Retrospective study assessing efficacy and safety of left atrial appendage occlusion.

OBJECTIVE: To describe the initial experience with Amplatzer Amulet in left atrial appendage occlusion in Slovakia. To evaluate procedural efficacy and safety. BACKGROUND: Atrial fibrillation increases the risk of stroke. While anticoagulation therapy can reduce the risk of stroke, it is associated with bleeding risk and often unsatisfactory prescribed. Most thrombi form in the left atrium appendage, hence left atrium appendage occlusion may be a suitable therapeutic alternative for these patients. METHODS: This is an observational, retrospective, single-centre, case-series study including 30 patients with atrial fibrillation at a high risk of stroke, undergoing left atrial appendage occlusion from June 2015 to December 2018. RESULTS: The left atrial appendage was successfully closed in 29 (96.7 %) patients. Three months after the procedure, 4 patients had small leaks (< 2 mm). No complications were reported so far. Prior to the procedure, patients mostly received low molecular weight heparin (53.3 %). Three months after the procedure, patients mostly received acetylsalicylic acid (60.7 %) and clopidogrel (32.1 %). CONCLUSION: Left atrial appendage occlusion was shown to be an effective and safe alternative to anticoagulation therapy in patients with atrial fibrillation, at a high risk of stroke and bleeding. The procedure is safe, when performed carefully even by less experienced cardiologists (Tab. 6, Fig. 4, Ref. 29). Text in PDF www.elis.sk Keywords: atrial fibrillation, stroke, haemorrhage, left atrial appendage occlusion, Amplatzer Amulet.

Tolerability and acceptability of real-time continuous glucose monitoring and its impact on diabetes management behaviours in individuals with Type 2 Diabetes - A pilot study.

INTRODUCTION: Emerging evidence suggests us of real-time continuous glucose monitoring systems (RT-CGM), can assist to improve glucose control in Type 2 Diabetes (T2D) treatment, however the impact of these devices on patients' stress levels and behaviour is poorly understood. This study aimed to examine the effects of RT-CGM on tolerance and acceptability of device wear, stress and diabetes management and motivation to change. METHODS: Twenty adults (10 men, 10 women) with T2D (aged 60.6 ±â€¯8.4 years, BMI 34.2 ±â€¯4.7 kg/m2), were randomised to a low-carbohydrate lifestyle plan whilst wearing a RT-CGM or an 'offline-blinded' (Blinded-CGM) monitoring system continuously for 12 weeks. Outcomes were glycaemic control (HbA1c), weight (kg) perceived stress scale (PSS), CGM device intolerance, acceptability, motivation to change and diabetes management behaviour questionnaires. RESULTS: Both groups experienced significant reductions in body weight (RT-CGM -7.4 ±â€¯4.5 kg vs. Blinded-CGM -5.5 ±â€¯4.0 kg) and HbA1c (-0.67 ±â€¯0.82% vs. -0.68 ±â€¯0.74%). There were no differences between groups for perceived stress (P = 0.47) or device intolerance at week 6 or 12 (both P > 0.30). However, there was evidence of greater acceptance of CGM in the RT-CGM group at week 12 (P = 0.03), improved blood glucose monitoring behaviour in the RT-CGM group at week 6 and week 12 (P ≤ 0.01), and a significant time x group interaction (P = 0.03) demonstrating improved diabetes self-management behaviours in RT-CGM. CONCLUSION: This study provides preliminary evidence of improved behaviours that accompany RT-CGM in the context of diabetes management and glucose self-monitoring. RT-CGM may provide an alternative approach to glucose management in individuals with T2D without resulting in increased disease distress.

Endorsement by the primary care practitioner consistently improves participation in screening for colorectal cancer: a longitudinal analysis.

OBJECTIVES: To investigate the effect of general practice (GP) and general practitioner (GPR) endorsement for faecal occult blood test (FOBT)-based screening on maintenance of participation in screening over four successive screening rounds. SETTING: South Australian residents aged > or = 50 years. METHODS: Random selection of four groups (n = 600 per group): one from the Commonwealth electoral roll (ER) and three from the combined patient lists of two collaborating GPs (GP1, GP2, GP3). Subjects were mailed offers to screen using a faecal immunochemical test over four successive rounds, spaced approximately 18 months apart. The GP1 and ER groups were invited to screen without any endorsement from a GPR or medical practice; GP2 invitees received an invitation indicating support for screening from their medical practice; and GP3 invitations were printed on practice letterhead and were signed by a GPR. RESULTS: Multivariate analyses indicated that initial participation as well as re-participation over four successive rounds was significantly enhanced in the GP2 (39%, 42%, 45% and 44%) and GP3 groups (42%, 47%, 48% and 49%) relative to the ER group (33%, 37%, 40% and 36%). The analyses also indicated that 60-69 year olds were most likely to participate in all rounds (relative risk [RR] 1.49, 1.39, 1.43 and 1.25), and men were generally less likely to participate than women in all screening rounds (RR 0.86, 0.84, 0.80 and 0.83). CONCLUSIONS: Associating a GPR or medical practice of recent contact with an invitation to screen achieves better participation and re-participation than does an invitation from a centralized screening unit. Furthermore, enhanced participation can be achieved by practice endorsement alone without requiring actual GPR involvement.

Brequinar sodium: monitoring immunosuppressive activity.

There has been remarkable consistency in our laboratory for the experimental results derived from a variety of allogeneic and xenogeneic models of organ transplantation using BQR, a primary immunosuppressive agent, to prevent graft rejection. Considerable knowledge exists in a number of species with respect to the dose-response immunosuppressive efficacy, organ specificity, peripheral drug measurements, toxic side-effects, species sensitivity, and synergistic drug interactions. Despite the complexity of transferring experimental results to the clinical setting, the cumulative experience with this new immunosuppressive compound suggests that it may be highly effective when used for clinical transplantation. The identification of a predictive monitoring technique(s) would provide clinicians with a highly sensitive marker to effectively regulate BQR posttransplantation immunosuppressive therapies. Although the maintenance of a "therapeutic window" of immunosuppressive efficacy did not necessarily prevent the rejection of allografts or xenografts in the rat models tested, there was an important correlation between elevated BQR levels and the onset of recipient toxicity. Increased morbidity and mortality was noted when BQR blood levels were elevated above 16 micrograms/mL. The measurement of pyrimidine biosynthetic pathway metabolites provided a direct correlation between graft viability, global depletion of nucleotides (UTP, CTP, ATP, GTP), and suppression of PHA-mitogenic lymphocyte proliferative responses when different doses of BQR were tested. The analysis of these parameters were less informative following combination therapy with CsA. As with other immunosuppressive agents, the difficulty in relying exclusively on plasma trough drug levels as an accurate means to project graft viability may be influenced by individual differences in absorption, metabolism, and excretion of the compound. Additional parameters that may provide valuable information for the posttransplant therapeutic course include drug bioavailability, peak levels, drug clearance, or inhibition of immune response. It is anticipated that these studies will provide important baseline information for further refinement of these monitoring techniques to aid in posttransplant patient management.

The prolongation of concordant hamster-to-rat cardiac xenografts by brequinar sodium.

Brequinar sodium (BQR) prevents cell proliferation by virtue of its inhibition of de novo pyrimidine biosynthesis. The immunosuppressive activity of BQR is highly effective in prolonging heart, liver, and kidney allograft survival in the rat. In these experiments, we have tested the ability of BQR to prevent the rejection of concordant cardiac xenografts. LEW inbred rats transplanted with heterotopic hamster hearts were treated orally with brequinar sodium as a single agent. The survival of the cardiac xenografts was significantly prolonged with a variety of treatment regimens. The most effective treatment was the daily oral administration of BQR at 3 mg/kg. At this level, the median graft survival was approximately 25 days. Four animals had hamster heart xenografts that functioned for more than 90 days. The prolonged survival of the xenografts was associated with relatively constant plasma drug levels of approximately 1 to 3 micrograms/ml and a marked suppression of IgM production. At rejection, there was a significant rise in IgM levels compared with those of recipients with stable xenografts. In vitro MLR responses were effectively inhibited by BQR, with an IC50 of 0.08 microgram/ml. The results of these experiments demonstrate that BQR is a new immunosuppressive agent that is highly effective as a single agent in prolonging the survival of hamster-to-rat cardiac xenografts. The prolonged xenograft survival is associated with effective suppression of rat antihamster antibody production, suggesting that brequinar sodium may be an important addition to multidrug immunosuppressive regimes designed to prevent B and T lymphocyte-mediated immune responses.

Mechanism of action of DuP 721: inhibition of an early event during initiation of protein synthesis.

The mode of action of DuP 721 was investigated. This compound was active primarily against gram-positive bacteria, including multiply resistant strains of staphylococci. Although inactive against wild-type Escherichia coli, DuP 721 did inhibit E. coli when the outer membrane was perturbed by genetic or chemical means. Pulse-labeling studies with E. coli PLB-3252, a membrane-defective strain, showed that DuP 721 inhibited amino acid incorporation into proteins. The 50% inhibitory concentration of DuP 721 for protein synthesis was 3.8 micrograms/ml, but it was greater than 64 micrograms/ml for RNA and DNA syntheses. The direct addition of DuP 721 to cell-free systems did not inhibit any of the reactions of protein synthesis from chain initiation through chain elongation with either synthetic or natural mRNA as template. However, cell extracts prepared from DuP 721 growth-arrested cells were defective in initiation-dependent polypeptide synthesis directed by MS2 bacteriophage RNA. These cell-free extracts were not defective in polypeptide elongation or in fMet-tRNA(fMet)-dependent polypeptide synthesis stimulated by poly(G.U). We conclude, therefore, that DuP 721 exerts its primary action at a step preceding the interaction of fMet-tRNA(fMet) and 30S ribosomal subunits with the initiator codon.

Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721.

DuP 721 (p-acetylphenyloxooxazolidinylmethylacetamide) and DuP 105 (a methylsulfinyl derivative) are orally active representatives of the oxazolidinones, a new class of synthetic antibacterial agents. Their antibacterial spectrum includes staphylococci, streptococci, and Bacteroides fragilis strains. The compounds have equal activity against staphylococcal strains susceptible or resistant to beta-lactam antibiotics, including methicillin-resistant strains. The MICs for 90% of the strains (MIC90s) against staphylococcal isolates were 1 to 4 micrograms/ml for DuP 721 and 4 to 16 micrograms/ml for DuP 105, compared with 1 to 2 micrograms/ml for vancomycin, 0.5 microgram/ml for ciprofloxacin, and 2 to greater than 16 micrograms/ml for imipenem. The MIC90s against group D streptococci were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 2 micrograms/ml for vancomycin, ciprofloxacin, and imipenem. MIC90s against B. fragilis isolates were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 8 micrograms/ml for cefoxitin. DuP 721 and DuP 105 administered by either the oral or the parenteral route were protective against staphylococcal and streptococcal infections in mice. The 50% effective doses were 2 to 10 mg/kg for DuP 721, 9 to 23 mg/kg for DuP 105, and 2 to 12 mg/kg for vancomycin. These results indicate that further studies of compounds of the oxazolidinone series are warranted.

Indications that the erythrocyte receptor involved in enterotoxigenic Escherichia coli attachment is a sialoglycoconjugate.

A reverse hemagglutination assay was used to study adherence to human erythrocytes by Escherichia coli H10407, which possesses colonization factor antigen I. Pretreatment of erythrocytes with trypsin, chymotrypsin, papain, protease, and neuraminidase completely abolished attachment reactivity. In addition, the hemagglutination reaction was prevented by the presence of urea and guanidine. In contrast, the lipases, nucleotide hydrolases, exoglycosidases, and reagents affecting disulfide or sulfhydryl moieties did not alter receptor reactivity. Glycoconjugates containing sialic acid inhibited the hemagglutination reaction. Furthermore, a sialoglycoprotein isolated from the erythrocyte membrane inhibited the hemagglutination reaction. Collectively, these data indicate that the erythrocyte receptor responsible for attachment by E. coli possessing colonization factor antigen I is a sialoglycoconjugate.

Five cephalosporins: pharmacokinetics and their relation to antibacterial potency.

In a group of adult volunteers, pharmacokinetic profiles of five cephalosporins were correlated with their minimal inhibitory concentrations (MICs90) against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter aerogenes. Subjects received the following intravenous regimens in a randomized, crossover fashion: (1) 0.5 gm, 1 gm, or 2 gm of cefazolin; (2) 2 gm of cephalothin; (3) 1 gm of cephapirin; (4) 1 gm of cefoxitin; or (5) 0.5 gm of cefamandole. The 500-mg dose of cefazolin produced serum concentrations that exceeded those of any of the other cephalosporins at 0.5, 1, 2, 4, and 6 hours after administration. The area under the curve for this dose of cefazolin was at least twice that of any of the other antibiotics. Two hours after a 500-mg dose of cefazolin, serum levels exceeded the MIC90 for all seven groups of pathogens; at six hours, the 500-mg dose of cefazolin continued to achieve serum levels above the MIC90 against the majority of bacterial groups. In contrast, at two hours after administration none of the other cephalosporins maintained serum levels above the MIC90 for all pathogens; at six hours, the levels of cephapirin were adequate to inhibit the two streptococci, but serum levels of all other cephalosporins were inadequate to inhibit any of the pathogens. These data indicate that a 500-mg dose of cefazolin maintains serum levels above the MICs90 longer than any of the other cephalosporins tested and support the use of a 500-mg dose of cefazolin every eight hours for surgical prophylaxis and treatment of most community-acquired infections. Such a comparatively low dosage offers substantial savings to both patient and hospital.

Isopycnic separation of Escherichia coli cultures possessing colonization factor antigen I.

A culture of Escherichia coli possessing colonization factor antigen I was subjected to isopycnic separation on Percoll gradients. The results demonstrated successful division of the culture into two populations: (i) bacteria which cause mannose-resistant hemagglutination and (ii) bacteria which lack the ability to hemagglutinate in the presence of mannose.

Use of a hemadsorption technique to evaluate the stability of the hemagglutination reaction of Escherichia coli cultures possessing human colonization factor antigens.

Two strains of Escherichia coli, producing different colonization factor antigens (CFA), were monitored for the population density of CFA-producing bacteria after repeated subculture. The production of CFA was estimated by flooding agar plates containing isolated colonies with suspensions of human or bovine erythrocytes. The erythrocytes were suspended in a low-ionic-strength buffer and were fixed to CFA-positive colonies with a 1.0% tannic acid solution. Strain H-10407, possessing CFA/I fimbriae, showed a rapid loss of the hemagglutinin when subcultured, whereas strain CL-9699, producing CFA/II, was very stable. By using the hemadsorption assay, we could rapidly and easily distinguish CFA- positive colonies from the CFA-negative variants. A survey of additional E. coli strains demonstrated the utility and specificity of the hemadsorption technique used.

Analysis of parameters affecting the hemagglutination activity of Escherichia coli possessing colonization factor antigens: improved medium for observing erythrocyte agglutination.

The hemagglutination (HA) activity of two strains of Escherichia coli, each possessing different colonization factor antigens (CFA), was examined under different test conditions. The effects of ionic strength, temperature, pH, cations, and reaction surface on erythrocyte (RBC) agglutination were analyzed. Strain H-10407 (CFA/I) caused the agglutination of human, bovine, and chicken RBC, whereas strain CL-9699 (CFA/II) agglutinated only bovine and chicken RBC. The HA activity of both strains increased with decreasing ionic strength, pH, and temperature, the effects of temperature being negligible at low ionic strength. When accounting for ionic strength, the presence of Ca2+, Mg2+, Fe2+, or Fe3+ ions did not increase the HA activity of these bacteria. Optimum conditions for HA of reactive RBC by bacteria included low ionic strength (less than 50 mM) and slightly acidic pH (6.0 to 7.0). Use of a low-ionic-strength medium permitted application of microtitration methods to visualize the HA reactions. Storage of RBC in low-ionic-strength medium did not change their HA properties, and the use of this medium proved superior to saline in overcoming HA variation observed with different preparations of RBC.

In vitro and in vivo laboratory studies on three hydroxyiminophenylacetyl cephalosporins with particular reference to SK&F 80303, an unusually long-acting cephalosporin.

Three cephalosporins with 7-(2-hydroxyiminophenylacetamido) side chains (SK&F 79433, 80000 and 80303), differing in their 3-substituents, exhibited similar broad-spectrum antibacterial activity in vitro against strains of Staphylococcus aureus, Streptococcus faecalis and various Gram-negative bacilli. All three were active in vivo (s.c., mouse) against S. aureus, Escherichia coli or Klebsiella pneumoniae, but they differed significantly in serum pharmacokinetic profiles. SK&F 80303 produced high and extremely prolonged serum levels and protected mice when administered up to 24 hours prior to challenge with beta-lactamase-producing S. aureus or K. pneumoniae. It was resistant to hydrolysis by beta-lactamases from S. aureus, and variably so to beta-lactamases from E. coli strains. SK&F 80303 was bacteriolytic to logarithmically growing S. aureus, E. coli, Proteus mirabilis, K. pneumoniae and Enterobacter cloacae (partially). SK&F 80303 illustrates further the effect of the 3-sulfoalkyltetrazole substituent on the pharmacokinetic properties of cephalosporins. Its combined biological properties make it a possible candidate for therapeutic and long-term prophylactic use.