap could directly degraded either JMJD6 or CCT5 with different catalytic efficiency. In summary, our study expands repertoire of PCV2 Cap and promotes the development of inhibitors toward the anti-PCV2.     

2型糖尿病患者与正常人骨密度的比较

目的　探讨2型糖尿病(T2DM)患者的骨密度(BMD)是否低于正常人。　方法　肾功能正常的T2DM患者615例,与同一地区1116名正常人的BMD比较。　结果　(1)女性 T2DM患者各年龄组腰椎和股骨Ward区的BMD均与正常人近似; 男性 T2DM患者 40 岁和 60 岁以上年龄组腰椎和股骨Ward区的BMD与正常人近似,但是50岁和70岁以上年龄组高于正常人(P<0.05)。(2)多元线形回归分析显示,影响女性T2DM患者 BMD的因素为年龄、体质指数(BMI)和总胆固醇水平,而影响男性T2DM患者的 BMD的因素为 BMI和餐后胰岛素水平。　结论　肾功能正常的T2DM患者的BMD不比正常人低。     

Gastric PCO2 Tonometry Is Independent of Carbonic Anhydrase Inhibition

Tonometric measurement of an elevatedintragastric PCO₂ and a decreased calculatedgastric intramucosal pH can be used to detect gastricmucosal ischemia, provided that intraluminal productionof CO₂ through acid buffering by bicarbonate is avoided byadequate acid secretion suppression. If the diffusionrate is known, steady state PCO₂ can becalculated when measurement intervals are used that areshorter than needed for complete equilibration. TheCO₂ diffusion might be influenced by thechoice of acid-suppressive drugs, since some of theminhibit gastric carbonic anhydrase (CA) and CAfacilitates diffusion of CO₂/bicarbonate over thegastrointestinal mucosa. We therefore performed gastricPCO₂ tonometry, using acidsuppressiveregimens with and without CA inhibition. The diffusionrate of CO₂ in a gastric tonometer was studied in healthy volunteers,following intravenously administered ranitidine (groupI, N = 8) or ranitidine plus pirenzepine (group II, N =12), a muscarinic antagonist with CA inhibitingcapacities. Measurement intervals were 10, 20, 30 and 60min. Neither the diffusion rate of CO₂ (k =0.13 ± 0.02/min in group I and 0.11 ±0.02/min in group II), nor the steady-statePCO₂ (38 ± 3 mm Hg in group I and 40± 4 mm Hg in group II), nor the gastric- blooddifferences in PCO₂ and pH differed betweengroups. These results indicate that diffusion ofCO₂ into the tonometer balloon is independentof CA and thus of the type of gastric acid secretioninhibition.     

Evidence that the Granulocyte-Specific Antigen NC1 Is Identical with NA2

The neutrophil-specific antigen NC1 is defined by an antibody in the serum of a mother who gave birth to a child with alloimmune neonatal neutropenia. NC1 has been reported to be associated with the neutrophil-specific antigen NA2, but the precise relation of NC1 and NA2 remained unclear. Therefore, we investigated the serum using the antigen capture assay MAIGA and the granulocyte (GIFT) and lymphocyte (LIFT) immunofluorescence tests. In GIFT, no NA association was observed. In LIFT, serum antibodies bound preferably to lymphocytes with the HLA antigens HLA-B7 and cross-reacting antigens. In MAIGA, an antibody specific for the NA2 variant of the granulocyte Fcγ-receptor III was observed. The NA2 specificity was confirmed by testing granulocytes from 40 further different donors. This indicates that the NC1 and NA2 antigens are identical. A positive GIFT result but a negative one in LIFT using cells of an NA2-negative typed individual suggest the presence of an additional, non-NA2-specific granulocyte antibody.     

Alloantiserum Recognizing a DQw2 Split Which Is Associated with DR3

A typing serum MUE 38539 II, was found to recognize a DR3-associated split of DQw2. In cytotoxicity tests, MUE 38539 II yielded positive test results with B lymphocytes but not with monocytes of DR3-positive cell donors. This was in contrast to other typing reagents for DR3 that react with B lymphocytes as well as monocytes. Lymphocytotoxicity tests using MUE 38539 II were negative with DR7- and DQw2-positive cells. The assumption that the serum recognizes a DR3-associated split of DQw2, and not DR3 itself, was confirmed by the lack of reactivity with a DQw4- and DR3-positive lymphoblastoid cell line (RSH). The assumption was also corroborated using reagents from a family in which DR3 and DQw2 were not found in the usually described linkage. In two lines, DR3 was associated with DQw- (2707 and 2710), and in the cell line 2704, DQw2 was associated with DRw-. The serum MUE 38539 II was exclusively cytotoxic with lymphoblastoid cell lines from those family members who were positive for DQw2, independently of the DR3 antigens of the cells.     

The Viral Chemokine Macrophage Inflammatory Protein-II Is a Selective Th2 Chemoattractant

Kaposi's sarcoma (KS) lesions are characterized by a prominentleukocyte infiltrate composed of mononuclear phagocytes and T cells.KS-associated CD4⁺ and CD8⁺ cells showedpredominantly a type II cytokine profile. The CC chemokine viralmacrophage inflammatory protein-II (vMIP-II) encoded by theKS-associated herpes virus 8 was a selective chemoattractant for Thelper 2 (Th2 cells) and for monocytes, whereas it was inactive onother leukocytes, including Th1 cells, dendritic cells, and naturalkiller (NK) cells. vMIP-II was an agonist for CCR8, a chemokinereceptor selectively expressed on CD4⁺ andCD8⁺ cells with a type II cytokine profile. Hence,vMIP-II has agonist activity for a chemokine receptor (CCR8), which ispreferentially expressed on polarized Th2 cells. The capacity ofvMIP-II to attract type II T cells selectively is likely to be acomponent of the virus strategy to subvert the host immune response.     

Fatal Neurodissemination and SARS-CoV-2 Tropism in K18-hACE2 Mice Is Only Partially Dependent on hACE2 Expression

Animal models recapitulating COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Intranasally inoculated transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. We evaluated the clinical and virological dynamics of SARS-CoV-2 using two intranasal doses (10⁴ and 10⁶ PFUs), with a detailed spatiotemporal pathologic analysis of the 10⁶ dose cohort. Despite generally mild-to-moderate pneumonia, clinical decline resulting in euthanasia or death was commonly associated with hypothermia and viral neurodissemination independent of inoculation dose. Neuroinvasion was first observed at 4 days post-infection, initially restricted to the olfactory bulb suggesting axonal transport via the olfactory neuroepithelium as the earliest portal of entry. Absence of viremia suggests neuroinvasion occurs independently of transport across the blood-brain barrier. SARS-CoV-2 tropism was neither restricted to ACE2-expressing cells (e.g., AT1 pneumocytes), nor inclusive of some ACE2-positive cell lineages (e.g., bronchiolar epithelium and brain vasculature). Absence of detectable ACE2 protein expression in neurons but overexpression in neuroepithelium suggest this as the most likely portal of neuroinvasion, with subsequent ACE2 independent lethal neurodissemination. A paucity of epidemiological data and contradicting evidence for neuroinvasion and neurodissemination in humans call into question the translational relevance of this model.