Anticoagulation management of postoperative atrial fibrillation after cardiac surgery: A systematic review.

BACKGROUND: Postoperative atrial fibrillation (POAF) often complicates cardiac surgery and is associated with increased mortality and risk of thromboembolism. However, the optimal oral anticoagulation (OAC) strategy is uncertain. We performed a systematic review to examine the OAC practice patterns and efficacy in these circumstances. METHODS: MEDLINE and EMBASE were searched from 2000 to 2019 using the search terms cardiac surgical procedures, cardiac surgery, postoperative complications, atrial fibrillation, atrial flutter, and terms for anticoagulants. Collected data included anticoagulation patterns (time of initiation, type, and duration) and outcomes (stroke, bleeding, and mortality). RESULTS: From 763 records, 4 prospective and 13 retrospective studies were included totaling 44,908 patients with 8929 (19.9%) who developed POAF. Anticoagulation rates ranged from 4% to 43% (mean 21% overall). Sixteen studies used warfarin, 3 nonvitamin K OAC (NOAC), and 2 both. Four studies reported the use of bridging unfractionated or low-molecular-weight heparin. Concomitant antiplatelet therapy was reported in half the studies, ranging from 80% to 99%. OAC use was associated with lower risk of thromboembolic events in two retrospective studies (including a national Danish cohort with 2108 patients with POAF). Patients discharged on warfarin experienced reduced mortality in a large, single center, retrospective analysis, but no association was observed in the Danish cohort. CONCLUSION: There is wide practice variation in the uptake, timing of initiation, duration, and choice of OAC for POAF following cardiac surgery. The evidence is largely retrospective and insufficient to assess the efficacy of different OAC strategies. Further studies are warranted to guide clinical practice.

Regulatory interventions improve the biosynthesis of limiting amino acids from methanol carbon to improve synthetic methylotrophy in Escherichia coli.

Synthetic methylotrophy aims to engineer methane and methanol utilization pathways in platform hosts like Escherichia coli for industrial bioprocessing of natural gas and biogas. While recent attempts to engineer synthetic methylotrophs have proved successful, autonomous methylotrophy, that is, the ability to utilize methane or methanol as sole carbon and energy substrates, has not yet been realized. Here, we address an important limitation of autonomous methylotrophy in E. coli: the inability of the organism to synthesize several amino acids when grown on methanol. We targeted global and local amino acid regulatory networks. Those include removal of amino acid allosteric feedback inhibition (argAH15Y , ilvAL447F , hisGE271K , leuAG462D , proBD107N , thrAS345F , trpES40F ), knockouts of transcriptional repressors (ihfA, metJ); and overexpression of amino acid biosynthetic operons (hisGDCBHAFI, leuABCD, thrABC, trpEDCBA) and transcriptional regulators (crp, purR). Compared to the parent methylotrophic E. coli strain that was unable to synthesize these amino acids from methanol carbon, these strategies resulted in improved biosynthesis of limiting proteinogenic amino acids (histidine, leucine, lysine, methionine, phenylalanine, threonine, tyrosine) from methanol carbon. In several cases, improved amino acid biosynthesis from methanol carbon led to improvements in methylotrophic growth in methanol minimal medium supplemented with a small amount of yeast extract. This study addresses a key limitation currently preventing autonomous methylotrophy in E. coli and possibly other synthetic methylotrophs and provides insight as to how this limitation can be alleviated via global and local regulatory modifications.

The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis.

The study aims to investigate the frequency of CD4(+)CD25(+)Foxp3(+)CD127(-) T regulatory cells (Tregs) and the expression of CCR4, CCR6 and/or other chemokine receptors on Tregs in peripheral blood (PB) in patients with rheumatoid arthritis, as well as in PB, draining lymph nodes (dLNs), lungs and spleens in collagen-induced arthritis (CIA) mice. We also study the possible role of CCR4 and CCR6 abnormal expression on Tregs in RA patients and the underlying mechanisms. The numbers of Tregs and chemokine receptors expression profile on Tregs in PB from RA patients and healthy controls were investigated by flow cytometry (FACS) using three- or four-color intracellular staining. DBA/1 Foxp3(gfp) reporter mice were immunized with collagen II (CII) emulsified with CFA. At day 60 after CII immunization, mice were sacrificed and Foxp3 (GFP) expression in PB, dLNs, Lungs and spleens was examined by FACS. The numbers of Tregs in PB were significantly lower in RA patients than in healthy controls (1.21±0.43% vs 3.50±0.98%, P<0.05). The levels of chemokine receptor CCR4 or CCR6 expression on Tregs in PB were higher in active RA patients than in healthy controls (91.13±2.98% vs 79.45±4.72%, P<0.05; or 67.33±7.53% vs 42.73±5.60%, P<0.05). The levels of CCR4 or CCR6 expression on Tregs in active RA patients were positively correlated to DAS28 scores (r=0.42, P<0.03; or r=0.58, P<0.02). Similarly, the numbers of CCR6 expression on GFP(+) cells in the spleens, dLNs, lungs and blood of CIA were all increased than those of normal mice (P<0.01). Frequency of CCR4 expression on GFP(+) cells in dLNs of CIA was somehow higher but slightly lower in the spleens of CIA compared to normal mice without significant differences (P>0.05). Frequency of CCR5 expression on GFP(+) cells in the spleens and dLNs of CIA were both increased than those of normal mice, but there were no significant differences (P>0.05). CCR7 or CCR9 expression on Tregs from spleen and dLN of either normal or CIA mice was undetectable. Although the frequency of CD4(+)Foxp3(+)Tregs in peripheral blood was decreased in active rheumatoid arthritis patients, the levels of chemokine receptors such as CCR4 and CCR6 among the Tregs were increased, implicating that Tregs in active RA have obtained the ability migrating to inflammatory joints and may reflect the feedback regulation of the body to local inflammation. Furthermore, CCR4 and CCR6 expressed on Tregs may be related to the activity and severity of RA.

Pathologic finding of increased expression of interleukin-17 in the synovial tissue of rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a common autoimmune disease of chronic systemic inflammatory disorder that will affect multiple tissues and organs such as skin, heart or lungs; but it principally attacks the joints, producing a nonsuppurative inflammatory and proliferative synovitis that often progresses to major damaging of articular cartilage and joint ankylosis. Although the definite etiology is still unknown, recent studies suggest that T-helper cells (Th17) may play a pivotal role in the pathogenesis of RA. And interleukin-17 (IL-17), which is a cytokine of Th17 cells, may be a key factor in the occurrence of RA. The binding of IL-17 to specific receptor results in the expression of fibroblasts, endothelial and epithelial cells and also synthesis of several major factors such as tumor necrosis factor alpha (TNF-α), IL-1ß that result in the structural damage of RA joints. Though some previous studies have shown that IL-17 exists in the synovium of RA, few has definite proof quantitatively by pathology about its existence in synovial membrane. This study comprised of 30 RA patients and 10 healthy control, pathologic study of the synovial membrane showed increased expression of IL-17 in the synovial tissue of RA patients, the intensity is compatible with clinical severity of disease as validated by DAS28 score and disease duration. Northern blot study also confirmed the increased expression of IL-17 in the synovial tissues. This study sheds further light that IL-17 may be a key factor in the pathogenesis of RA and a determinant of disease severity.

Pathologic diagnosis of spontaneous splenic rupture in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a common autoimmune disease that involved multiple organ systems. Diagnosis is usually not difficult. However, SLE involved spleen with spontaneous rupture is a rare condition that has been only 5 cases reported previously; and no definite pathologic diagnosis has been reported. We present the case of a 54 year-old white American woman who had SLE for 10 years with multiple immunosuppressive agents treatment at stable condition. She had acute abdomen presented to the emergency department and received timely surgical treatment which confirmed she had spontaneous spleen rupture (SSR). Detailed pathologic study, with control of a traumatic rupture spleen of almost the same age and sex, revealed marked congestion of the red pulp and atrophy of white pulp notified in the SLE spleen. Congestion of red pulp may be the cause of SSR in the SLE spleen.

Quantitative measurement of mRNA coding for the receptors controlling acid secretion in the ovine fundus and antrum by using RT-PCR.

BACKGROUND AND AIMS: Gastric acid secretion is stimulated by the action of gastrin, histamine and acetylcholine on their respective receptors. To determine the regulation of synthesis of these receptors during different gastric secretory states a competitive RT-PCR method for quantitating the mRNA for these receptors was developed. METHODS: Partial cDNA clones (400-500 base pairs (bp)) for the ovine gastrin, histamine (H2) and acetylcholine (M3) receptors were isolated and sequenced. These cDNA constructs were modified by the inclusion of approximately 100 bp of unrelated sequence within the plasmids. cDNA was synthesized from a mixture of known amounts of RNA transcribed from the modified plasmids and from total RNA extracted from sheep stomach. Proportional coamplification of mixed cDNA was demonstrated using common primer sets. RESULTS: All three receptors were more highly expressed in the fundus than the antrum. The concentration of cholecystokinin-B/gastrin receptor mRNA was 75-fold higher in the fundus than in the antrum, and the concentration of both histamine and acetylcholine receptor mRNA were fivefold higher in the fundus than in the antrum. Infusion of gastrin caused a significant increase in fundic histamine mRNA receptor expression, but not in the expression of the gastrin or muscarinic receptors. CONCLUSIONS: No significant differences were observed in the levels of receptor mRNA between normal adult and fetal animals despite markedly reduced gastric secretion in the fetus, suggesting that gastric receptor gene expression is not the rate-limiting factor in determining gastric acid secretion in the neonatal animal.

Decreased antitoxic activities among children with clinical episodes of malaria.

Healthy Gambian children, children with clinical Plasmodium falciparum malaria, and children with asymptomatic P. falciparum infections were studied to investigate whether antitoxic activities may contribute to protection against malarial symptoms. Markers of inflammatory reactions, soluble tumor necrosis factor receptor I, and C-reactive protein were found in high concentrations in children with symptomatic P. falciparum malaria compared with levels in children with asymptomatic P. falciparum infections or in healthy children, indicating that inflammatory reactions are induced only in children with clinical symptoms. Concentrations of soluble tumor necrosis factor receptor I and C-reactive protein were associated with levels of parasitemia. We detected antitoxic activities in sera as measured by their capacity to block toxin-induced Limulus amoebocyte lysate (LAL) activation. Symptomatic children had decreased capacity to block induction of LAL activation by P. falciparum exoantigen. The decreased blocking activity was restored in the following dry season, when the children had no clinical malaria. Symptomatic children also had the highest immunoglobulin G (IgG) reactivities to conserved P. falciparum erythrocyte membrane protein 1 and "Pfalhesin" (band #3) peptides, indicating that such IgG antibodies are stimulated by acute disease but are lost rapidly after the disease episode. Half of the children with symptomatic infections had low levels of haptoglobin, suggesting that these children had chronic P. falciparum infections which may have caused symptoms previously. Only a few of the children with asymptomatic P. falciparum infections had high parasite counts, and antitoxic immunity in the absence of antiparasite immunity appears to be rare among children in this community.

Molecular cloning and sequence of the ovine gastrin gene.

A clone encoding ovine preprogastrin was isolated from a sheep genomic library. The deduced 104 amino acid sequence of ovine preprogastrin was 92% and 68% identical to the sequences of bovine and human preprogastrin, respectively. While the similarity was greatest in the gastrin-17 sequence, and unexpected similarity was also observed in the N-terminus of mature progastrin.

Integration of endochondral bone grafts in the presence of demineralized bone matrix.

The use of endochondral bone grafts (EC) and demineralized bone matrix (DBM), which contains a potent osteoinductive matrix, may promote the repair of nonregenerative defects. The purpose of the current work is to assess qualitatively and quantitatively the effect of DBM on the healing of EC bone grafts and to compare it to the healing of EC bone grafts alone. Twenty-four defects in rabbit skulls were filled with EC bone grafts alone, DBM alone, or combined EC and DBM. Histologic and immunohistologic changes were examined in 2 weeks. The amount of new bone formation was quantified by image analysis. Healing of all the groups was characterized by the presence of a cartilage intermediate stage. In the EC bone grafts alone, healing was localized to the host bone/graft interface. In the composite group, amalgamation of the new bone, DBM, and bone graft progressed throughout the whole width and depth of the defect, uniting the graft to the recipient bed. The amount of new bone formed was significantly greater (47%) in the composite group than the EC group. In conclusion, DBM powder augments the bone-induction capacity of the recipient bed as well as the bone graft. The composite EC bone grafts and added DBM possess properties required for an effective graft material and merit further clinical evaluation.

Soluble products of inflammatory reactions are not induced in children with asymptomatic Plasmodium falciparum infections.

A proportion of children with Plasmodium falciparum infection have a high parasitaemia without accompanying fever, indicative of different clinical thresholds of parasitaemia. Higher levels of IL-10, IL-1Ra and sIL-4R but not sIL-2R were found in children with P. falciparum malaria, compared with levels in children with asymptomatic P. falciparum infections and in healthy children. Concentrations of IL-10 and IL-1Ra were correlated with levels of parasitaemia, but the association of cytokine levels with disease was independent of the association with parasitaemia. Children may tolerate a high parasitaemia by neutralizing the parasite-derived toxins. When studying potential anti-toxic molecules we found that children with symptomatic infections had lower concentrations of a phospholipid-binding molecule, beta 2-glycoprotein I (beta 2-GPI), compared with children with asymptomatic infections or healthy children. In conclusion, cytokines were found in much higher concentrations in children with symptomatic P. falciparum malaria than in children with asymptomatic infections, whilst the former had lower concentrations of beta 2-GPI.

Dose-finding study of imidapril, a novel angiotensin converting enzyme inhibitor, in patients with stable chronic heart failure.

OBJECTIVE: To study the haemodynamic profile and tolerability of imidapril, a new long-acting ACE inhibitor, and to investigate the effect of inhibition of circulating ACE on blood pressure in patients with stable chronic heart failure. METHODS: Twenty-four patients with stable, chronic heart failure (New York Heart Association (NYHA) functional Class II-III) were randomised to receive either 2.5 mg or 5 mg imidapril. Other vasodilators were withheld for > or = 5 half-lives. Blood pressure and ACE activity were carefully monitored for 24 h after dosing. RESULTS: Both 2.5 mg and 5 mg imidapril decreased systolic blood pressure, while diastolic blood pressure fell only after 5 mg imidapril. The two doses produced a significant and similar inhibition of circulating (serum) ACE. No serious adverse effects were observed, although symptomatic hypotension occured in 1 patient (5 mg). The decrease in blood pressure was not related to baseline ACE activity, serum sodium or serum creatinine concentration. CONCLUSIONS: Imidapril significantly lowered systolic blood pressure and was well tolerated. The difference in the first dose response to the two doses with respect to diastolic blood pressure suggests that this haemodynamic effect of ACE-inhibition is not related to inhibition of circulating ACE.

[Effects of ethylene oxide on hepatic microsomal cytochrome P-450: an in vitro study].

The effect of ethylene oxide on rat hepatic microsomal cytochrome P-450 was studied in vitro. Cytochrome P-450, but not b5, was decreased by ethanol. When hepatic microsome was bubbled with ethylene oxide gas, cytochrome P-450 content remained unchanged when compared with CO2 bubbling. The addition of NADPH 1 mM also did not change cytochrome P-450 significantly. The excessive high exposure to 500 mM ethylene oxide also did not affect microsomal cytochrome P-450. These results indicate that ethylene oxide does not destroy directly the hepatic microsomal cytochrome P-450 under these conditions.