Glaucoma after penetrating keratoplasty and keratoprosthesis.

PURPOSE: To compare visual and glaucoma outcomes in patients with known glaucoma after a penetrating keratoplasty (PKP) or a Boston Keratoprosthesis Type 1 (KPro) as a second corneal replacement procedure. DESIGN: Retrospective interventional case series. PARTICIPANTS: Charts of 141 eyes that underwent either a PKP or KPro at the Centre hospitalier de l'Université de Montréal after one failed PKP from 2008 to 2020 were reviewed. Forty-six eyes with preoperative glaucoma were included. METHODS: Data collected included demographics, indication for the initial surgery, best corrected visual acuity (BCVA), concurrent ocular disorders, number of glaucoma medications, need for glaucoma surgery, cup-to-disc ratios (CDRs), mean RNFL thickness, and visual field (VF) characteristics. Primary outcomes were glaucoma progression trends. Secondary outcomes were visual outcomes and need for additional procedures. RESULTS: Mean follow-up was 4.7 years for the PKP and 7.3 for the KPro group (P<0.007). 30.6% of PKP compared to 70.5% of KPro patients were diagnosed with glaucoma preoperatively. Glaucoma worsened similarly in both groups; this is based on an analysis of the number of glaucoma medications, CDR, need for glaucoma surgery, and characteristic VF changes. Patients in the PKP group required significantly more regrafts than patients in the KPro group (31.8 vs. 8.3%; P=0.045). CONCLUSIONS: A preoperative diagnosis of glaucoma does not preclude KPro implantation. In glaucomatous eyes, the disease progressed similarly in both groups. Since both procedures increase the risk of worsening glaucoma, close follow-up is recommended. KPro may decrease the need for further corneal transplantation surgery.

[Toxicity of metformin, pro- or con- a future restriction to its contraindications?]. / Toxicité de la metformine: pour ou contre une restriction de ses contre-indications?

Type 2 diabetes, a world-wide epidemic, is a major concern of health systems around the world. The recommandation of its early management with metformin by the majority of guidelines has made metformin the object of multiple studies to demonstrate its benefits, but more importantly its side effects among whom the most serious is lactic acidosis. The latter is rare, but responsible for high mortality rates and is strongly associated with acute and chronic conditions for which diabetics are prone. These conditions reduce tissue perfusion and activate anaerobic metabolism producing lactate. Despite the beneficial effects of metformin and the debate about its causal role, we should remain vigilant about this serious complication by respecting its usage's contraindications, for the time being unchanged.

Linezolid in the treatment of vancomycin-resistant Enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate-use trial.

Vancomycin-resistant Enterococcus faecium (VRE) is increasing in incidence in solid organ transplant recipients and has a high (up to 83%) associated mortality rate. Until recently, there have been no consistently effective antimicrobial therapies for VRE infection. Linezolid is a new antibiotic that belongs to the class of oxazolidinones approved by the FDA for the treatment of VRE infections, including those with bacteremia. Here, we report the experience with linezolid in an open-label, compassionate-use trial at 53 US centers for the treatment of documented VRE infections in patients with solid organ transplants. Eighty-five patients with solid organ transplants and documented VRE infections were studied. Blood cultures were positive for VRE in 43 patients, while 42 patients had other, non-rectal, sites of infection. Fifty-three patients responded well to treatment, with clinical resolution of the infection (62.4% survival rate). Of these, 47 had documented negative cultures post therapy. The mean duration of therapy for cured patients was 23.5 days. Thirty-two (37.6%) patients died, 28 due to sepsis and organ failure (32.9% failure rate), and 4 due to unrelated causes. Mortality rates for patients with bacteremia were comparable to mortality rates observed with patients who had positive cultures from other sites. Adverse reactions to linezolid included thrombocytopenia (4.7%), decreased leukocyte count (3.5%), and an increase in blood pressure (1.2%), none of which led to discontinuation of therapy. Linezolid appears to be a safe and effective treatment option for VRE, even in the presence of bacteremia, and may lead to decreased mortality in solid organ transplant recipients with VRE infection.

Postmenopausal tubo-ovarian abscess due to Pseudomonas aeruginosa in a renal transplant patient: a case report and review of the literature.

BACKGROUND: Pseudomonas aeruginosa is an uncommon cause of infection in the female genital tract. We report a case of postmenopausal tubo-ovarian abscess (TOA) due to P. aeruginosa in a renal transplant recipient. The presentation included mild abdominal symptoms with rapid progression of peritonitis and surgical abscess drainage. This is the first such case in an organ transplant recipient described in the English literature. METHODS AND RESULTS: Published reports of 1040 cases of TOA were reviewed. The most common features were a history of sexually transmitted disease or pelvic inflammatory disease, and symptoms including abdominal pain and fever. Escherichia coli, Bacteroides spp., and Klebsiella pneumoniae were the most frequently encountered pathogens. Neisseria gonorrhoeae and Chlamydia trachomatis, which are frequently isolated from cervical cultures, are uncommonly isolated from tubo-ovarian abscesses. Forty percent of patients were treated with antibiotics alone, 18.8% with abdominal surgery, and 32% with surgery and antimicrobial therapy. CONCLUSION: This report illustrates the muted presentation and atypical microbiology of gynecologic infection in an organ transplant recipient.

MR arthrography of the hip: normal intra-articular structures and common disorders.

This pictorial review illustrates the anatomical features of normal intra-articular components of the hip and their common disorders on MR arthrography. On T1-weighted MR arthrograms, the normal contrast-filled joint cavity shows a homogeneous high signal intensity. Normal acetabular labrum appears as a well-delineated triangle showing a low signal intensity, surrounded by contrast material in the perilabral recess. Intra-articular paramagnetic contrast outlines labral tears, loose bodies, communicating labral cysts and cartilage lesions (traumatic tears, focal defects, degenerative fissures and thinning), and improves their detection. Overall, MR arthrography enables accurate detection and staging of hip intra-articular structure abnormalities.

Protection from lethal gram-positive infection by macrophage scavenger receptor-dependent phagocytosis.

Infections with gram-positive bacteria are a major cause of morbidity and mortality in humans. Opsonin-dependent phagocytosis plays a major role in protection against and recovery from gram-positive infections. Inborn and acquired defects in opsonin generation and/or recognition by phagocytes are associated with an increased susceptibility to bacterial infections. In contrast, the physiological significance of opsonin-independent phagocytosis is unknown. Type I and II class A scavenger receptors (SR-AI/II) recognize a variety of polyanions including bacterial cell wall products such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), suggesting a role for SR-AI/II in innate immunity to bacterial infections. Here, we show that SR-AI/II-deficient mice (MSR-A(-/-)) are more susceptible to intraperitoneal infection with a prototypic gram-positive pathogen, Staphylococcus aureus, than MSR-A(+/+) control mice. MSR-A(-/-) mice display an impaired ability to clear bacteria from the site of infection despite normal killing of S. aureus by neutrophils and die as a result of disseminated infection. Opsonin-independent phagocytosis of gram-positive bacteria by MSR-A(-/-) macrophages is significantly decreased although their phagocytic machinery is intact. Peritoneal macrophages from control mice phagocytose a variety of gram-positive bacteria in an SR-AI/II-dependent manner. Our findings demonstrate that SR-AI/II mediate opsonin-independent phagocytosis of gram-positive bacteria, and provide the first evidence that opsonin-independent phagocytosis plays a critical role in host defense against bacterial infections in vivo.

Differential regulation of beta1 integrins by chemoattractants regulates neutrophil migration through fibrin.

Chemoattractants differ in their capacity to stimulate neutrophils to adhere to and to migrate through matrices containing fibrin. Formyl methionyl leucyl phenylalanine (fMLP) stimulates neutrophils to adhere closely to, but not to migrate into, fibrin gels. Leukotriene B4 (LTB4) stimulates neutrophils to adhere loosely to and to migrate through fibrin gels. We report that alpha5beta1 integrins regulate the different migratory behaviors on fibrin gels of neutrophils in response to these chemoattractants. fMLP, but not LTB4, activated neutrophil beta1 integrins, as measured by binding of mAb 15/7 to an activation epitope on the beta1 integrins. Antibodies or peptides that block alpha5beta1 integrins prevented fMLP-stimulated neutrophils from forming zones of close apposition on fibrin and reversed fMLP's inhibitory effect on neutrophil chemotaxis through fibrin. In contrast, neither peptides nor antibodies that block beta1 integrins affected the capacity of LTB4-stimulated neutrophils to form zones of loose apposition or to migrate through fibrin gels. These results suggest that chemoattractants generate at least two different messages that direct neutrophils, and perhaps other leukocytes, to accumulate at specific anatomic sites: a general message that induces neutrophils to crawl and a specific message that prepares neutrophils to stop when they contact appropriate matrix proteins for activated beta1 integrins.

Complementary roles for scavenger receptor A and CD36 of human monocyte-derived macrophages in adhesion to surfaces coated with oxidized low-density lipoproteins and in secretion of H2O2.

Oxidized low-density lipoprotein (oxLDL) is considered one of the principal effectors of atherogenesis. To explore mechanisms by which oxLDL affects human mononuclear phagocytes, we incubated these cells in medium containing oxLDL, acetylated LDL (acLDL), or native LDL, or on surfaces coated with these native and modified lipoproteins. The presence of soluble oxLDL, acLDL, or native LDL in the medium did not stimulate H2O2 secretion by macrophages. In contrast, macrophages adherent to surfaces coated with oxLDL secreted three- to fourfold more H2O2 than macrophages adherent to surfaces coated with acLDL or native LDL. Freshly isolated blood monocytes secreted little H2O2 regardless of the substrate on which they were plated. H2O2 secretion was maximal in cells maintained for 4-6 d in culture before plating on oxLDL-coated surfaces. Fucoidan, a known ligand of class A macrophage scavenger receptors (MSR-A), significantly reduced macrophage adhesion to surfaces coated with oxLDL or acLDL. Monoclonal antibody SMO, which blocks oxLDL binding to CD36, did not inhibit adhesion of macrophages to oxLDL-coated surfaces but markedly reduced H2O2 secretion by these cells. These studies show that MSR-A is primarily responsible for adhesion of macrophages to oxLDL-coated surfaces, that CD36 signals H2O2 secretion by macrophages adherent to these surfaces, and that substrate-bound, but not soluble, oxLDL stimulates H2O2 secretion by macrophages.

[Subacute intestinal obstruction due to bladder distension]. / Occlusion intestinale subaiguë par globe vésical.

We report a case of subacute bowel obstruction due to a compression of the rectosigmoid junction by a chronically distended bladder, occurring in a 91-year-old male suffering from a long-standing diabetes mellitus and a prostatic adenoma. Radiographic, water-soluble contrast enema and pelvic CT features are reported.

Microglia, scavenger receptors, and the pathogenesis of Alzheimer's disease.

The senile plaque is the pathological hallmark of Alzheimer's disease. Senile plaques are composed of beta amyloid fibrils, associated with activated microglia, astrocytes, and dystrophic neurons. We have recently identified class A scavenger receptors as the main receptors mediating the interaction of microglia with beta amyloid fibrils. Adhesion of microglia to beta amyloid fibrils leads to immobilization of these cells on the fibrils, and induces them to produce reactive oxygen species. We propose that interactions of microglial scavenger receptors with fibrillar beta amyloid may stimulate the microglia to secrete apolipoprotein E and complement proteins, which may further contribute to neurotoxicity and neuronal degeneration. Therefore, microglial scavenger receptors may be novel targets for therapeutic interventions in Alzheimer's disease.

Human immunodeficiency virus-1 env impairs Fc receptor-mediated phagocytosis via a cyclic adenosine monophosphate-dependent mechanism.

Human immunodeficiency virus (HIV)-1 expression in mononuclear phagocytes is associated with multiple functional defects, including phagocytosis. To assess Fcgamma receptor (FcgammaR) function in cells expressing HIV-1, human promonocytic cells (U937) acutely or chronically infected with HIV-1, or stably transfected with a noninfectious reverse transcriptase (RT) defective HIV-1 provirus (Deltapol), were treated with phorbol 12-myristate 13-acetate for 48 hours and tested for their ability to ingest sheep erythrocytes coated with IgG (E-IgG). HIV-1-infected or transfected U937 cells ingested 50% to 65% fewer E-IgG than controls despite normal surface expression of FcgammaRs. HIV-1 specifically impaired FcgammaR-mediated phagocytosis, as ingestion of complement-coated erythrocytes was unaffected. U937 cells transfected with an env deficient mutant of HIV-1 ingested E-IgG normally, suggesting that the expression of HIV-1 env was required for HIV-1 to inhibit FcgammaR-mediated phagocytosis. Expression of HIV-1 in U937 cells was associated with an increased accumulation of intracellular cyclic adenosine monophosphate (cAMP); addition of the adenylate cyclase inhibitor 2',5'-dideoxyadenosine to these cells decreased intracellular cAMP levels to that of controls and restored FcgammaR-mediated phagocytosis. Addition of either interferon (IFN)-gamma or an inhibitor of cAMP-dependent protein kinase A (KT 5720) to HIV-1-transfected U937 cells also restored FcgammaR-mediated phagocytosis. Expression of HIV-1 induces a specific defect of FcgammaR function in mononuclear phagocytes that correlates with increased levels of cAMP, and can be corrected by pharmacologic manipulation.

Histopathologic analysis of transjugular intrahepatic portosystemic shunts.

This prospective study was undertaken in 17 patients treated with 22 transjugular intrahepatic portosystemic shunt (TIPS) procedures and aimed to evaluate the nature and causes of short- and long-term shunt abnormalities. Specimens were collected after autopsy in 6 patients and after liver transplantation in 11 patients; the time from shunting ranging from 4 to 385 days. During the first 2 weeks the shunt surface was covered by poorly organized fibrin platelet clots that were mixed with inflammatory and red blood cells. Thereafter, a pseudointima developed, initially made of loose granulation tissue that was formed by edema, myofibroblasts, neo-capillaries, collagen fibers, and inflammatory cells. This pseudo-intima extended with time as the myofibroblasts increased in number, as the collagen fibers thickened, and as the inflammatory cells grew more scarce. Its thickness ranged from 50 to 3,500 microm, the maximal values being observed in the middle of the shunt. The shunt was obstructed by a clot in 4 patients (18%). In 7 shunts (31.8%) the pseudo-intima was thicker than 1,000 microm and was referred to as hyperplastic pseudo-intima. It showed more dense inflammatory infiltrate and anarchic deposition of more scarce collagen fibers. Pseudo-intima hyperplasia was associated with previously diagnosed thrombosis, which had been treated by dilatation in 2 cases and by biliary deposits in 3 cases, while it remained unexplained in 2 cases. Accordingly, this study confirms the following: 1) that early TIPS obstruction results from thrombosis; 2) that 2 weeks after insertion, the stent is covered by a smooth pseudo-intima; 3) that thereafter, pseudo-intimal hyperplasia is the main cause of TIPS stenosis or occlusion; and 4) that biliary secretions and previous thrombosis could be important triggering mechanisms for this pseudo-intima overgrowth.

Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein.

We have studied the interactions of phosphodiester and phosphorothioate oligodeoxynucleotides with Mac-1 (CD11b/CD18; alpha M beta 2), a heparin-binding integrin found predominantly on the surface of polymorphonuclear leukocytes (PMNs), macrophages and natural killer cells. Binding of a homopolymer of thymidine occurred on both the alpha M and beta 2 subunits. Soluble fibrinogen, a natural ligand for Mac-1, was an excellent competitor of the binding of a phosphorothioate oligodeoxynucleotide to both TNF-alpha-activated and nonactivated PMNs. Upregulation of cell-surface Mac-1 expression increased cell-surface binding of oligodeoxynucleotides. Binding was inhibited by anti-Mac-1 monoclonal antibodies, and the increase in cell-surface binding was correlated with a three- to fourfold increase in internalization by PMNs. An oligodeoxynucleotide inhibited beta 2-dependent migration through Matrigel, but the production of reactive oxygen species in PMNs adherent to fibrinogen dramatically increased. Thus, our data demonstrate that Mac-1 is a cell-surface receptor for oligodeoxynucleotides that can mediate their internalization and that this binding may have important functional consequences.

Osteosarcomatosis with Rothmund-Thomson syndrome.

We describe the second reported case of multicentric osteosarcoma associated with Rothmund-Thomson syndrome (RTS), a rare hereditary cancer-prone genodermatosis characterized by typical cutaneous lesions and other non-dermatological pathological manifestations, particularly skeletal changes. A high incidence of malignant disorders has been found in RTS patients. This could be explained by the diminished capacity of DNA-repair demonstrated in the fibroblasts of RTS patients following exposure to oncogenic stimuli. The severe cutaneous lesions and the benign bone lesions found in RTS may be considered a predisposing factor to the particularly frequent skin carcinoma and osteogenic sarcoma encountered in these cancer-prone patients. A brief review of the literature is given, with a discussion of the association between these two rare conditions.

Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils.

A pathological hallmark of Alzheimer's disease is the senile plaque, containing beta-amyloid fibrils, microglia and astrocytes. Beta-amyloid fibrils exert a cytotoxic effect on neurons, and stimulate microglia to produce neurotoxins, such as reactive oxygen species. Mononuclear phagocytes, including microglia, express scavenger receptors that mediate endocytosis of oxidized low-density lipoproteins, and adhesion to glucose-modified extra-cellular matrix proteins. Here we report that class A scavenger receptors mediate adhesion of rodent microglia and human monocytes to beta-amyloid fibril-coated surfaces leading to secretion of reactive oxygen species and cell immobilization. Thus, class A scavenger receptors are potential therapeutic targets in Alzheimer's disease.

Fibrin regulates neutrophil migration in response to interleukin 8, leukotriene B4, tumor necrosis factor, and formyl-methionyl-leucyl-phenylalanine.

We have examined the capacity of four different chemoattractants/cytokines to promote directed migration of polymorphonuclear leukocytes (PMN) through three-dimensional gels composed of extracellular matrix proteins. About 20% of PMN migrated through fibrin gels and plasma clots in response to a gradient of interleukin 8 (IL-8) or leukotriene B4 (LTB4). In contrast, < 0.3% of PMN migrated through fibrin gels in response to a gradient of tumor necrosis factor alpha (TNF) or formyl-methionyl-leucyl-phenylalanine (FMLP). All four chemoattractants stimulated PMN to migrate through gels composed of collagen IV or of basement membrane proteins (Matrigel), or through filters to which fibronectin or fibrinogen had been adsorbed. PMN stimulated with TNF or FMLP adhered and formed zones of close apposition to fibrin, as measured by the exclusion of a 10-kD rhodamine-polyethylene glycol probe from the contact zones between PMN and the underlying fibrin gel. By this measure, IL-8- or LTB4-treated PMN adhered loosely to fibrin, since 10 kD rhodamine-polyethylene glycol permeated into the contact zones between these cells and the underlying fibrin gel. PMN stimulated with FMLP and IL-8, or FMLP and LTB4, exhibited very little migration through fibrin gels, and three times as many of these cells excluded 10 kD rhodamine-polyethylene glycol from their zones of contact with fibrin as PMN stimulated with IL-8 or LTB4 alone. These results show that PMN chemotaxis is regulated by both the nature of the chemoattractant and the composition of the extracellular matrix; they suggest that certain combinations of chemoattractants and matrix proteins may limit leukocyte movements and promote their localization in specific tissues in vivo.

P2Z adenosine triphosphate receptor activity in cultured human monocyte-derived macrophages.

The present study shows that human mononuclear phagocytes express a P2Z-like purinergic membrane receptor activity. Extracellular adenosine triphosphate (ATP) induces the formation of nonselective membrane pores in human mononuclear phagocytes that allow the entry of otherwise membrane impermeant fluorescent dyes (YO-PRO-1 or Lucifer yellow) into the cytoplasm of these cells. The percentage of mononuclear phagocytes that was permeabilized by ATP increased as monocytes matured into macrophages. Their response to ATP was inhibited by Mg2+ and oxidized ATP. Benzoylbenzoic-ATP (BzBzATP) was approximately 60% as effective as ATP and adenosine-5 -O-(thiophosphate) (ATP gamma S) was less than 20% as effective as ATP in permeabilizing human macrophages to YO-PRO-1 or Lucifer Yellow. Thus, the human P2Z-like receptor differs from its murine counterpart because BzBzATP, ATP, and ATP gamma S are equally efficacious in permeabilizing murine macrophage-like J774 cells to these dyes. UTP, GTP, and CTP were ineffective in permeabilizing human or murine macrophages to YO-PRO-1. Taken together, these data indicate that human monocyte-derived macrophages express a P2Z-like activity that is pharmacologically distinct from that expressed by their murine counterparts and that expression of these receptors is developmentally regulated in human mononuclear phagocytes.

Macrophages adhere to glucose-modified basement membrane collagen IV via their scavenger receptors.

Scavenger receptors have been reported to mediate macrophage adhesion to serum-coated plastic surfaces. We report here that scavenger receptors promote the divalent cation independent adhesion of human monocytes and macrophages to surfaces coated with non-enzymatically glycated collagen IV but not to surfaces coated with native collagen IV. Ligands for scavenger receptor types I and II blocked adhesion of monocytes and macrophages to non-enzymatically glycated collagen IV but had no effect on adhesion of these cells to albumin-coated surfaces. U937 human promonocyte-like cells transfected with cDNA encoding bovine scavenger receptor I or II adhered to surfaces coated with glycated-collagen IV but not to surfaces coated with native collagen IV. A synthetic peptide homologous to the domain of bovine scavenger receptor that binds modified low density lipoproteins (residues 327-343) inhibited the adhesion of U937 cells transfected with cDNA encoding bovine scavenger receptor II to glycated collagen IV, whereas a control peptide from the alpha helical domain of scavenger receptor II (residues 121-137) had no effect on adhesion of these cells. Macrophages plated on surfaces coated with glycated collagen IV were unable to endocytose acetylated low density lipoproteins from the medium, suggesting that their scavenger receptors were occupied in binding these cells to the substrate. These findings suggest new roles for scavenger receptors in the accelerated development of vascular lesions observed in diabetics.