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Biomedical subjects

Ofer Levy

Publications and source records attributed to Ofer Levy.

At least 19 recordsLinked to original sources
PubMed2025

High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.

CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies.

Humans↗
PubMed2007

The "purse-string" technique: an arthroscopic technique for stabilization of anteroinferior instability of the shoulder with early and medium-term results.

PURPOSE: We report the early and midterm results of the "purse-string" technique, a simple, new arthroscopic technique for stabilization of anteroinferior instability of the glenohumeral joint that addresses both the Bankart lesion and capsular stretching. METHODS: The patients comprised 36 individuals (37 shoulders), with a mean age of 26 years, who had recurrent anteroinferior post-traumatic instability as a result of a traumatic Bankart lesion. They had sustained a mean of 5 dislocations per shoulder (range, 1 to 11). The cohort included 5 professional and 6 semiprofessional athletes, all of whom were involved in collision or overhead sports. A purse-string suture anchor at the 4-o'clock position was used to ensure a purse-string effect in tightening the capsule in the inferior-superior plane and creation of anterior glenoid bumper. All of the patients were assessed by an independent investigator (T.M.) at a mean of 36 months (range, 27 to 87 months) after surgery. RESULTS: Postoperatively, the mean Rowe score was 93 (range, 55 to 100), the mean Walch-Duplay score was 93 (range, 70 to 100), and the mean Constant score was 97 (range, 77 to 100). Of the patients, 97% returned to the same sport that they had played before injury. Furthermore, 66% of patients returned to their preinjury level of sports, and all of the professional athletes resumed full activities. One patient continued to have symptoms of instability, and one patient had a further dislocation after a new traumatic event. CONCLUSIONS: The early and medium-term results obtained are very encouraging, with a rate of failure of only 5.4%, a high level of return to preinjury sporting activities (with 97% of patients returning to the same sport and 66% returning to their preinjury level of sports), and a high patient satisfaction rate (with excellent or good results in 94% of patients). LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Arthroscopy↗
PubMed2006

Histologic evaluation of the glenohumeral joint capsule after radiofrequency capsular shrinkage for atraumatic instability.

We evaluated histologically 10 biopsy specimens taken preoperatively from the anterior-inferior glenohumeral ligament from patients with atraumatic instability who had undergone radiofrequency capsular shrinkage, 10 taken immediately postoperatively, and 13 taken before revision. The synovial and subsynovial layers returned to normal histology in biopsy specimens taken from 6 months onwards. Collagen bundles in the fibrous layer continued to have a reparative histology during the period of the study (up to 37 months). The type of radiofrequency probe used (monopolar or bipolar) had no effect on the histologic healing process (P > 0.5, chi2 test). A histologic score was introduced, and this was found to have an excellent intraobserver agreement (weighted kappa, 0.840) and a moderate interobserver agreement (weighted kappa, 0.698).

Adolescent↗
PubMed2006

Recombinant bactericidal/permeability-increasing protein rBPI21 protects against pneumococcal disease.

Bactericidal/permeability-increasing (BPI) protein has been shown to play an important role in innate immunity to gram-negative bacteria, by direct microbicidal as well as endotoxin-neutralizing action. Here we examined potential interactions between a recombinant 21-kDa bioactive fragment of BPI, rBPI21, and the gram-positive pathogen Streptococcus pneumoniae. rBPI21 bound to pneumococci and pneumolysin (Ply) in a direct and specific fashion. We observed an enhanced inflammatory response in mouse macrophages when rBPI21 was combined with killed pneumococci or supernatant from overnight growth of pneumococci. In addition, rBPI21 augmented the proapoptotic activity of Ply+ (but not Ply-) pneumococci in TLR4-defective murine macrophages (known to be defective also in their apoptotic response to pneumolysin) in a tumor necrosis factor alpha-dependent manner. rBPI21 also enhanced the association of pneumococci with murine macrophages. In a model of invasive pneumococcal disease in TLR4-defective mice, the intranasal administration of rBPI21 following intranasal inoculation of Ply+ pneumococci both enhanced upper respiratory tract cell apoptosis and prolonged survival. We have thus discovered a novel interaction between pneumococcus and rBPI21, a potent antimicrobial peptide previously considered to target only gram-negative bacteria.

Animals↗
PubMed2006

Subacromial plica as a cause of impingement in the shoulder.

The subacromial bursa is the largest bursa in the body. In 1934, Codman described the presence of subacromial plicae, similar to the suprapatellar plicae found in the knee. It is recognized that plicae in the knee can cause anterior knee pain with impingement against the patella in young persons. We investigated the possibility that a similar situation exists with plicae of the subacromial bursa. The aims of this study were to document the prevalence of bursal plicae seen at bursoscopy during arthroscopic subacromial decompression of the shoulder and to assess whether there is any pattern in the occurrence of these plicae, as well as the relationship to impingement lesions seen at bursoscopy. Between January 1996 and July 2001, all cases undergoing arthroscopic decompression were evaluated for anatomic-pathologic changes of the subacromial bursa, including the presence of plicae and impingement lesions. A total of 1732 cases complying with inclusion criteria were recorded, with plicae observed in 104 (6.0%). The occurrence of plicae showed a highly significant younger age predilection (P = .0008, chi(2) test) but no differences between sexes or sides. The occurrence of subacromial plicae was highly associated with the combined severity of the impingement lesion on the acromial and bursal side. Plicae were most common in shoulders showing an impingement lesion on the cuff bursal side, with no impingement lesion on the acromial side. The odds of the impingement lesion being milder on the acromial side was 3.41 times higher in shoulders with a plica compared with shoulders without a plica. This suggests that impingement of the cuff may be due to the plica itself. This study is the first to describe the presence of subacromial plicae in living subjects and correlates with previous anatomic studies. The younger age predominance correlates with the findings of plicae in the knee. Our findings suggest that subacromial plicae may be a cause of impingement in young patients.

Adolescent↗
PubMed2006

TCR zeta down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs.

T cell AgR zeta chain down-regulation associated with T cell dysfunction has been described in cancer, infectious, and autoimmune diseases. We have previously shown that chronic inflammation is mandatory for the induction of an immunosuppressive environment leading to this phenomenon. To identify the key immunosuppressive components, we used an in vivo mouse model exhibiting chronic inflammation-induced immunosuppression. Herein, we demonstrate that: 1) under chronic inflammation secondary lymphatic organs display various immunological milieus; zeta chain down-regulation and T cell dysfunction are induced in the spleen, peripheral blood, and bone marrow, but not in lymph nodes, correlating with elevated levels of Gr1(+)Mac-1(+) myeloid suppressor cells (MSC); 2) MSC are responsible for the induction of such an immunosuppression under both normal and inflammatory conditions; and 3) normal T cells administered into mice exhibiting an immunosuppressive environment down-regulate their zeta expression. Such an environment is anticipated to limit the success of immunotherapeutic strategies based on vaccination and T cell transfer, which are currently under investigation for immunotherapy of cancer.

Animals↗
PubMed2006

The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn.

Human newborns are susceptible to microbial infection and mount poor vaccine responses, yet the mechanisms underlying their susceptibility are incompletely defined. We have previously reported that despite normal basal expression of TLRs and associated signaling intermediates, human neonatal cord blood monocytes demonstrate severe impairment in TNF-alpha production in response to triacylated (TLR 2/1) and diacylated (TLR 2/6) bacterial lipopeptides (BLPs). We now demonstrate that in marked contrast, BLP-induced synthesis of IL-6, a cytokine with anti-inflammatory and Th2-polarizing properties, is actually greater in neonates than adults. Remarkably, newborn blood plasma confers substantially reduced BLP-induced monocyte synthesis of TNF-alpha, while preserving IL-6 synthesis, reflecting the presence in neonatal blood plasma of a soluble, low molecular mass inhibitory factor (<10 kDa) that we identify as adenosine, an endogenous purine metabolite with immunomodulatory properties. The neonatal adenosine system also inhibits TNF-alpha production in response to whole microbial particles known to express TLR2 agonist activity, including Listeria monocytogenes, Escherichia coli (that express BLPs), and zymosan particles. Selective inhibition of neonatal TNF-alpha production is due to the distinct neonatal adenosine system, including relatively high adenosine concentrations in neonatal blood plasma and heightened sensitivity of neonatal mononuclear cells to adenosine A3 receptor-mediated accumulation of cAMP, a second messenger that inhibits TLR-mediated TNF-alpha synthesis but preserves IL-6 production. We conclude that the distinct adenosine system of newborns polarizes TLR-mediated cytokine production during the perinatal period and may thereby modulate their innate and adaptive immune responses.

Adenosine↗
PubMed2006

Neck injury and fibromyalgia-- are they really associated?

OBJECTIVE: To investigate whether whiplash injury may be a trigger for the onset of fibromyalgia (FM). METHODS: One hundred fifty-three patients presenting to the emergency room with the diagnosis of whiplash injury were examined. The control group included 53 patients hospitalized with fractures of the limbs, spine, and ribs due to road accident. The study and control groups were interviewed shortly after presenting and then followed prospectively. Patients complaining of musculoskeletal symptoms during followup were examined and a count of 18 tender points was conducted. FM was diagnosed if the patient fulfilled currently accepted 1990 American College of Rheumatology criteria. RESULTS: The mean followup period for the study and control groups was 14.5 months (range 12-18) and 9 months (range 6-14), respectively. There were no differences between the groups with regard to age, sex, marital, education, or employment status. During the followup period only one patient in the study group and no patients in the control group developed signs and symptoms of FM. Three patients in the study group (2%) and 15 patients in the control group (16%) filed insurance claims; none was associated with FM. CONCLUSION: Whiplash injury and road accident trauma were not associated with an increased rate of FM after more than 14.5 months of followup.

Adult↗
PubMed2006

Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells.

Newborns are prone to microbial infection and have poor memory responses to multiple antigens. We have previously shown that human neonatal blood monocytes exhibit impaired TNF-alpha responses to most known TLR agonists, including the pure TLR7 agonist imiquimod. Surprisingly, however, neonatal TNF-alpha responses to the imiquimod congener R-848 (TLR 7/8) were fully intact. We now show that TLR8 agonists, including R-848 (TLR7/8), the imidazoquinoline congeners 3M-003 (TLR7/8) and 3M-002 (TLR8), as well as single-stranded viral RNAs (TLR8) induced robust production of the Th1-polarizing cytokines TNF-alpha and IL-12 from neonatal antigen-presenting cells (APCs) that substantially exceeds responses induced by TLR-2, -4, or -7 (alone) agonists. TLR8 agonists also effectively induced up-regulation of the costimulatory molecule CD40 on neonatal and adult myeloid dendritic cells (DCs). The strong activity of TLR8 agonists correlates with their induction of p38 MAP kinase phosphorylation and with degradation of IkappaB-alpha in both neonatal and adult monocytes. We conclude that TLR8 agonists are uniquely efficacious in activating costimulatory responses in neonatal APCs and suggest that these agents are promising candidate adjuvants for enhancing immune responses in human newborns.

Adjuvants, Immunologic↗
PubMed2006

Arthroscopic management of the painful snapping scapula.

PURPOSE: The aim of this study was to evaluate the results of the arthroscopic management of the snapping scapula syndrome. TYPE OF STUDY: Case series. METHODS: Thirteen patients underwent surgery for painful scapular snapping that had not responded to adequate conservative treatment. They had no evidence of anatomic abnormalities on plain radiographs. All patients underwent bursectomy and resection of bands of fibrous tissue at the superomedial angle. Bone was resected from the superomedial angle only if it appeared to be prominent during arthroscopy. This occurred in 3 cases. The patients' outcomes were assessed subjectively by their ability to return to work and their return to leisure, as well as the Constant score. RESULTS: At the time of follow-up, 9 patients (69%) reported an improvement in their symptoms. Their median Constant score was 87 (range, 95 to 58). Four patients felt that their symptoms were unchanged or worse. Their median Constant score was 55 (range, 66 to 32). Of 9 employed patients, 8 returned to their previous careers. This group included 2 patients with physically demanding jobs. Of 9 patients who played sports regularly, 6 returned to their presymptomatic level of sporting activity. There were no complications. CONCLUSIONS: Subscapular bursectomy is a safe procedure with a low rate of morbidity. In the absence of a definable anatomic abnormality, arthroscopic bursectomy for the painful snapping scapula can result in satisfactory outcomes in approximately 70% of patients. More clearly defined indications for and contraindications against surgery are required to avoid poor results. Complete resolution of the snapping in the subscapular bursa is not necessary to obtain a satisfactory result. LEVEL OF EVIDENCE: Level IV, case series, no control group.

Adult↗
PubMed2006

Neonatal babesiosis: case report and review of the literature.

A case of transfusion-associated neonatal babesiosis is presented. Jaundice, hepatosplenomegaly, anemia and conjugated hyperbilirubinemia developed in this preterm infant. The diagnosis was eventually made by blood smear, serology and polymerase chain reaction. The patient was treated with clindamycin and quinine and made a favorable recovery. Of neonatal babesiosis reported in the literature, 9 other cases are reviewed, including 6 that were transfusion-associated, 2 congenital and 2 tick transmitted.

Adult↗
PubMed2006

Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-alpha production in vitro and in vivo.

Human newborns are susceptible to microbial infection related to incompletely defined aspects of the neonatal immune system. To characterize neonatal innate immunity, we studied production of two early response cytokines in response to Toll-like receptor (TLR)-activating microbial stimuli in vitro: the pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha and IL-6, a multifunctional cytokine with antiinflammatory and Th2-polarizing properties. Neonatal cord blood responses to multiple TLR agonists, including poly dI:dC (TLR3), lipopolysaccharide (LPS) (TLR4), flagellin (TLR5), and CpG DNA (TLR9), are characterized by a higher IL-6/TNF-alpha ratio than in adult peripheral blood. Robust LPS-induced IL-6 production is due to both neonatal cellular (monocyte-) and humoral (serum-) factors. Remarkably, serum collected from newborns during the first week of life demonstrates higher IL-6/TNF-alpha ratios than does cord blood, associated with elevations of the IL-6-inducible acute phase reactants CRP and LPS-binding protein in the first days of life. A high ratio of stimulus-induced IL-6/TNF-alpha production is likely to profoundly modulate both innate and adaptive immune responses in the human newborn.

Adult↗
PubMed2005

Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein.

Epithelial cells of many mucosal organs have adapted to coexist with microbes and microbial products. In general, most studies suggest that epithelial cells benefit from interactions with commensal microorganisms present at the lumenal surface. However, potentially injurious molecules found in this microenvironment also have the capacity to elicit local inflammatory responses and even systemic disease. We have recently demonstrated that epithelia cells express the anti-infective molecule bactericidal/permeability-increasing protein (BPI). Here, we extend these findings to examine molecular mechanisms of intestinal epithelial cell (IEC) BPI expression and function. Initial experiments revealed a variance of BPI mRNA and protein expression among various IEC lines. Studies of BPI promoter expression in IECs identified regulatory regions of the BPI promoter and revealed a prominent role for CCAAT/enhancer binding protein and especially Sp1/Sp3 in the basal regulation of BPI. To assess the functional significance of this protein, we generated an IEC line stably transfected with full-length BPI. We demonstrated that, whereas epithelia express markedly less BPI protein than neutrophils, epithelial BPI contributes significantly to bacterial killing and attenuating bacterial-elicted proinflammatory signals. Additional studies in murine tissue ex vivo revealed that BPI is diffusely expressed along the crypt-villous axis and that epithelial BPI levels decrease along the length of the intestine. Taken together, these data confirm the transcriptional regulation of BPI in intestinal epithelia and provide insight into the relevance of BPI as an anti-infective molecule at intestinal surfaces.

Animals↗
PubMed2005

"Wet diapers--dry patients": an effective dressing for patients undergoing arthroscopic shoulder surgery.

Shoulder arthroscopy is very commonly associated with postoperative leakage of irrigation fluid. This causes apprehension to patients and their relatives and leads to frequent change of dressings. We describe a simple and effective diaper dressing for patients undergoing arthroscopic shoulder surgery. It is highly absorbent, cost-effective, and easy to apply. We have used this dressing successfully in more than 1,500 shoulder arthroscopies over the last 3 years with no adverse reaction.

Arthroscopy↗
PubMed2005

Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation.

The nuclear factor (NF)-kappaB family of transcription factors serves vital roles in a wide array of cell functions. An increasing number of human genetic lesions that result in defined disease entities are linked to inappropriate activation of NF-kappaB. The resulting aberrant NF-kappaB function can lead to cellular defects that ultimately impair normal developmental processes, host immune defenses, or both. Molecular defects that lie upstream in cell-signaling pathways and rely upon NF-kappaB activation tend to give a more specific phenotype, whereas those closer to the actual NF-kappaB proteins have broader defects. A detailed study of these diseases can provide insight into the biochemistry of NF-kappaB activation as well as the role of NF-kappaB in human health.

Genetic Diseases, Inborn↗
PubMed2005

Innate immunity of the human newborn: distinct cytokine responses to LPS and other Toll-like receptor agonists.

Human newborns are at increased risk of microbial invasion and display diminished responses to many vaccines indicating a functional immaturity of the immune system at birth. Such altered immune reactivity may reflect the demands of in utero existence, including the need to avoid potentially harmful inflammatory immune reactions. Despite normal basal expression of Toll-like receptors and membrane CD14, innate immune responses of neonatal mononuclear cells to lipopolysaccharide are characterized by markedly reduced release of the pro-inflammatory Th1-polarizing cytokines TNF-alpha and interferon-gamma with relative preservation of anti-inflammatory Th2-polarizing cytokines. Differences between newborns and adults with respect to TLR-induced TNF-alpha release extend to a range of TLR agonists, including bacterial lipopeptides, and are due to differences in soluble factors present in blood plasma. Soluble factors in neonatal blood plasma suppress TLR-induced TNF-alpha release from monocytes and efforts to identify and characterize these inhibitors are on-going. Such altered immunity to TLR agonists is likely to alter both innate and adaptive immune responses in newborns profoundly. Definition of the mechanisms underlying distinct neonatal immunity promises to identify novel ways to prevent and treat infection in this relatively high-risk population.

Cytokines↗
PubMed2004

Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848.

Newborns are at increased risk of overwhelming infection, yet the mechanisms underlying this susceptibility are incompletely defined. In this study we report a striking 1- to 3-log decrease in sensitivity of monocytes in human neonatal cord blood, compared with monocytes in adult peripheral blood, to the TNF-alpha-inducing effect of multiple TLR ligands, including bacterial lipopeptides (BLPs), LPS, and the imidazoquinoline compound, imiquimod. In marked contrast, TNF-alpha release in response to R-848, a TLR ligand that is a congener of imiquimod, was equivalent in newborn and adult blood. Differences in ligand-induced TNF-alpha release correlated with divergent ligand-induced changes in monocyte TNF-alpha mRNA levels. Newborn and adult monocytes did not differ in basal mRNA or protein expression of TLRs or mRNA expression of functionally related molecules. Newborn monocytes demonstrated diminished LPS-induced, but equivalent R-848-induced, phosphorylation of p38 mitogen-activated protein kinase and altered BLP- and LPS-induced acute modulation of cognate receptors, suggesting that the mechanism accounting for the observed differences may be localized proximal to ligand recognition by surface TLRs. Remarkably, newborn plasma conferred substantially reduced BLP-, LPS-, and imiquimod-induced TNF-alpha release on adult monocytes without any effect on R-848-induced TNF-alpha release, reflecting differences in a plasma factor(s) distinct from soluble CD14. Impaired response to multiple TLR ligands may significantly contribute to immature neonatal immunity. Conversely, relative preservation of responses to R-848 may present unique opportunities for augmenting innate and acquired immunity in the human newborn.

Adult↗