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1.
Am J Orthod Dentofacial Orthop ; 163(1): 95-101, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36184392

ABSTRACT

INTRODUCTION: This study aimed to find out the frequency of sleep-related breathing disorders (SRBD) in young orthodontic patients in Israel. SRBD is characterized by prolonged upper airway obstruction during sleep. METHODS: The study group consisted of 309 children aged 6-17 years who attended the Orthodontic Clinic at Hadassah Medical Center. Parents were asked to complete a translated validated Pediatric Sleep Questionnaire. RESULTS: Of the examined children, 10% were at high risk for SRBD. Boys were at higher risk for SRBD and were at high risk at a younger age than girls. Girls had a low risk of SRBD after adenotonsillectomy, whereas 50% of the boys that underwent adenotonsillectomy were at high risk for SRBD. CONCLUSIONS: Our findings propose that 10% of the children aged 6-17 years, who were seeking orthodontic consultation at our medical center, were at high risk for SRBD. Boys were significantly at a higher risk for SRBD than girls and were at high risk at a younger age. It is important to screen young orthodontic patients for SRBD and to refer high-risk patients to their physicians for further evaluation and treatment.


Subject(s)
Sleep Apnea Syndromes , Sleep Apnea, Obstructive , Tonsillectomy , Male , Female , Child , Humans , Sleep , Sleep Apnea, Obstructive/surgery , Adenoidectomy
2.
Transfus Med Hemother ; 44(3): 183-187, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28626369

ABSTRACT

BACKGROUND: Red blood cells (RBCs) undergo a natural aging process occurring in the blood circulation throughout the RBC lifespan or during routine cold storage in the blood bank. The aging of RBCs is associated with the elevation of mechanical fragility (MF) or osmotic fragility (OF) of RBCs, which can lead to cell lysis. The present study was undertaken to identify RBC properties that characterize their susceptibility to destruction under osmotic/mechanical stress. METHODS: RBCs were isolated from freshly donated blood or units of packed RBCs (PRBCs) and suspended in albumin-supplemented phosphate-buffered saline (PBS). In addition, PRBCs were separated by filtration through a microsphere column into two fractions: enriched with rigid (R-fraction) and deformable (D-fraction) cells. The RBCs were subjected to determination of deformability, MF and OF, moreover, the level of cell surface phosphatidylserine (PS) and the stomatin level in isolated RBC membranes were measured. RESULTS: In the RBC population, the cells that were susceptible to mechanical and osmotic stress were characterized by low deformability and increased level of surface PS. The OF/MF was higher in the R-fraction than in the D-fraction. Stomatin was depleted in destroyed cells and in the R-fraction. CONCLUSION: RBC deformability, the levels of surface PS, and membrane stomatin can be used as markers of RBC fragility.

3.
Microcirculation ; 23(7): 479-486, 2016 10.
Article in English | MEDLINE | ID: mdl-27406436

ABSTRACT

OBJECTIVE: There is a growing concern regarding the risks in the transfusion of PRBC, as numerous studies have reported negative transfusion outcomes, including reduced blood perfusion. In search of this phenomenon's mechanism, the effect of PRBC deformability, a major determinant of blood flow, on transfusion outcome was explored. METHODS: The effect of PRBC deformability was examined by the transfusion-induced change in recipients' ∆SBF, in ß-TM patients, who are routinely treated with lifelong frequent transfusions. SBF was determined using a laser Doppler imager. RESULTS: ∆SBF was examined vs PRBC deformability, the transfusion-induced increase in ∆Hct and the recipients' SBF before transfusion (SBFB ). ∆SBF elevated with increasing PRBC deformability, with a highly significant dependence, while its elevation with ∆Hct was much less significant. ∆SBF was inversely proportional to the SBFB . CONCLUSIONS: This study provides, for the first time in humans, direct evidence that the deformability of transfused PRBC is a potent effector of transfusion outcome. Currently, PRBC are supplied primarily by the first-in-first-out criteria, while their functionality is ignored. The testing of PRBC hemodynamic quality would introduce a new paradigm into blood banking, which would contribute substantially to improving transfusion therapy.


Subject(s)
Blood Flow Velocity , Erythrocyte Deformability , Erythrocyte Transfusion/adverse effects , Adult , Female , Hematocrit , Humans , Laser-Doppler Flowmetry , Male , Middle Aged , Skin/blood supply , beta-Thalassemia/blood , beta-Thalassemia/therapy
4.
Proc Natl Acad Sci U S A ; 110(51): 20723-8, 2013 Dec 17.
Article in English | MEDLINE | ID: mdl-24297898

ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.


Subject(s)
Absorbable Implants , Carcinoma, Pancreatic Ductal/drug therapy , Drug Delivery Systems/methods , Pancreatic Neoplasms/drug therapy , Proto-Oncogene Proteins/antagonists & inhibitors , RNA, Small Interfering/pharmacology , ras Proteins/antagonists & inhibitors , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cell Proliferation , Drug Evaluation, Preclinical , Female , Gene Silencing , Humans , Mice , Mice, SCID , Mutation , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins p21(ras) , RNA, Small Interfering/genetics , ras Proteins/genetics , ras Proteins/metabolism
5.
Am J Pathol ; 177(6): 3159-68, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21088216

ABSTRACT

Evolution of apoptosis resistance in both lymphoma and leukemia cells is well documented, and induction of apoptosis in malignant cells is a major goal of cancer therapy. Up-regulation of anti-apoptotic signals is one of the mechanisms whereby resistance to apoptosis emerges. We have previously described the fusion proteins CD40·FasL and CTLA-4·FasL, which are formed from two functional membrane proteins and induce apoptosis of activated T cells. The present study explores the potential use of CD40·FasL and CTLA-4·FasL for the killing of malignant cells of lymphatic origin. Using malignant B and T cell lines that differ in surface expression of costimulatory molecules, we found that CTLA-4·FasL induces effective apoptosis of cells expressing CD95 and activates caspases 3, 8, and 9. Only B7-expressing B cells responded to CTLA-4·FasL with rapid abrogation of cFLIP expression. CD40·FasL effectively killed only the T cells that express high levels of CD40L in addition to CD95. In these cells, CD40·FasL significantly diminished cFLIP expression. Importantly, each of the fusion proteins is more potent than its respective components parts, alone or in combination. Thus, the proteins with their two functional ends deliver a pro-apoptotic signal and, in parallel, inhibit an anti-apoptotic signal, thus optimizing the wanted, death-inducing effect. Therefore, these proteins emerge as promising agents to be used for targeted and specific tumor cell killing.


Subject(s)
Antigens, CD/pharmacology , Apoptosis/drug effects , CD40 Antigens/pharmacology , Fas Ligand Protein/pharmacology , Neoplasms/pathology , Recombinant Fusion Proteins/pharmacology , Antigens, CD/genetics , CD40 Antigens/genetics , CTLA-4 Antigen , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , Drug Evaluation, Preclinical , Fas Ligand Protein/genetics , Humans , Jurkat Cells , Molecular Targeted Therapy , Neoplasms/drug therapy , Recombinant Fusion Proteins/genetics , Signal Transduction/drug effects , Up-Regulation/drug effects
6.
J Immunol ; 179(11): 7287-94, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-18025171

ABSTRACT

The fusion protein CTLA-4 . FasL, a paradigmatic "trans signal converter protein", can attach to APC surfaces and in effect convert B7-activating costimulator signals into inhibitory Fas receptor-generated signals. The present study investigates CTLA-4 . FasL's mechanism of action. A combination of p27(kip) and proliferating cell nuclear Ag Western blot and propidium iodide flow cytometric analysis showed no CTLA-4 . FasL effect on cell cycle entry and progression, pointing away from the kind of classical anergy associated with CTLA-4 . Ig. Significantly, CTLA-4 . FasL elicited apoptosis (as detected by annexin-V/propidium iodide costaining) as early as 24 h after T cell activation, suggesting that some coordinate signaling might be capacitating the Fas receptor. Significantly, CTLA-4 . FasL, but not CTLA-4 . Ig, anti-Fas mAb, or the two in combination, abrogated the usual increase in expression of the anti-apototic protein, cFLIP. Furthermore, activation of caspases 8 and 3 were not affected by CTLA-4 . FasL. These findings suggest a model for CTLA-4 . FasL action wherein there is coordinate triggering of a death receptor and suppression of a proapoptotic protein.


Subject(s)
Antigens, CD/immunology , Antigens, Differentiation/immunology , Apoptosis/immunology , Fas Ligand Protein/immunology , Recombinant Fusion Proteins/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , Amino Acid Chloromethyl Ketones/pharmacology , Animals , Antigens, CD/drug effects , Antigens, Differentiation/drug effects , CASP8 and FADD-Like Apoptosis Regulating Protein/immunology , CTLA-4 Antigen , Cell Cycle/immunology , Cell Proliferation/drug effects , Cells, Cultured , Fas Ligand Protein/antagonists & inhibitors , Female , Mice , Mice, Inbred C57BL , Recombinant Fusion Proteins/antagonists & inhibitors , Up-Regulation/immunology
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