АРТРОПЛАСТИКА ТАЗОБЕДРЕННОГО СУСТАВА ПРИ ДЕСТРУКТИВНО-ДИСТРОФИЧЕСКИХ ПОРАЖЕНИЯХ

Introduction. Hip arthroplasty is considered to be the most effective method providing social and household reintegration for destructive-dystrophic lesions. Goal of the study is to improve the results of surgical treatment using the technology of arthroplasty in patients with decompensated forms of destructive-dystrophic hip joint lesions. Material and methods. It was an open prospective, randomized study carried out on the base of traumatology and ortopaedics department of the Bashkir State Medical University including 710 patients with decompensated destructivedystrophic hip joint lesions. All patients (n=710, of which 6.1% were female) depending on the diacritic approach were divided into groups: the control group included (n=406) patients with hip joint trauma who were provided a conventional range of diagnostic and treatment procedures; the experimental group (n=304) included patients who had a range of diagnostics and treatment of destructive-dystrophic lesions of hip joints based on assessment of the connective tissue phase state. Results. Biometric indicators of stance and walking phase firmly improved in all groups 3 years after arthroplasty (p<0.05). Comparative analysis of arthroplasty results in the research groups showed effectiveness of the developed concept to surgically treat destructive and dystrophic lesions of hip joint on the basis of the system approach in the form of improved parameters of the components of the local and systemic level by 2.38% and 2.3% for osteoarthrosis (p<0.05), by 1.61% and 1.84% for aseptic necrosis of femoral head (p>0.05), by 5.62% and 4.37% for post-traumatic damage of hip joint (p<0.05). Conclusion. Analysis of short-term and long-term results of arthroplasty showed high efficiency of the developed concept of surgical treatment and monitoring of connective tissue phase state at destructive-dystrophic lesions of hip joints based on the system approach in the form of reduced pain syndrome, improvement of functional possibilities and patients life quality.Введение. Эндопротезирование тазобедренного сустава (ТБС) считается наиболее эффективным методом, обеспечивающим социальную и бытовую реинтеграцию при деструктивно-дистрофических поражениях.Цель исследования: улучшить результаты хирургического лечения по технологии артропластики пациентов с декомпенсированными формами деструктивно-дистрофических поражений ТБС.Материалы и методы. На клинических базах кафедры травматологии и ортопедии Башкирского государственного медицинского университета проведено открытое проспективное рандомизированное исследование, включающее 710 пациентов с декомпенсированными деструктивно-дистрофическими поражениями ТБС. Все пациенты (n=710, из них 61,97% женщин), в зависимости от диагностических подходов, были разделены на группы: контрольную группу составили (n=406) пациенты с поражением ТБС, которым проводился традиционный комплекс диагностических и лечебных процедур; исследуемая группа (n=304) включала пациентов, которым проводились комплексная диагностика и лечение деструктивно-дистрофических поражений ТБС на основе оценки фазового состояния соединительной ткани.Результаты. Показатели биометрии фаз опоры и ходьбы достоверно улучшились во всех группах через три года после артропластики (р<0,05). Сравнительный анализ результатов артропластики в группах показал эффективность разработанной концепции хирургического лечения при поражениях ТБС на основе системного подхода в виде улучшения показателей компонент локального и системного уровня на 2,38 и 2,3% при остеоартрозе (р<0,05), на 1,61 и 1,84% при асептическом некрозе головки бедра (р>0,05), на 5,62 и 4,37% при посттравматических поражениях ТБС (р<0,05).Заключение. Анализ ближайших и отдаленных результатов артропластики показал высокую эффективность разработанной концепции хирургического лечения и мониторинга фазового состояния соединительной ткани при деструктивно-дистрофических поражениях ТБС на основе системного подхода в виде уменьшения болевого синдрома, улучшения функциональных возможностей и качества жизни пациентов.

Circular Permutation in the Ω-Loop of TEM-1 β-Lactamase Results in Improved Activity and Altered Substrate Specificity

Generating diverse protein libraries that contain improved variants at a sufficiently high frequency is critical for improving the properties of proteins using directed evolution. Many studies have illustrated how random mutagenesis, cassette mutagenesis, DNA shuffling and similar approaches are effective diversity generating methods for directed evolution. Very few studies have explored random circular permutation, the intramolecular relocation of the N- and C-termini of a protein, as a diversity-generating step for directed evolution. We subjected a library of random circular permutations of TEM-1 β-lactamase to selections on increasing concentrations of a variety of β-lactam antibiotics including cefotaxime. We identified two circularly permuted variants that conferred elevated resistance to cefotaxime but decreased resistance to other antibiotics. These variants were circularly permuted in the Ω-loop proximal to the active site. Remarkably, one variant was circularly permuted such that the key catalytic residue Glu166 was located at the N-terminus of the mature protein

The role of acyl-coenzyme A carboxylase complex in lipstatin biosynthesis of Streptomyces toxytricini

Streptomyces toxytricini produces lipstatin, a specific inhibitor of pancreatic lipase, which is derived from two fatty acid moieties with eight and 14 carbon atoms. The pccB gene locus in 10.6 kb fragment of S. toxytricini chromosomal DNA contains three genes for acyl-coenzyme A carboxylase (ACCase) complex accA3, pccB, and pccE that are presumed to be involved in secondary metabolism. The pccB gene encoding a β subunit of ACCase [carboxyltransferase (CT)] was identified upstream of pccE gene for a small protein of ε subunit. The accA3 encoding the α subunit of ACCase [biotin carboxylase (BC)] was also identified downstream of pccB gene. When the pccB and pccE genes were inactivated by homologous recombination, the lipstatin production was reduced as much as 80%. In contrast, the accumulation of another compound, tetradeca-5.8-dienoic acid (the major lipstatin precursor), was 4.5-fold increased in disruptant compared with wild-type. It implies that PccB of S. toxytricini is involved in the activation of octanoic acid to hexylmalonic acid for lipstatin biosynthesis

Dimerisation induced formation of the active site and the identification of three metal sites in EAL-phosphodiesterases

The bacterial second messenger cyclic di-3′,5′-guanosine monophosphate (c-di-GMP) is a key regulator of bacterial motility and virulence. As high levels of c-di-GMP are associated with the biofilm lifestyle, c-di-GMP hydrolysing phosphodiesterases (PDEs) have been identified as key targets to aid development of novel strategies to treat chronic infection by exploiting biofilm dispersal. We have studied the EAL signature motif-containing phosphodiesterase domains from the Pseudomonas aeruginosa proteins PA3825 (PA3825EAL) and PA1727 (MucREAL). Different dimerisation interfaces allow us to identify interface independent principles of enzyme regulation. Unlike previously characterised two-metal binding EAL-phosphodiesterases, PA3825EAL in complex with pGpG provides a model for a third metal site. The third metal is positioned to stabilise the negative charge of the 5′-phosphate, and thus three metals could be required for catalysis in analogy to other nucleases. This newly uncovered variation in metal coordination may provide a further level of bacterial PDE regulation

Enumerating Pathways of Proton Abstraction Based on a Spatial and Electrostatic Analysis of Residues in the Catalytic Site

The pathways of proton abstraction (PA), a key aspect of most catalytic reactions, is often controversial and highly debated. Ultrahigh-resolution diffraction studies, molecular dynamics, quantum mechanics and molecular mechanic simulations are often adopted to gain insights in the PA mechanisms in enzymes. These methods require expertise and effort to setup and can be computationally intensive. We present a push button methodology – Proton abstraction Simulation (PRISM) – to enumerate the possible pathways of PA in a protein with known 3D structure based on the spatial and electrostatic properties of residues in the proximity of a given nucleophilic residue. Proton movements are evaluated in the vicinity of this nucleophilic residue based on distances, potential differences, spatial channels and characteristics of the individual residues (polarity, acidic, basic, etc). Modulating these parameters eliminates their empirical nature and also might reveal pathways that originate from conformational changes. We have validated our method using serine proteases and concurred with the dichotomy in PA in Class A β-lactamases, both of which are hydrolases. The PA mechanism in a transferase has also been corroborated. The source code is made available at www.sanchak.com/prism

Hip arthroplasty in post-traumatic lesions of the acetabulum

Hip arthroplasty after acetabular injuries is complex and urgent problems of modem orthopedics. Objective: to study the outcomes of hip arthroplasty after acetabular injuries, presents survey data on 17 patients with an average age of 47,96 + 13,31 years. Were compared with patients with a destructive- dystrophic diseases who underwent hip arthroplasty. Hip arthroplasty with decompensated lesions are among the most effective technologies for surgical treatment, improving the quality of life of patients, but in patients after injuries of the acetabulum range of useful properties of this surgical technology is significantly reduced, which requires a special approach to the treatment of these patients based on the evaluation of the phase state connective tissue.Артропластика тазобедренного сустава после повреждений вертлужной впадины представляет сложную и актуальную проблему современной ортопедии. Цель исследования: изучить исходы артропластики тазобедренного сустава после повреждений вертлужной впадины, представлены данные обследования 17 пациентов, средний возраст которых составлял 47,96+13,31 лет. Проводилось сравнение с пациентами с деструктивно-дистрофическими заболеваниями, которым выполнялась артропластика тазобедренного сустава. Артропластика тазобедренного сустава при декомпенсированных поражениях относится к числу наиболее эффективных технологий оперативного лечения, улучшающих качество жизни пациентов, однако у лиц после повреждений вертлужной впадины диапазон полезных свойств данной хирургической технологии значительно уменьшается, что требует особого подхода к лечению этой категории пациентов на основе оценки фазового состояния соединительной ткани

Structural Basis for c-di-GMP-Mediated Inside-Out Signaling Controlling Periplasmic Proteolysis

X-ray crystallographic structural analyses of the bacterial transmembrane receptor LapD identify conserved molecular mechanisms that control biofilm formation in response to changes in the intracellular levels of the second messenger c-di-GMP

Analysis of results of hip arthroplasty after osteosynthesis of the proximal femur

Hip arthroplasty with the destructive and degenerative lesions in the modem development of science, technology and medicine is considered the most effective method of ensuring social reintegration and home. However, according to a number of specialists increased complication rate arthroplasty in patients after osteosynthesis of the proximal femur. The purpose of research — to compare patient outcomes for hip arthroplasty technology after osteosynthesis of the proximal femur. Material and Methods: The study group comprised 38 patients who underwent hip arthroplasty after osteosynthesis of the proximal femur. The control group consisted of 43 patients with idiopathic hip osteoarthritis who underwent primary arthroplasty. Results: conducting joint replacement in patients of the main group was accompanied by an increase in the frequency of intraoperative and postoperative complications. Therefore, this group of patients requires a special approach to diagnosis and treatment.Артропластика тазобедренного сустава при деструктивно-дистрофических поражениях при современном развитии науки, технологии и медицины считается наиболее эффективным методом, обеспечивающим социальную и бытовую реинтеграцию. Однако, по мнению целого ряда специалистов частота осложнений эндопротезирования увеличивается у лиц после остеосинтеза проксимального отдела бедра. Цель исследования— сравнить результаты лечения пациентов по технологии артропластики тазобедренного сустава после остеосинтеза проксимального отдела бедра. Материал и методы: основную группу составили 38 пациентов, которым проводилась артропластика тазобедренного сустава по­ сле остеосинтеза проксимального отдела бедра. Контрольная группа представлена 43 пациентами с идиопатическим остеоартрозом тазобедренного сустава, которым проводилась первичная артропластика. Результаты: проведение эндопротезирования у пациентов основной группы сопровождалось увеличением частоты интраоперационных и послеоперационных осложнений. В связи с этим данная группа пациентов требует особого подхода к диагностике и лечению

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor That Attenuates Disease Progression in Alzheimer’s Disease Mouse Models

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150’s exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior