Reduced incidence and severity of accelerated graft atherosclerosis in cardiac transplant recipients treated with prophylactic antilymphocyte globulin.

Allograft coronary artery disease (ACAD) is the major factor limiting long-term survival of cardiac transplant recipients (CTRs). Although cyclosporine based triple drug immunosuppression has not decreased the occurrence of ACAD, some preliminary data suggests that prophylactic antilymphocyte preparations may reduce the incidence of this problem. All CTRs at Henry Ford Hospital have uniformly received prophylactic Minnesota Antilymphocyte Globulin (ALG), thereby providing a unique opportunity to investigate this hypothesis. One hundred three CTRs were followed for a median duration of 34 months with annual angiograms begun one year after transplant. Patients who died without an angiogram were considered to have ACAD based on autopsy results or if their death was clinically suspicious. Ninety-two patients underwent at least one angiogram. Fourteen patients had abnormal angiograms. Nine patients were identified as having ACAD by non-angiographic criteria. Five had autopsy proven disease, 3 died suspiciously, and 1 underwent successful re-transplantation for ACAD. By Kaplan-Meier analysis, the risk of developing ACAD was 12% in 1 year, 16% in 2 years, 22% in 3 years, 26% in 4 years, and 29% in 5 years. Risk of ACAD increased with older recipient's age, higher triglyceride levels, and diabetes, but was not affected by active CMV infection, number of acute rejection episodes, and HLA mismatching. These results suggest that prophylactic ALG reduces the occurrence of ACAD.     

Human tumor strains defective in the repair of alkylated DNA fail to regenerate rapidly-sedimenting nucleoids after N-methyl-N' -nitro-N-nitrosoguanidine treatment

Upon treatment with N-methyl-N'-nitro-N-nitroso-guanidine (MNNG),human cell strains characterized as either proficient or defectiveboth in repair of alkyla-tion-damaged DNA and in supportingthe growth of MNNG-treated adenovirus (Mer⁺ and Mer^– pheno-types(1,2), all underwent a rapid relaxation of nucleokl DNA, asjudged by sedimentation in 15–30% neutral sucrose gradients.DNA in the repair-proficient Mer⁺ strains (normal fibroblastand tumor) was restored to the rapidly-sedimenting (control)form within 2–4 h after the removal of MNNG. In contrast,nucleoid DNA of the repair-deficient Mer^– tumor strainsremained slowly-sedimenting even after 48 h of incubation. Thedelayed recovery of Mer^– nucleoid DNA was specific forMNNG damage, since after u.v. irradiation, to which Mer⁺ andMer^– strains are equally resistant (2), all cell linestested underwent DNA relaxation within the first hour afterirradiation (3 J/m²) and regenerated rapidly-sedimenting nucleoidswithin 4–6 h of repair incubation.     

Rational design,preparation and characterization of recombinant Ag85B variants and their glycoconjugates with T-cell antigenic activity against Mycobacterium tuberculosis

Tuberculosis is the deadliest infectious disease in the world. The variable efficacy of the current treatments highlights the need for more effective agents against this disease. In the past few years, we focused on the investigation of antigenic glycoconjugates starting from recombinant Ag85B (rAg85B), a potent protein antigen from Mycobacterium tuberculosis. In this paper, structural modifications were rationally designed in order to obtain a rAg85B variant protein able to maintain its immunogenicity after glycosylation. Lysine residues involved in the main T-epitope sequences (namely, K30 and K282) have been substituted with arginine to prevent their glycosylation by a lysine-specific reactive linker. The effectiveness of the mutation strategy and the detailed structure of resulting neo-glycoconjugates have been studied by intact mass spectrometry, followed by peptide and glycopeptide mapping. The effect of K30R and K282R mutations on the T-cell activity of rAg85B has also been investigated with a preliminary immunological evaluation performed by enzyme-linked immunospotting on the different variant proteins and their glycosylation products. After glycosylation, the two variant proteins with an arginine in position 30 completely retain the original T-cell activity, thus representing adequate antigenic carriers for the development of efficient glycoconjugate vaccines against tuberculosis.

Recombinant Ag85B variants were designed and prepared to improve the immunogenicity of a potential glycoconjugate vaccine against tuberculosis.     

MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response

MicroRNAs (miRNAs) are small noncoding RNAs, 19-24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs. Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is implicated in tumor-immune system communication and is important in tumor growth and spread, thus representing a possible target for cancer treatment.     

Arterial Anastomosis in Liver Transplantation for Rendu-Osler-Weber Disease: Two Case Reports

Liver transplantation (LT) in patients with hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber, disease is a problematic procedure. In patients with hepatic involvement due to clinically significant arterovenous malformations, there is high risk of intraoperative bleeding and intra- or perioperative complications. Some surgical corrections have been proposed for venous problems, concerning the vena caval anastomosis. A common finding in HHT is arterial enlargement of the celiac trunk and of the common hepatic artery. We report 2 cases of LT in HHT where the arterial anastomosis was successfully performed using the splenic artery of the recipient, which shows less tendency for enlargement than the celiac trunk.     

Value of the 24 hour intraoesophageal pH monitoring in children.

Twenty four hour oesophageal intraluminal pH probe studies were performed in 114 children (range age: one month-12 years) referred for symptoms or signs compatible with gastroesophageal reflux. Forty five patients had reflux disease alone, 69 had evidence of oesophagitis which was assessed endoscopically and histologically. Recordings were also performed in 63 control patients. The occurrence of reflux was analysed for the total study period and particularly while awake, asleep, fasting, and during postcibal periods. Oesophageal acid exposure time and the number of reflux episodes lasting greater than five minutes during the total study period provided the best discrimination between patients and controls; however, 20% and 30% of all reflux patients had both normal (with 2 SD of control) acid exposure time and number of long lasting reflux episodes, respectively. Patients with oesophagitis had significantly more acid reflux than those with simple uncomplicated disease during postcibal, fasting, awake periods, but not during sleep; however, increasing severity of oesophagitis was not associated with increasing acid exposure. The ability of the intraluminal oesophageal pH test to discriminate patients with various degrees of reflux disease decreased if only postprandial pH variables were taken into account. We conclude that: (1) the 24 hour intraoesophageal pH monitoring may present false negative results that limit overall sensitivity of the test; (2) the presence of oesophagitis does not seem to be associated with increased oesophageal acid exposure during sleep; (3) limiting the pH recording to postprandial periods reduces the discriminatory power of the test.     

Comparison of Clinical and Echocardiographic Outcomes After Surgical Redo Mitral Valve Replacement and Transcatheter Mitral Valve-in-Valve Therapy

Objectives

There are minimal data regarding clinical outcomes and echocardiographic findings after transcatheter mitral valve-in-valve replacement (TMVR) compared with redo surgical mitral valve replacement (SMVR).