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Biomedical subjects

Ofer Levy

Publications and source records attributed to Ofer Levy.

At least 37 records · Page 2Linked to original sources
PubMed2004

Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes.

Phagocytic leukocytes are a central cellular element of innate-immune defense in mammals. Over the past few decades, substantial progress has been made in defining the means by which phagocytes kill and dispose of microbes. In addition to the generation of toxic oxygen radicals and nitric oxide, leukocytes deploy a broad array of antimicrobial proteins and peptides (APP). The majority of APP includes cationic, granule-associated (poly)peptides with affinity for components of the negatively charged microbial cell wall. Over the past few years, the range of cells expressing APP and the potential roles of these agents have further expanded. Recent advances include the discovery of two novel families of mammalian APP (peptidoglycan recognition proteins and neutrophil gelatinase-associated lipocalin), that the oxygen-dependent and oxygen-independent systems are inextricably linked, that APP can be deployed in the context of novel subcellular organelles, and APP and the Toll-like receptor system interact. From a clinical perspective, congeners of several of the APP have been developed as potential therapeutic agents and have entered clinical trials with some evidence of benefit.

Acute-Phase Proteins↗
PubMed2004

The effect of balneotherapy on osteoarthritis. Is an intermittent regimen effective?

Background: Balneotherapy is used as a treatment modality for various musculoskeletal disorders. The aim of this study was to evaluate the effectiveness of intermittent balneotherapy in patients with knee osteoarthritis (OA). Methods: Seventy-two patients with knee OA were included in the study. Patients were divided into two groups: group A (48 patients) was given intermittent once weekly treatment for 6 weeks; group B (24 patients) served as a control group. Evaluation was done prior to study entry, at weeks 4 and 6, and 4 weeks following completion of treatment (week 10). Assessment included global pain score (VAS), WOMAC index, Lequesne's functional index, patients' and physician's disease severity score, and NSAID/analgesic consumption. Results: Following balneotherapy, a statistically significant improvement, determined by the reduction in the mean changes of most outcome parameters (VAS, WOMAC, and Lequesne's index), was noted in group A at weeks 4 and 6 and was sustained 4 weeks after cessation of treatment (week 10). Significant improvement in both physician's and patients' disease severity scores, as well as a reduction in analgesic and NSAID consumption, were also noted in group A. No improvement was found in the control group in any of the tested parameters. Conclusions: Intermittent balneotherapy appears to be effective in the treatment of knee OA.

Journal Article↗
PubMed2004

Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia.

BACKGROUND: Many receptors rely on the appropriate activation of nuclear factor (NF) kappa B to induce cellular function. This process depends critically on the phosphorylation of the inhibitor of NF-kappa B (I kappa B) by the I kappa B kinase. This targets I kappa B for ubiquitination and degradation, allowing NF-kappa B to translocate to the nucleus, where it can direct transcription. Hypomorphic human mutations affecting one I kappa B kinase component, the NF-kappa B essential modulator (NEMO), result in impaired signaling from receptors required for ectodermal development and immune function. Male subjects with these mutant NEMO molecules have an X-linked syndrome known as ectodermal dysplasia with immunodeficiency, which is characterized by severe infections, with herpesviruses, bacteria, and mycobacterial susceptibility. OBJECTIVE: We sought to genetically and biochemically characterize a patient with a mutant NEMO molecule without ectodermal abnormalities. METHODS: We evaluated NEMO in a patient who had immunodeficiency and atypical mycobacterial infection but normal ectoderm. RESULTS: We identified a novel NEMO mutant causing immunodeficiency without ectodermal dysplasia. The mutation, which altered the exon 9 splice site, was present in cells of ectodermal and hematopoetic origin and resulted in a heterogeneous mixture of mutant and wild-type cDNA species. Immunologic function was variably impaired, with reduced CD40-induced B-cell proliferation, partially reduced NF-kappa B p65 nuclear translocation, and variable Toll-like receptor-induced TNF production. This variability might be explained by an inconsistent ratio of mutant to wild-type NEMO. The lack of any ectodermal phenotype, however, suggested a separation in the hematopoetic and ectodermal function of NEMO that leads to NF-kappa B activation. CONCLUSION: Mutation of the gene encoding NEMO can result in immunodeficiency without ectodermal dysplasia.

Adolescent↗
PubMed2004

Copeland surface replacement arthroplasty of the shoulder in rheumatoid arthritis.

BACKGROUND: Shoulder arthroplasty with a stemmed prosthesis is a recognized treatment for rheumatoid arthritis of the shoulder. The humeral component of the Copeland cementless surface replacement arthroplasty consists of a cup for surface replacement with a short central peg for primary fixation to the bone. We hypothesized that surface replacement may offer some advantages over stemmed prostheses. METHODS: Between 1986 and 1998, seventy-five shoulders underwent surface replacement arthroplasty (thirty-three hemiarthroplasties and forty-two total shoulder arthroplasties) for the treatment of rheumatoid arthritis. The results of these procedures were reviewed after an average duration of follow-up of 6.5 years. Patients were assessed with use of the Constant score, a patient satisfaction score, and radiographs. RESULTS: The average Constant score was 47.9 points (age and sex-adjusted score, 71%) in the hemiarthroplasty group and 53.4 points (age and sex-adjusted score, 76%) in the total shoulder replacement group. The mean range of active flexion improved from 50 degrees in the hemiarthroplasty group and 47 degrees in the total shoulder replacement group to 101 degrees and 104 degrees, respectively. Seventy-two of the seventy-five shoulders were considered by the patients to be much better or better at the time of the review. Of the sixty-eight humeral implants that were evaluated radiographically, fifty-six (82%) showed no lucencies, eleven (16%) showed localized lucencies of <1 mm in width, and one was definitely loose. Of the thirty-nine glenoid implants that were evaluated radiographically, nineteen (49%) showed no lucencies, nineteen showed localized lucencies of <1 mm, and one was definitely loose. No lucencies were observed adjacent to the hydroxyapatite-coated implants. Thirty-nine (57%) of the sixty-eight shoulders showed some degree of superior subluxation. Three patients required a major reoperation: two required a revision because of loosening of both components, and one patient with pain at the site of a hemiarthroplasty had a revision to a total shoulder arthroplasty to provide relief. CONCLUSIONS: The indications for this surface replacement are the same as those for the conventional stemmed prostheses, but the surface replacement has the advantage of bone preservation as well as avoidance of the potential complications associated with a long humeral stem in rheumatoid bone. This procedure is not suitable for severely damaged joints in which the humeral head is insufficient or too soft. LEVEL OF EVIDENCE: Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence.

Activities of Daily Living↗
PubMed2003

Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells.

An 11-year-old girl presented with a papulovesicular rash and severe respiratory distress 5 weeks after receiving varicella vaccine. Restriction fragment length-polymorphism analysis of virus isolated from an endotracheal-tube aspirate and from bronchoalveolar lavage revealed that this patient's illness was due to the Oka vaccine strain of varicella. An extensive immunologic analysis failed to identify a known diagnostic entity to explain her susceptibility to this attenuated vaccine strain. Analysis of her lymphocytes on separate occasions, months after recovery from her illness, revealed a profound deficiency of natural killer T (NKT) cells and of NKT-cell activity, suggesting that NKT cells contribute to host defense against varicella virus.

Antigens, Viral↗
PubMed2003

Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function.

The nonclassical class I MHC molecule HLA-G is selectively expressed on extravillous cytotrophoblast cells at the maternal-fetal interface during pregnancy. HLA-G can inhibit the killing mediated by NK cells via interaction with the inhibitory NK cell receptor, leukocyte Ig-like receptor-1 (LIR-1). Comparison of the sequence of the HLA-G molecule to other class I MHC proteins revealed two unique cysteine residues located in positions 42 and 147. Mutating these cysteine residues resulted in a dramatic decrease in LIR-1 Ig binding. Accordingly, the mutated HLA-G transfectants were less effective in the inhibition of NK killing and RBL/LIR-1 induced serotonin release. Immunoprecipitation experiments demonstrated the involvement of the cysteine residues in the formation of HLA-G protein oligomers on the cell surface. The cysteine residue located at position 42 is shown to be critical for the expression of such complexes. These oligomers, unique among the class I MHC proteins, probably bind to LIR-1 with increased avidity, resulting in an enhanced inhibitory function of LIR-1 and an impaired killing function of NK cells.

Amino Acid Sequence↗
PubMed2003

Endotoxemia and elevation of lipopolysaccharide-binding protein after hematopoietic stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation (SCT) carries a significant risk of severe therapy-associated complications chief among which is acute graft vs.host disease (aGVHD). Animal models indicate that myeloablative chemotherapy compromises the mucosal barrier, thereby allowing translocation of intestinal flora-derived lipopolysaccharides (or endotoxin) that subsequently trigger aGVHD, but there are no comparable data in humans. Our aim was to gain insight into the potential role of endotoxin and endotoxin-induced acute phase proteins in children undergoing SCT. METHODS: Plasma concentrations of C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) were measured in 57 pediatric patients undergoing SCT. In addition plasma endotoxin levels were measured in 25 patients. RESULTS: The previously described rise in CRP was confirmed, and a marked elevation of LBP was observed that peaked at Day 7 (median value, 6.6 microg/ml; P < 0.03 for all pairwise comparisons). CRP and LBP values were significantly correlated (r = 0.77, P < 0.001). A significant but complex relationship was noted between LBP concentrations at Day 0 and severity of subsequent aGVHD (P = 0.02). Of the 25 patients assayed, 11 (44%) had detectable endotoxemia, including 4 who were endotoxin-positive at Day 0. CONCLUSIONS: The detection of endotoxemia coupled with marked elevations in LBP at Day 7 raises the possibility that inflammatory responses early after SCT may be driven in part by the entry of lipopolysaccharide into the bloodstream.

Acute-Phase Proteins↗
PubMed2003

Critical role of the complement system in group B streptococcus-induced tumor necrosis factor alpha release.

Group B Streptococcus (GBS) is a major cause of newborn sepsis and meningitis and induces systemic release of tumor necrosis factor alpha (TNF-alpha), believed to play a role in morbidity and mortality. While previous studies have shown that GBS can induce TNF-alpha release from monocytes and macrophages, little is known about the potential modulating effect of plasma or serum on GBS-induced TNF-alpha release, and there are conflicting reports as to the host receptors involved. In a human whole-blood assay system, GBS type III COH-1 potently induced substantial monocyte TNF-alpha release in adult peripheral blood and, due to a higher concentration of monocytes, 10-fold-greater TNF-alpha release in newborn cord blood. Remarkably, GBS-induced TNF-alpha release from human monocytes was enhanced approximately 1000-fold by heat-labile serum components. Experiments employing C2-, C3-, or C7-depleted serum demonstrated that C3 activation via the alternative pathway is crucial for potent GBS-induced TNF-alpha release. Accordingly, whole blood from C3-deficient mice demonstrated significantly reduced GBS-induced TNF-alpha release. Preincubation with human serum enhanced the TNF-alpha-inducing activity of GBS in a C3- and factor B-dependent manner, implying deposition of complement components via the alternative pathway. GBS-induced TNF-alpha release was inhibited by monoclonal antibodies directed against each of the components of CR3 and CR4: the common integrin beta subunit CD18 and the alpha subunits CD11b (of CR3) and CD11c (of CR4). Blood derived from CR3 (CD11b/CD18)-deficient mice demonstrated a markedly diminished TNF-alpha response to GBS. We conclude that the ability of plasma and serum to greatly amplify GBS-induced TNF-alpha release reflects the activity of the alternative complement pathway that deposits fragments on GBS and thereby enhances CR3- and CR4-mediated monocyte activation.

Adult↗
PubMed2002

Neutrophil defense in patients undergoing bone marrow transplantation: bactericidal/permeability-increasing protein (BPI) and defensins in graft-derived neutrophils.

BACKGROUND: Even after neutrophil counts return to near normal levels, patients undergoing myeloablative chemotherapy and bone marrow transplantation (BMT) are at risk for invasive bacterial infections, raising the possibility that their neutrophil function might be impaired. To assess potential qualitative defects in neutrophil function in patients undergoing BMT, we measured neutrophil content of the antimicrobial (poly)peptides BPI and defensins. METHODS: Neutrophil extracts were analyzed for content of BPI by Western blotting and ELISA and for defensin peptides by acid-urea polyacrylamide gel electrophoresis (PAGE). Antibacterial activity of neutrophil extracts was measured against Escherichia coli K1/r, a clinical isolate sensitive to synergistic killing by BPI and defensins. RESULTS: Neutrophil extract BPI content on post-BMT days +20, +30, and +100 (169+/-35, 232+/-57, and 160+/-55 ng per 106 neutrophils, respectively) was similar to the neutrophil BPI content of normal controls (163+/-35 ng per 106 neutrophils). Neutrophil defensin content also did not vary during this time-span. Activity of neutrophil extracts against E. coli K1/r did not differ between BMT patients and controls. CONCLUSION: At post-BMT days +20 to +100, neutrophils derived from engrafted marrow contain normal quantities of BPI and defensins. Any deficiencies of neutrophil function during this phase are not due to inadequate expression of these antimicrobial (poly)peptides but could reflect abnormalities in other aspects of neutrophil function.

Adolescent↗
PubMed2002

Lipid mediator-induced expression of bactericidal/ permeability-increasing protein (BPI) in human mucosal epithelia.

Epithelial cells which line mucosal surfaces are the first line of defense against bacterial invasion and infection. Recent studies have also indicated that epithelial cells contribute significantly to the orchestration of ongoing inflammatory processes. Here, we demonstrate that human epithelial cells express bactericidal/permeability-increasing protein (BPI), an antibacterial and endotoxin-neutralizing molecule previously associated with neutrophils. Moreover, we demonstrate that such BPI expression is transcriptionally regulated by analogs of endogenously occurring anti-inflammatory eicosanoids (aspirin-triggered lipoxins, ATLa). Initial studies to verify microarray analysis revealed that epithelial cells of wide origin (oral, pulmonary, and gastrointestinal mucosa) express BPI and each is similarly regulated by aspirin-triggered lipoxins. Studies aimed at localization of BPI revealed that such expression occurs on the cell surface of cultured epithelial cell lines and dominantly localizes to epithelia in human mucosal tissue. Functional studies employing a BPI-neutralizing anti-serum revealed that surface BPI blocks endotoxin-mediated signaling in epithelia and kills Salmonella typhimurium. These studies identify a previously unappreciated "molecular shield" for protection of mucosal surfaces against Gram-negative bacteria and their endotoxin.

Anti-Bacterial Agents↗
PubMed2002

Fatal disseminated Candida lusitaniae infection in an infant with chronic granulomatous disease.

A 3-month-old boy born to a mother carrying an X-linked form of chronic granulomatous disease presented with persistent fever and hepatosplenomegaly. The diagnosis was confirmed as a gp91phox defect by genetic analysis, and the patient was managed with broad spectrum antibacterial agents, gamma-interferon and later amphotericin B. A liver biopsy revealed granulomata with budding yeast forms, and cultures of blood and urine grew Candida lusitaniae. The patient died 26 days after admission.

Amphotericin B↗
PubMed2002

Therapeutic potential of the bactericidal/permeability-increasing protein.

Innate immune mechanisms respond rapidly to bacterial infection. A key cellular component of the innate immune response is the neutrophil, whose cytoplasmic granules contain a variety of antimicrobial proteins and peptides. Among these is the bactericidal/permeability-increasing protein (BPI), a cationic 55 kDa protein whose selective anti-infective action against Gram-negative bacteria is based on its high (nM) affinity for lipopolysaccharide (LPS, or "endotoxin"). Binding of BPI to Gram-negative bacteria results in growth inhibition, serves as an opsonin that enhances phagocytosis of bacteria and inhibits bacteria-induced inflammatory responses by blocking the interaction of LPS with host pro-inflammatory pathways. Expression of BPI appears to be developmentally regulated as human newborns apparently have lower neutrophil BPI levels than adults. BPI expression has also recently been demonstrated in human epithelial cells where it appears to be inducible by endogenous anti-inflammatory lipids (lipoxins). BPI's potent anti-endotoxic activity against a broad range of Gram-negative bacterial pathogens is manifest in biological fluids and renders it an attractive template for pharmaceutical development. Indeed, rBPI(21), an active recombinant protein derived from human BPI, has proven safe in Phase I human trials, shown promise in Phase II trials and has recently completed a Phase III trial for severe meningococcaemia with apparent benefit. Identification and evaluation of additional disease entities characterised by Gram-negative bacteraemia and/or endotoxaemia as possible targets for BPI therapy continues.

Anti-Bacterial Agents↗
PubMedDate not supplied

Mechanical properties of regenerated coracoacromial ligament after subacromial decompression.

Recent publications suggest that the coracoacromial ligament regenerates after it has been partially excised during subacromial decompression or acromioplasty. This observation may aid the understanding of the successes and failures of this very commonly performed surgical procedure. This study determines the mechanical properties of the apparently regenerated ligament. Eight regenerated coracoacromial ligaments were excised during revision surgery after subacromial decompression and were taken for mechanical testing. It appears that the ligament does have the ability to re-form relatively quickly after subacromial decompression or acromioplasty but takes time to regain strength. The results indicate that the ligament may possibly regain normal mechanical properties after regeneration times in excess of 3 years.

Acromioclavicular Joint↗
PubMedDate not supplied

Cementless surface replacement arthroplasty (Copeland CSRA) for osteoarthritis of the shoulder.

Clinical experience with the Copeland cementless surface replacement arthroplasty (CSRA) of the shoulder now spans 17 years. Between 1986 and 1997, 79 CSRAs (42 total shoulder replacements and 37 hemiarthroplasties) were performed for primary osteoarthritis of the shoulder. Total shoulder replacement was done in 12 men and 30 women with a mean age of 71.5 years (range, 50-87 years). Hemiarthroplasty was used in 9 men and 28 women; 5 patients had bilateral hemiarthroplasty. The mean age was 73.4 years (range, 53-88 years). Thirty-nine total shoulder arthroplasties and thirty hemiarthroplasties with a follow-up of more than 2 years were available for review. The mean follow-up was 7.6 years (range, 48 months to 13 years) for total shoulder replacement and 4.4 years (range, 24 months to 6.5 years) for hemiarthroplasty. The Constant scores improved from an age-adjusted Constant score of 33.8% (20.0 points) to 94% (61.9 points) for total shoulder replacement and from an age-adjusted Constant score 40.0% (25.3 points) to 91% (58.1 points) for hemiarthroplasty. Active elevation improved by a mean of 59.9 degrees to a mean of 128 degrees for total shoulder replacement and to a mean of 124 degrees for hemiarthroplasty. Of the patients, 89.9% considered the shoulder to be much better or better as a result of the operation. Radiographically, one humeral implant and three glenoid implants had evidence of loosening. Four revisions were performed in the total shoulder replacement group. No revision surgery was needed in the hemiarthroplasty group. The results of this series are at least comparable to those reported for stemmed prostheses with a comparable length of follow-up. The results of total shoulder replacement and hemiarthroplasty in osteoarthritis of the shoulder seem to be comparable. With use of the CSRA prosthesis, several severe complications mainly concerning the humeral shaft and periprosthetic fractures can be avoided. Should the need for revision surgery or arthrodesis arise, these procedures are easily performed, as bone stock has been maintained and no loss of length has been encountered. It does seem that the humeral component does not need a stem or cement for fixation.

Aged↗
PubMedDate not supplied

Geometrical analysis of Copeland surface replacement shoulder arthroplasty in relation to normal anatomy.

This study examines the effect of humeral head surface replacement on the geometry of the arthritic glenohumeral joint and correlates changes to clinical outcome. Thirty-nine patients undergoing resurfacing arthroplasty were prospectively followed up clinically and radiologically for a mean of 38 months (range, 24 to 72 months). Measurements were taken from coronal radiographs by use of a validated technique. There was an estimated mean 6 mm erosion of preoperative lateral offset (coracoid base to greater tuberosity). The prosthesis reduced the humeral head radius by a mean of 3.5%. Humeral offset (greater tuberosity to center of instant rotation) increased by a mean of 5 mm (95% CI, 3.8 to 6.4; P<.01). Mean age-/sex-adjusted Constant scores improved from 26 to 83 points (P<.01). The improved postoperative motion showed a nonlinear relationship with humeral offset. We conclude that surface replacement restores humeral offset and the lever arm of the deltoid and supraspinatus while otherwise mimicking individual anatomy. Function depends on adequate restoration of this lever arm without overstuffing the joint.

Adult↗