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1.
Acta Chir Orthop Traumatol Cech ; 89(5): 380-383, 2022.
Article in English | MEDLINE | ID: mdl-36322040

ABSTRACT

Glenohumeral joint is the most frequently dislocated joint of the human body. Concomitant fractures of the coracoid process and tuberculum majus in humeral dislocation of the shoulder joint are rarely described. Concomitant fractures are results of a significant contraction of the surrounding muscles and rotator cuff during a cerebral paroxysm. Due to the small number of cases, the treatment of such injuries is not simple and it is based on an algorithm for treatment of isolated injuries of these anatomical structures. In this case report, we describe a concomitant fracture of the coracoid process and tuberculum majus during an anterior shoulder dislocation in 25-year-old patient after an epileptic seizure. The injury was treated in our department surgically, with a good functional result. The absolute Constant score for the operated arm is 95 points, the relative Constant score is 97%, DASH score 0, VAS score 0.


Subject(s)
Fractures, Bone , Shoulder Dislocation , Shoulder Joint , Humans , Adult , Shoulder Dislocation/complications , Shoulder Dislocation/surgery , Coracoid Process , Humerus , Fractures, Bone/complications
2.
Perspect Public Health ; 141(4): 204-213, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34159848

ABSTRACT

AIMS: The aim of this systematic literature review is to assess the impact of social prescribing (SP) programmes on loneliness among participants and the population. METHODS: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to search EBSCOHost (CINAHL Complete, eBook Collection, E-Journals, MEDLINE with Full Text, Open Dissertations, PsycARTICLES, and PsycINFO), UK National Institute for Health and Care Excellence (NICE), Web of Science Core Collection, and grey literature. We included studies measuring the effectiveness and impact of SP programmes in terms of loneliness. We excluded systematic reviews and studies without evaluations. Due to the absence of confidence intervals and the low number of studies, we conduct no meta-analysis. RESULTS: From 4415 unique citations, nine articles met the inclusion criteria. The studies do not use uniform measures or randomised samples. All nine studies report positive individual impacts; three report reductions in general practitioner (GP), A&E, social worker, or inpatient/outpatient services; and one shows that belonging to a group reduces loneliness and healthcare usage. CONCLUSION: The findings of this systematic review indicate that individuals and service providers view SP as a helpful tool to address loneliness. However, evidence variability and the small number of studies make it difficult to draw a conclusion on the extent of the impact and the pathways to achieving positive change. More research is needed into the impact of SP programmes on participants, populations, and communities in terms of loneliness, isolation, and connectedness, especially in light of the surge in SP activity as a key part of pandemic response.


Subject(s)
Loneliness , Prescriptions , Social Participation , Humans , Program Evaluation
3.
Hernia ; 24(3): 551-558, 2020 06.
Article in English | MEDLINE | ID: mdl-30976937

ABSTRACT

PURPOSE: The study aimed to evaluate the histologic properties and infection resistance of three different mesh materials in a rat model. METHODS: Each mesh, in both infectious (n = 96) and non-infectious groups (n = 270), was positioned both in sublay (preperitoneally) and onlay (subcutaneously) locations. Properties of the biological (Surgisis; Cook Surgical), composite, partially resorbing (Vypro II mesh; Ethicon) and non-resorbing (TiMesh; GFE Medizintechnik GmbH) mesh were evaluated and compared. Animals were killed at 7, 21 and 90 days after implantation. The following parameters were evaluated to assess the host response to the mesh material: inflammation, vascularization, fibrosis, collagen formation, Ki67, and a foreign body reaction by granuloma formation (FBG). RESULTS: Surgisis mesh produced more pronounced inflammation and cell proliferation, and less intense granuloma formation, as well as fibrosis, compared to the other two groups. When the infected materials were examined, we found signs of local infection to be more often present in Surgisis group of animals. CONCLUSIONS: In the presence of bacterial contamination, no benefits were observed in the use of the Surgisis prosthesis over the use of TiMesh and Vypro II.


Subject(s)
Prosthesis Implantation/methods , Prosthesis-Related Infections/etiology , Staphylococcal Infections/etiology , Surgical Mesh , Animals , Coated Materials, Biocompatible/administration & dosage , Coated Materials, Biocompatible/adverse effects , Collagen/administration & dosage , Collagen/adverse effects , Disease Models, Animal , Fibrosis/etiology , Foreign-Body Reaction/etiology , Inflammation/etiology , Male , Polyglactin 910/administration & dosage , Polyglactin 910/adverse effects , Polypropylenes/administration & dosage , Polypropylenes/adverse effects , Prosthesis Implantation/adverse effects , Prosthesis-Related Infections/microbiology , Rats , Rats, Wistar , Staphylococcus aureus , Surgical Mesh/adverse effects , Titanium/administration & dosage , Titanium/adverse effects
4.
J Org Chem ; 82(24): 13115-13120, 2017 12 15.
Article in English | MEDLINE | ID: mdl-29131956

ABSTRACT

Selective deuteration of drugs and biologically relevant molecules is becoming increasingly important in the pharmaceutical industry. Site-selective isotopic reinforcement of polyunsaturated fatty acids (PUFAs) at their bis-allylic sites has been identified as a unique approach in preventing oxidative damage in these molecules, which had been linked to neuronal and retinal diseases, atherosclerosis, and aging. Typical methods for preparation of site-selectively deuterated PUFAs require rather long, laborious, and expensive syntheses. In this report, we disclose a very efficient catalytic protocol for site-specific deuteration of PUFAs and analogous poly-alkenes under exceptional kinetic control. Deuterium oxide (D2O) has been identified not only as a deuterium source but also as a crucial component in the overall reaction mechanism responsible for averting the formation of thermodynamically favored side-products.


Subject(s)
Alkenes/chemistry , Deuterium Oxide/chemistry , Deuterium , Fatty Acids, Unsaturated/chemistry , Models, Molecular , Radiopharmaceuticals , Substrate Specificity
5.
Dalton Trans ; 46(41): 14244-14250, 2017 Oct 24.
Article in English | MEDLINE | ID: mdl-28991293

ABSTRACT

Complex [Cp*Ru(NCMe)3][PF6], 1a, has been identified as a cis-to-trans isomerization catalyst of various non-conjugated cis-polyalkenes under exceptional kinetic control as no alkene conjugation was observed. According to the experimental and theoretical data, the cis-trans isomerization occurred via an alkene-assisted mechanism in which one cis-double bond always served as an anchoring site. Using a combination of multinuclear NMR spectroscopic evidence and mathematical methods it was possible to determine the extent of trans isomerization.

6.
Eur J Med Res ; 20: 76, 2015 Sep 17.
Article in English | MEDLINE | ID: mdl-26381501

ABSTRACT

Inguinal hernia repair is a common worldwide surgical procedure usually done in the outpatient setting. The purpose of this systematic review is to make an evidence-based meta-analysis to determine the possible benefits of regional (neuraxial block) anesthesia compared to general anesthesia in open inguinal hernia repair in adults. Cochrane Library, Medline, EMBASE, CINAHL, SCI-EXPANDED, SCOPUS as well as trial registries, conference proceedings and reference lists were searched. Only randomized controlled trials (RCT) that compare neuraxial block (spinal or/and epidural) anesthesia (NABA) and general anesthesia (GA) were included. Main outcome measures were postoperative complications, urinary retention and postoperative pain. Seven RCTs were included in this review. A total of 308 patients were analyzed with 154 patients in each group. Overall complications were evenly distributed in NABA and in GA group [OR 1.17, 95 % CI (0.52-2.66)]. Urinary retention was statistically less frequent in GA group compared to NABA group [OR 0.25, 95 % CI (0.08-0.74)]. Movement-associated pain score 24 h after surgery was significantly lower in NABA group [SMD 5.59, 95 % CI (3.69-7.50)]. Time of first analgesia application was shorter in GA group [SMD 8.99, 95 % CI 6.10-11.89]. Compared to GA, NABA appears to be a more adequate technique in terms of postoperative pain control. However, when GA is applied, patients seem to have less voiding problems.


Subject(s)
Anesthesia, Conduction , Hernia, Inguinal/surgery , Adult , Humans , Randomized Controlled Trials as Topic , Treatment Outcome
7.
Eur J Paediatr Dent ; 16(2): 107-10, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26147815

ABSTRACT

AIM: The aim of this study was to evaluate the occurrence of dental and facial injuries, the habit of wearing mouthguard and the awareness regarding injury prevention and first aid after tooth avulsion among young taekwondo athletes in Croatia. MATERIALS AND METHODS: A survey on a sample of 484 taekwondo athletes was conducted, which included 271 male (56%) and 213 female (44%) athletes aged between 8 and 28 years. The questionnaire submitted to the athletes contained 15 questions about dental trauma, use of mouthguard, dental trauma prevention, level of awareness about tooth avulsion and replantation and disturbances associated with mouthguard use. Collected data were evaluated according to gender, age groups and duration of actively engagement in taekwondo. Descriptive statistics and Chi-square tests were used for comparisons between groups. RESULTS: From the survey 300 (62%) of 484 athletes had sustained one serious injury and 103 (21%) had sustained an orofacial injury, while 194 (40%) had observed another player sustaining a dental injury. Higher number of orofacial injuries was observed in males (24%) than in females (18%). Furthermore, 98 (20%) athletes have experienced one or more dental injuries, and out of these 98 suffering dental injury 60 were male (61%) and 38 were female (39%). The frequency of orofacial injuries in the older group (42%) is higher than in three younger groups (younger cadets 25%; cadets 13%; juniors 20%) (p<0.05). Mouthguard wearing was recorded in 465 athletes (96%), 47.1% of them wear stock mouthguard, 47.6% wear boil and bite mouthguard, but only 5.3% were custom-made mouthguards. Most of them (96%) consider that mouthguards are useful for injury prevention in taekwondo. CONCLUSION: The results of this survey show that dental and orofacial injuries occur in taekwondo in all age groups but mostly in the senior group. Taekwondo players know the importance of mouthguard use, but only 5% use custom made mouthguards. This is not adequate for dental injury prevention and highlights the important role of dental professional in education of athletes for advocating the use of custom made mouthguards.


Subject(s)
Martial Arts/injuries , Tooth Injuries/epidemiology , Adolescent , Adult , Age Factors , Attitude to Health , Child , Croatia/epidemiology , Equipment Design , Facial Injuries/epidemiology , Facial Injuries/prevention & control , Female , First Aid/statistics & numerical data , Health Knowledge, Attitudes, Practice , Humans , Male , Martial Arts/statistics & numerical data , Mouth/injuries , Mouth Protectors/statistics & numerical data , Prevalence , Sex Factors , Tooth Injuries/prevention & control , Tooth Replantation/statistics & numerical data , Young Adult
8.
Dalton Trans ; 44(25): 11669, 2015 Jul 07.
Article in English | MEDLINE | ID: mdl-26067586

ABSTRACT

Correction for 'Iminoborylene complexes: evaluation of synthetic routes towards BN-allenylidenes and unexpected reactivity towards carbodiimides' by J. Niemeyer et al., Dalton Trans., 2015, DOI: 10.1039/c5dt00131e.

9.
Dalton Trans ; 44(25): 11294-305, 2015 Jul 07.
Article in English | MEDLINE | ID: mdl-25710128

ABSTRACT

The synthetic and reaction chemistries of cationic iminoborylene complexes [LnM=B=N=CR2](+), which feature a unique heterocumulene structure, have been systematically investigated. Precursors of the type CpFe(CO)2B(Cl)NCAr2 (Ar = p-Tol/Mes, 5c/d) have been generated by B-centred substitution chemistry using CpFe(CO)2BCl2 and suitable lithiated ketimines - a reaction which is found to be highly sensitive to the steric bulk at both the metal fragment and the ketimino group. Carbonyl/phosphine exchange (using PCy3 or PPh3), followed by halide abstraction allows for the generation of the cationic iminoborylenes [CpFe(PR3)(CO)(BNCAr2)](+)[BAr(X)4](-) (R = Cy, Ar = p-Tol/Mes, 12c/d; R = Ph, Ar = Mes, 13d; Ar(X) = 3,5-X2C6H3 where X = Cl, CF3) which have been characterized spectroscopically and by X-ray crystallography. The reactivity of these iminoborylene systems towards a range of nucleophiles and unsaturated substrates has been investigated. The latter includes the first examples of M=B metathesis reactivity with a carbodiimide, and results in Fe=B cleavage and formation of the isonitrile complexes [CpFe(PCy3)(CO)(CNR)](+)[BAr(Cl)4](-) (R = (i)Pr/Cy, 16/17).

10.
Pharmazie ; 67(5): 374-9, 2012 May.
Article in English | MEDLINE | ID: mdl-22764566

ABSTRACT

Protein-protein interactions (PPI) tend to involve extensive, flat, and featureless interfaces that are difficult to disrupt by small molecule binding. However, recently, PPIs are being recognized as increasingly valuable 'druggable' targets. We have identified several small molecule inhibitors of the immunologically relevant CD40-CD154 co-stimulatory interaction that bind to the homotrimeric CD154, a member of the tumor necrosis factor superfamily (TNFSF). Recently, on the basis of the co-crystal structure of CD154 with another small molecule (BIO8898), it has been suggested that these PPIs could be particularly susceptible to small molecule blockade due to a subunit fracture mechanism resulting in a distortion of the trimeric structure. To investigate whether this mechanism can occur with our organic dye-related inhibitors, we performed exploratory computational docking experiments. Possible druggable pockets that can serve as binding sites for small molecule inhibitors were identified with the FFT map algorithm both along the CD154-CD40 binding interface (competitive, orthosteric model) and in the interior core of the CD154 trimer corresponding to the BIO8898 binding site (allosteric model). Docking experiments (using Glide) were performed at these sites using the PDB ID: 3QD6 (CD40-CD154) and 3LKJ (BIO8898-CD154) co-crystal structures, respectively. The docking algorithm was able to better discriminate binders from non-binders at the deeper allosteric site than at the competitive site. Accordingly, an allosteric inhibitory mechanism that involves intercalation between monomeric subunits seems feasible for our small molecules making the constitutively trimeric CD154 a likely druggable target.


Subject(s)
CD40 Antigens/antagonists & inhibitors , CD40 Ligand/antagonists & inhibitors , Algorithms , Binding Sites , Computer Simulation , Humans , Ligands , Models, Molecular , Protein Binding , Small Molecule Libraries
11.
Water Sci Technol ; 63(11): 2560-6, 2011.
Article in English | MEDLINE | ID: mdl-22049749

ABSTRACT

Over time, the radial collector wells of the Belgrade Groundwater Source, located in the alluvial sediments of the Sava River, exhibit a decline in discharge and a reduction in operating efficiency due to well ageing. An increase in hydraulic losses at the lateral screens, due to chemical and biochemical clogging, has been identified as the primary cause. Certain hydrogeological, hydrochemical and microbiological parameters reflect the well-ageing process and can, therefore, be considered as its indicators. An indicator-based determination of scale is an important aspect in the selection of appropriate well locations, structural characteristics, and maintenance approaches. Well ageing was studied over a period of 5 years (2005-2009). The objective was to investigate the causes of well ageing. The correlations established between the groundwater redox potential, the total iron concentration in groundwater, the grain-size distribution of the aquifer, and well discharge, are presented in the paper.


Subject(s)
Environmental Monitoring/methods , Water Pollutants, Chemical/chemistry , Water Supply/analysis , Water/chemistry , Rivers , Serbia , Time Factors
12.
Eur Psychiatry ; 24(8): 507-12, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19540728

ABSTRACT

BACKGROUND: The objective of the present study was to examine the association of insight into the illness with demographic variables and symptomatology in a sample of 1213 patients with schizophrenia. METHOD: Data were collected with the Psychosis Evaluation tool for Common use by Caregivers (PECC), a semi-structured interview evaluating five symptom domains of schizophrenia and the insight items 'awareness of having a mental disorder' and 'attributing symptoms to a mental disorder'. RESULTS: Insight was positively associated with educational level and inversely with overall symptom severity, and the positive, negative, excitatory and cognitive symptom domains. At symptom level, the items 'delusions', 'grandiosity', 'poor rapport', 'social withdrawal' and 'guilt feelings' showed the strongest associations with both insight items. Overall, correlations between insight and symptomatology were modest, explaining less than 30% of the variance in insight. CONCLUSION: Lack of insight in schizophrenia is partially explained by clinical symptoms and demographic measures.


Subject(s)
Awareness , Schizophrenia/diagnosis , Schizophrenic Psychology , Self Concept , Activities of Daily Living/psychology , Adolescent , Adult , Aged , Aged, 80 and over , Analysis of Variance , Attitude to Health , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Regression Analysis , Retrospective Studies , Severity of Illness Index , Surveys and Questionnaires
13.
J Postgrad Med ; 53(1): 39-40, 2007.
Article in English | MEDLINE | ID: mdl-17244969

ABSTRACT

Idiopathic rupture of the urinary bladder is an uncommon condition and represents less than 1% of all bladder rupture cases. In most of the cases the main etiological factor was heavy alcohol ingestion. A combined injury of the spleen and bladder is a very rare condition that is almost often associated with trauma and foreign bodies. In this paper we present the extremely rare clinical course of acute abdomen caused by a combined spontaneous intraperitoneal injury; spontaneous rupture of the urinary bladder and spleen. According to our opinion, spontaneous bladder rupture caused by bladder distension due to alcohol ingestion led to urinary ascites and abdominal distension. Finally, repeated minor abdominal blunt trauma during everyday life, to a moderately distended abdomen caused a spontaneous splenic rupture in the patient with abnormal coagulation studies.


Subject(s)
Abdomen, Acute/physiopathology , Splenic Rupture/complications , Urinary Bladder , Aged, 80 and over , Alcohol Drinking/adverse effects , Humans , Male , Pressure/adverse effects , Rupture, Spontaneous/complications , Splenic Rupture/physiopathology
14.
Hernia ; 10(4): 322-5, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16705360

ABSTRACT

Incisional hernias occur primarily as a result of high tension and inadequate healing of a previous incision, the latter of which is frequently related to infection at the surgical site. Despite recent advances in operative techniques, the recurrence rate remains unacceptably high. To evaluate the impact of different predisposing factors for the recurrence of incisional hernia, we reviewed retrospectively the medical records of 297 patients who had undergone incisional herniorrhaphy (188 tissue repairs, 109 mesh repairs) in our hospital. Demographic data (age and gender), type of repair, body mass index, hernia size, presence of chronic illnesses and wound complications were evaluated in a univariate and multivariate manner analysis. The overall recurrence rate was 30.3%, with the recurrence rate in patients who underwent tissue repair being 39.4% and that in patients following prosthetic repair 14.6%. The recurrence rate was significantly influenced by type of repair, obesity, hernia size, wound healing disorders and some chronic comorbidities. We conclude that it is necessary to become familiar with the risk factors for recurrence of incisional hernia in order to eliminate or decrease their effect on the positive outcome of incisional herniorrhaphy.


Subject(s)
Herniorrhaphy , Adult , Aged , Aged, 80 and over , Body Mass Index , Female , Hernia/complications , Hernia/pathology , Humans , Male , Middle Aged , Postoperative Complications , Recurrence , Retrospective Studies , Risk Factors , Surgical Procedures, Operative/methods
15.
Forensic Sci Int ; 147 Suppl: S29-32, 2005 Jan 17.
Article in English | MEDLINE | ID: mdl-15694723

ABSTRACT

Gunshot wounds in the heart are frequent suicidal injuries, especially in men. Most of them are lethal, but some cases of survival due to immediate and proper surgical treatment are reported. However, survival without specific treatment is extremely rare. In our case, a 44-year man attempted suicide by home-made shooting device. A special 12 cm long and 2.5 mm wide needle-like missile entered his body at the left anterior part of his chest, passed through the heart and lower lobe of right lung and exited at the right side of his back. The patient was able to move normally and he also looked for medical help immediately after attempting suicide. We found large atypical-shaped entrance wound on the anterior part of the chest, which was surgically treated, and tiny pointed exit wound under the right scapula. The patient was stable from cardio-circulatory and respiratory aspects from the time of admission to discharge from the hospital. We found only minimal pericardial bleeding (up to 10 mm thick) and there was no need for surgical intervention. In the next 2 weeks the haematoma absorbed spontaneously. The gunshot injury healed without any complication. Paranoid psychosis was diagnosed by psychiatrist and this probably had been the cause of attempting suicide. We think that the favorable outcome of the proved heart gunshot injury in our patient was due to the needle-shaped low-energy missile, which caused only tiny gunshot (stab) hole in the heart. Such a heart injury caused only minimal bleeding into the pericardial sac without heart tamponade.


Subject(s)
Heart Injuries/pathology , Suicide, Attempted/psychology , Wounds, Gunshot/pathology , Adult , Forensic Medicine , Hemorrhage/pathology , Humans , Male , Paranoid Disorders/diagnosis
16.
Scand J Immunol ; 58(1): 1-8, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12828552

ABSTRACT

Proteins in their native form are incapable of stimulating antigen (Ag)-specific T cells, which can only recognize major histocompatibility complex (MHC)-bound peptides that have been generated by intracellular processing within antigen-presenting cells (APCs). Here, we show that APCs can trigger MHC class I-restricted T-cell responses after presenting proteins without conventional intracellular processing, provided the immunostimulatory MHC class I-binding peptide sequence is incorporated at the carboxy-terminal position. Such MHC-bound proteins do not stimulate T cells directly, because the contact between MHC/peptide complex and its cognate ligand is sterically hindered by the amino-terminal bulk of the protein. Removal of the latter via an extracellular Ag proteolysis by the T-cell- and/or APC-derived enzymes is required for effective T-cell stimulation. Our data challenge the established concept that only small peptides can bind to the MHC class I molecules.


Subject(s)
Antigen Presentation , Histocompatibility Antigens Class I/metabolism , Recombinant Fusion Proteins/metabolism , Animals , Female , Mice , Mice, Inbred C57BL , Ovalbumin/metabolism , Peptide Fragments/metabolism , Receptor, ErbB-2/metabolism
17.
J Chem Inf Comput Sci ; 41(4): 1002-5, 2001.
Article in English | MEDLINE | ID: mdl-11500116

ABSTRACT

If lambda(1), lambda(2),..., lambda(n) are the eigenvalues of a graph G, then the energy of G is defined as E(G) = the absolute value of lambda(1) + the absolute value of lambda(2) +.... + the absolute value of lambda(n). If G is a molecular graph, representing a conjugated hydrocarbon, then E(G) is closely related to the respective total pi-electron energy. It is not known which molecular graph with n vertices has maximal energy. With the exception of m = n - 1 and m = n, it is not known which molecular graph with n vertices and m edges has maximal energy. To come closer to the solution of this problem, and continuing an earlier study (J. Chem. Inf. Comput. Sci. 1999, 39, 984-996, ref 7), we performed a Monte Carlo-type construction of molecular (n,m)-graphs, recording those with the largest (not necessarily maximal possible) energy. The results of our search indicate that for even n the maximal-energy molecular graphs might be those possessing as many as possible six-membered cycles; for odd n such graphs seem to prefer both six- and five-membered cycles.

18.
Nat Biotechnol ; 18(12): 1269-72, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11101805

ABSTRACT

Soluble extracellular protein antigens are notoriously poor stimulators of CD8+ cytotoxic T-lymphocyte (CTL) responses, largely because these antigens have inefficient access to an endogenous cytosolic pathway of the major histocompatibility complex (MHC) class I-dependent antigen presentation. Here, we present a strategy that facilitates antigen penetration into the cytosol of antigen-presenting cells (APC) by addition to the antigen of charge-modifying peptide sequences. As a result of this intervention, the charge modification enhances antigen uptake into APC by counteracting the repulsive cell surface charge, and then endosomal membranes are disrupted with a subsequent release of antigen into the cytosol. This technology significantly improves MHC class I-dependent antigen presentation to CTL, enabling a more efficient generation of specific CTL immunity in vivo. The strategy described here has potential for use in developing efficient vaccines for antigen-specific immunotherapy of human malignancies.


Subject(s)
Antigen Presentation , Antigens/chemistry , Dendritic Cells/immunology , Hemagglutinin Glycoproteins, Influenza Virus , Histocompatibility Antigens Class I/metabolism , Peptides/chemistry , T-Lymphocytes, Cytotoxic/immunology , Animals , Antigens/immunology , Dendritic Cells/metabolism , Female , Hemagglutinins/chemistry , Histocompatibility Antigens Class I/immunology , Humans , Hybridomas , Immunologic Memory , Mice , Mice, Inbred C57BL , Ovalbumin/chemistry , Ovalbumin/immunology , Peptide Fragments/chemistry
19.
J Med Chem ; 43(11): 2135-48, 2000 Jun 01.
Article in English | MEDLINE | ID: mdl-10841792

ABSTRACT

Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.


Subject(s)
Antigen Presentation , Dipeptides/pharmacology , HLA-DR Antigens/chemistry , Molecular Mimicry , Binding, Competitive , Carbohydrates/chemistry , Cathepsin B/metabolism , Cell Division/drug effects , Crystallography, X-Ray , Dipeptides/chemical synthesis , Dipeptides/chemistry , Humans , Methylation , Models, Molecular , Peptide Biosynthesis , Protein Conformation , Structure-Activity Relationship , T-Lymphocytes/cytology , T-Lymphocytes/drug effects
20.
Croat Med J ; 40(3): 353-6, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10411962

ABSTRACT

AIM: To investigate whether in vivo toxicity of class II major histocompatibility complex (MHC) specific monoclonal antibodies (mAb) is contributed by mAb's constant region binding to Fc receptor (FcR). METHODS: Laboratory mice were injected intravenously (i.v.) with class II MHC-specific mAb of various isotypes and respective antigen-binding fragments, and their clinical status was observed subsequently. RESULTS: All anti-class II mAb of the IgG2a isotype exhibit acute toxicity, manifested in severe lethargy and a frequent death. No adverse effects were observed after the FcR-binding capability of the toxic mAb was eliminated via deletion or mutation of its Fc segment. CONCLUSION: In vivo toxicity of anti-class II mAb appears to be the consequence of the crosslinking of class II+ cells with cells expressing FcR.


Subject(s)
Antibodies, Monoclonal/immunology , Histocompatibility Antigens Class II/immunology , Receptors, Fc/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/genetics , Antigen-Antibody Reactions/immunology , Binding Sites, Antibody/genetics , Binding Sites, Antibody/immunology , Cause of Death , Female , Gene Deletion , Histocompatibility Antigens Class II/genetics , Immunoglobulin G/administration & dosage , Immunoglobulin G/immunology , Immunoglobulin Isotypes/administration & dosage , Immunoglobulin Isotypes/immunology , Injections, Intravenous , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Transgenic , Mutation/genetics , Sleep Stages/immunology
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