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A series of novel 4-aryl-pyrido[1,2-c]pyrimidine derivatives containing a 1-(2-quinoline)piperazine moiety was synthesized. The chemical structure of new compounds was confirmed by FT-IR, (1)H NMR, (13)C NMR and HRMS spectra as well as elemental analysis. Affinity of the novel pyrido[1,2-c]pyrimidine derivatives for 5-HT1A, 5-HT2A receptors and serotonin transporter (SERT) was evaluated in an in vitro radioligand binding assay. Tested compounds showed moderate to high affinity for 5-HT1AR and SERT and low affinity for 5-HT2AR. Selected ligands were subjected to in vivo tests, such as induced hypothermia and the forced swimming test in mice, which determined presynaptic agonistic activity of the ligands 8d, 8e, 9d and 9e and presynaptic antagonistic activity of the ligands 8a, 8b, 9a, 9b. Additionally, metabolic stability evaluation was performed for selected ligands, proving that a para-substitution in the 4-aryl-pyrido[1,2-c]pyrimidine moiety leads to an increase in stability, whereas a substitution in the ortho-position lowers the stability., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: The role of human papillomavirus (HPV) in bladder carcinogenesis remains controversial. Overexpression of p16(INK4a), a surrogate marker for infection with oncogenic HPV in other tumours, has been described for urothelial carcinoma in situ (UCIS). Our goal was therefore to evaluate whether overexpression of p16(INK4a) is associated with HPV infection and to identify mechanisms of p16(INK4a) upregulation in UCIS., Materials and Methods: In 60 tissue specimens from a total of 45 patients (UCIS and controls), we performed p16(INK4a) immunohistochemistry followed by detection and subclassification of HPV DNA. In a subset of samples, we tested for gene amplification of p16(INK4a) applying fluorescence in situ hybridization (FISH). RAS/MAPK signalling and epithelial-mesenchymal transition (EMT) was assessed using immunohistochemistry. Finally, we transfected urothelial carcinoma cells with KRAS and examined the expression of p16(INK4a) as well as markers of EMT., Results: We found overexpression of p16(INK4a) in 92.6% of UCIS and in all cervical intraepithelial neoplasia (CIN) controls. In contrast, we detected high-risk HPV DNA in 80% of CIN, but none in UCIS. There was no gene amplification of p16(INK4a). High levels of phosphorylated kinases and urokinase plasminogen activator (uPA) and loss of membraneous E-cadherin were detected in UCIS. KRAS transfection of urothelial carcinoma cells led to upregulation of p16(INK4a) and uPA accompanied by loss of E-cadherin that could be inhibited by application of the kinase-inhibitor Sorafenib., Conclusions: Our results show that overexpression of p16(INK4a) in UCIS is neither associated with HPV infection nor p16(INK4a) gene amplification but is a consequence of enhanced RAS/MAPK signalling that promotes EMT, possibly due to Sorafenib-sensitive paracrine secretion of the EMT activator uPA. These findings might open a novel therapeutic option for localized but aggressive urothelial cancer.

An exceptionally large size cuboctahedral imine cage is obtained from small size organic molecules in a thermodynamically driven [8+12] cyclocondensation. This is a demonstration of the role of entropy of symmetry as a driving force in reversible reactions.

We present a theoretical study of vibrationally resolved circular dichroism spectra, both in the adiabatic and non-adiabatic frameworks, with a full account of Franck-Condon and Herzberg-Teller vibrational contributions for the former. Model calculations have been performed on 2(R)-deuteriocyclopentanone, whose chirality is due solely to isotopic substitution. This molecule has two distinct, nearly isoenergetic, half-chair conformations in equilibrium, and its demanding nature in terms of computational accuracy makes it a perfect candidate for performing a detailed comparison between different vibronic models. Comparisons are made with experimental spectra, and we also consider temperature effects. In order to reproduce the experimental spectrum, it is necessary to consider the geometry relaxation occurring during the n→π* transition.

Introduction: Arthroscopy of the knee joint is regarded as the most objective diagnostic method in intra-articular knee joint lesions., Aim: The purpose of this study was to assess the objectivity and diagnostic value of orthopaedic examination (OE) and magnetic resonance imaging (MRI) in reference to the arthroscopic result., Material and Methods: In a group of 113 patients treated by arthroscopic surgery for post-traumatic knee pathology between 2008 and 2010 in our department, accuracy of clinical and MRI findings that preceded surgery were studied retrospectively using a statistical method. Sensitivity, specificity, accuracy and predictive negative and positive values were the subject of analysis., Results: In the presented trial, sensitivity values of the orthopaedic examination for injuries of the anterior cruciate ligament (ACL), meniscus medialis (MM), meniscus lateralis (ML) and chondral injuries (ChI) were 86%, 65%, 38% and 51%, respectively. Specificity values were 90%, 65%, 100% and 100%, respectively. The MR sensitivity and specificity values were 80%, 88%, 44% and 32%, and 86%, 64%, 93% and 97%, respectively., Conclusions: Assessment of intra-articular knee joint lesions is a difficult diagnostic problem. In making a decision about arthroscopy of the knee joint, an appropriate sequence of examinations should be carried out: OE, MRI and arthroscopy. The improvement in the effectiveness of the orthopaedic examination and MRI can limit the too high frequency of diagnostic arthroscopies, which generates the risk of operation treatment and costs.

Unlabelled: The authors describe the case of a 21 year old patient who suffered an politrauma injury in a traffic accident (motorcyclist)., Objectives: Presentation of possiblities of treatment femur bone fracture with critical bone loss using intramedullary nail., Methods: Patients's Injury included: fractures of the femur, temporal bone, and ulna. The patient's Severity Score (ISS) was 24. The dominant trauma fracture was open, comminuted fracture of femur shaft (AO 32-C2, Anderson-Gustilo IIIa) with bone loss stated as critical (loss of femoral shaft over 10 cm, including the loss of more than 50% of the circumference was about 8 cm length, and the loss of the full circumference of more than two branches of the missing bone). Osteosynthesisnad bone length reconstruction of the femur was with use of intramedullary locking nail., Results: Full reconstruction was regenerated after 12 months. Although there was extensive injury no local and general complications appeared., Conclusion: Early definitive fracture stabilization and secondary dynamisation possible to obtain the bone regeneration at the defect site.

Background: This retrospective cohort study analyses the long-term outcomes of total hip arthroplasty (THA) in arthritis patients with various forms of acetabular protrusion., Material: We analyse 135 consecutive cemented total hip arthroplasties in 127 patients. Mean age of the patients was 55.2 years (range: 30-72 years). The study group consisted of 119 women and 16 men who were followed up for a mean of 12.7 years. Mean preoperative function was poor, with a Harris score of 28.0 points., Methods: Clinical evaluation utilized the Harris hip score, and radiographic assessment relied on the criteria of the Joint Committee of the Hip Society, AAOS and SICOT., Results: Clinical outcomes of the study group were as follows: excellent in 35 (25.9%), good in 78 (57.8%), fair in 17 (12.6%), and poor in 5 (3.7%). The mean postoperative Harris score was 86.6 points. The radiographic outcomes were excellent in 47 (34.8%), good in 60 (44.5%), fair in 18 (13.3%), and poor in 10 hips (7.4%). Loosening of both components was observed in 6 hips and of the acetabular component in 4 hips. Complications other than aseptic loosening were observed in 25 (18.5%) hips., Conclusions: Implant survival following THA in arthritis with acetabular protrusion depends mainly on proper bone stock reconstruction. 80-85% patients after THA with acetabular bone stock reconstruction achieved very good and good results following an average of 12 years of follow-up. Patients with autogenic bone grafts achieved better outcomes. There was no substantial effect of aetiology, type of endoprosthesis, grade of acetabulum migration on the final outcome.

The purpose of this study was to compare the clinical results of total knee arthroplasty (TKA) in the early and late postoperative period using subvastus and medial parapatellar approach. A prospective randomized controlled study was conducted in a group of 169 patients (180 TKAs) with 2-year follow-up. Patients were divided into a study group (97 TKAs) with a subvastus approach and a control group (83 TKAs) with a parapatellar approach. Assessment of the results of both operating approaches was based on functional, clinical Knee Society Score, and pain (visual analog scale). Patients in the subvastus group achieved full active extension, better range of motion, and better Knee Society Score results at 12 days, 6 weeks, and 12 weeks earlier than patients in the medial parapatellar group. They also had less pain at 12 days. No statistically significant differences existed between assessed end points in both groups at 24- and 52-weeks, and 24-months postoperatively. The subvastus approach has given patients better early clinical results; however, at longer follow-up, both groups had similar outcomes. The potential benefits of the subvastus approach are: protection of the extensor mechanism from damage, less risk of damaging the blood supply to the patella, earlier clinical recovery, and less pain in the early postoperative period. The subvastus approach is an alternative to the standard medial parapatellar approach in TKA. It can be used with equally good results, especially taking into consideration positive clinical aspects in the early postoperative period., (Copyright 2011, SLACK Incorporated.)

Quaternary systems of copper(II) complexes with adenosine 5'-triphosphate, O-phospho L-serine and with equimolar or excessive amount of spermine have been investigated. The studies have been performed in aqueous solution. Types of complexes and the overall stability constants have been determined using the potentiometric method with computer analysis of the data. On the basis of the results of spectroscopic studies (nuclear magnetic resonance, visible, circular dichroism, Raman, infrared and electron paramagnetic resonance spectroscopies) as well as equilibrium studies, the mode of interactions has been proposed. The reaction centers in the systems studied are the phosphate, carboxyl and amine groups from phosphorylated serine, heterocyclic nitrogen atom from purine ring and phosphate groups from adenosine 5'-triphosphate as well as amine groups from polyamine. The influence of change in the concentration of the polyamine (spermine) on the mode of coordination is discussed. It has been shown that in the physiological conditions an increase in the polyamine concentration changes the mode of metal bonding in the CuH(3)(ATP)(Ser-P)(Spm) complexes (isomer I - coordination {2N,O(x)}, isomer II - coordination {3N,O(x)} and significant differences in sites of interaction)., ((c) 2010 Elsevier Inc. All rights reserved.)

The article discusses preliminary clinical results in patients with proximal femoral fractures treated with hemiarthroplasty using a FENIX implant. The study group comprised 41 subjects aged 69 to 97 (median age 82.3 year). The follow-up study provided data on 26 subjects (63.4%), among which 15 attended the check-up, 5 subjects refused to visit at the Department and 6 subjects were reported as deceased. Median follow-up period amounted to 6.8 month (1 to 22 months). General hospitalization-related complications occurred in 8 patients (19.5%). During hospitalization no deaths occurred, in the deceased group 3 patients died within 12 months after surgery, while another 3 died after the twelve-month postoperative period (median of 13.3%). According to Merle d'Aubigne-Postel score favorable long-term results were observed in 9 patients (59.9%), 13 patients regained the level of motor function similar to the functional ability prior to fracture. The need to postpone the surgery due to general health status and impaired pre-operative motor function are significant negative prognostic factors. The results obtained were compared with previous efficacy studies on femoral fracture treatment using an Austin-Moore implant. Functional ability and self-reliance was higher in the FENIX group. FENIX arthroplasty effectively helps patients regain self-reliance and motor function thanks to its modular characteristics and anatmoical construction.

Unlabelled: The aims of retrospective cohort study were: analysis of general and local factors, evaluation of clinical and radiographic results and presentation of authors' experience in total hip arthroplasty in rheumatoid arthritis. Study group consists of 222 consecutive total hip arthroplasties (205 cemented and 17 cementless) made in 216 patients. Mean patients' age was 58.4 y.o (range: 34-77 y.o.). In study group were 192 women and 24 men. Mean preoperative function was poor: 28.4 points (range: 24-32 p.). Clinical evaluation was made with Harris hip score, and radiographic one with criteria of Joined Committee of Hip Society, AAOS and SICOT. Clinical results of the study group were as follow: excellent--53 (23.9%), good--128 (57.6%), fair--34 (15.3%) and poor--7 (3.2%). Mean postoperative function was good: 86.8 points (range: 28-94 p.). There were following radiographic results of study group: good--176 (79.3%), fair--28 (12.6%) and poor--18 (8.1%). Complications another than aseptic loosening were observed in 56 (25.2%) hips., Conclusions: 1) general and local factors make total hip arthroplasty in rheumatoid arthritis more difficult procedure than the same one in osteoarthritis, 2) log-term survival rate of hip replacement in rheumatoid arthritis mainly depends on proper bone stock reconstruction, 3) 80-85% of excellent and good clinical and radiographic results are achieved at 12-year follow-up, 4) incidence of local and systemic postoperative complications are similar to osteoarthritis population, 5) preoperative autologous blood donation does not decrease demand of postoperative blood transfusion.

Thioureas and isothiocyanates, compounds of high importance in organic synthesis, have not been considered so far as chiroptical probes that can provide structural information from the analysis of circular dichroism spectra. CD spectra of a set of molecules containing the thiourea, isothiocyanate and phthalimide chromophores were obtained and analyzed on the grounds of the calculated populations of conformers and their individual contributions to the CD spectra. It is shown that the thiourea and isothiocyanate chromophores can provide useful structural information from the analysis of their exciton-coupled CD spectra. Exciton-coupled CD spectra of thioureas were found to be sensitive to the Z/E conformation of the chromophore. DFT calculations based on the B2LYP functional were shown to provide a better match with the experimental spectra collected in the short wavelength region, compared to the traditionally used B3LYP functional.

CD (circular dichroism) and X-ray investigations have been carried out in order to identify the prevalent conformations and define the forces that determine the molecular and supramolecular organization of the alkyl-bridged bichromophoric [NAB, ortho-(1,8-naphthalimido)benzoyl] units, each consisting of the benzoyl substituted in the ortho position with the 1,8-naphthalimide group. The results reveal that NAB bichromophores incorporated into the same molecule exist in a variety of conformation/helicity combinations. The molecular structures are largely stabilized by local 1,3-CH/CO dipole-dipole interactions, while the crystal packing besides dispersive H...H interactions is mostly governed by multiple C-H...O(=C) and C-H...pi interactions. The relatively small contribution of pi...pi interactions comes from a pairwise off-face stacking between naphthalimide rings or from pairwise carbonyl...pi interactions. All these types of intermolecular interactions have been summarized quantitatively by means of a Hirshfeld surface analysis.

Thermodynamically driven cyclocondensation of (R,R)-1,2-diaminocyclohexane and 1,3,5-triformylbenzene yields solely a [4 + 6] spherand type product. This is a unique example of spontaneous formation of an organic compound of permanent chiral tetrahedral (T) symmetry.

The aim of this study is to present the authors' own concept of the leg support device which facilitates stable positioning in a lateral position with the possibility of a controlled leg abduction in the pelvic, hip and thigh operation. The appliance of this device is a very good and cheap alternative of positioning patients in the hip operation in comparison with the improvised lateral position. As far as the operated leg is concerned the advantages of this device include: stable leg positioning, possibility of controlling the length of the leg, possibility of changing the leg position. The use of this device also reduces the number of medical staff assisting during the operation. Furthermore, this device prevents putting physical pressure on the leg that is not being operated. The experience of using this device for the last few years has proved its numerous advantages.

Aims: Evaluation of: 1. early clinical and radiographic results of total hip arthroplasty (THA) through a standard lateral direct approach, 2. early clinical and radiographic results of THA through a minimal lateral approach, 3. comparison of the results of THA in these two groups., Material and Methods: 120 THAs (60 cementless and 60 cemented) done in 120 patients due to degenerative changes were evaluated prospectively. 60 THAs were done through a minimal lateral approach and constituted a study group. 60 THAs were done through a direct lateral approach and constituted a control group. The mean age of the 120 patients (98 women and 22 men) was 45 y.o. (range: 32-67 y.o.). The duration of follow-up in the study group was from 6 to 12 months (mean: 8.5 months). The duration of follow-up in the control group was from 10 to 16 months (mean: 10.5 months). Mean preoperative functional status of the study group was 44.5 points according to the Harris hip score. Radiographic evaluation of the results was done according to the criteria of the Joint Committee of the Hip Society, AAOS and SICOT., Results: 6 months after THA, clinical results were 92 pts in the study group and 88 pts in the control group. Radiographic outcomes were very good in all 120 patients from both arms: there were no differences between the control and study group. The incidence of complications was similar in both groups., Conclusions: Minimally invasive THA demonstrated its value in the treatment of degenerative changes of the hip joint with regard to short-term outcomes. The clinical and radiographic outcomes were comparable between the standard and minimally invasive approaches. Success with THA using a minimally invasive approach depends on excellent operative technique and experience with standard hip approaches rather than on the use of special instruments.

A versatile system for preparing macrocyclic compounds with planar chirality is presented. In this system chiral diazacoronands are synthesized readily from lariat-type diesters 13 and 14 and unsymmetrical diamines 7, 8, 12, 15, and 16 under non-high-dilution conditions. The title compounds were subjected to structural analysis by X-ray crystallography and circular dichroism spectroscopy, and absolute configurations for two representative examples (compounds 2 and 3) were assigned by molecular modeling. The correctness of the theoretical approach was verified by the crystallographic results obtained experimentally.

Background. In a retrospective study of the time of survival, the quality of life and the methods used to reconstruct large bone defects around the hip joint, we examined 13 patients treated surgically in our orthopedic ward between 1989 and 2004 for primary and secondary bone tumors. Material and methods. The study group included 11 women and 7 men, mean age 56.4 years. 5 patients (22%) had primary tumors: myeloma in 2 patients, chondrosarcoma in 2 patients, and MFH in 1 patient. In 13 patients (87%) there were metastatic lesions. The technical solutions used to reconstruct large bone defects included post-resection endoprothesis in 5 cases, total endoprothesis in 10 cases, and partial endoprosthesis in 3 cases. The treatment outcome was evaluated using the authors' own clinical scoring system, which covers pain, range of motion, muscle strength, ambulation, and activities of daily living. Results. There were no deaths in the early post-operative period. The mean post-operative follow-up time was 15 months. Excellent or good outcomes were achieved in 92.3% of cases: good ambulation, independence in activities of daily living, and no pain. The mean time of patient survival was 16.5 months (range: 10-42 months). Conclusions. Surgical reconstruction of large bone defects due to a malignant tumor around the hip joint is very effective in relieving pain, improving ambulation and increasing daily activities. The time of survival of patients after resection of bone tumor and hip replacement confirms the usefulness of this treatment method.

The chiral but highly symmetrical acyclic and cyclic pyromellitic diimide dimers and trimers 2-5 have been obtained and characterized for the first time. The pyromellitdiimide chromophores in these molecules are linked by a rigid diequatorially 1,2-disubstituted cyclohexane skeleton. The structures of the compounds have been determined in detail by molecular modeling and, in the case of cyclic dimer 4 and trimer 5, by means of X-ray diffraction analysis. The electronically excited states of the pyromellitdiimide chromophore (1a) have been studied in these and other model compounds by means of linear dichroism (LD), magnetic circular dichroism (MCD), and circular dichroism (CD) spectroscopy. CD spectra of the rigid cyclic trimer 5 have provided the most detailed information on the excited states of the pyromellitdiimide chromophore. The low-energy tail (340-360 nm) of the absorption envelope can be assigned to out-of-plane polarized n-pi* transitions (I, II). The higher energy bands are due to contributions from up to six pi-pi* transitions, these being polarized either along the long (IV-VI, VIII) or short axis (III, VII). The results of ab initio CIS/cc-pVDZ and semiempirical INDO/S-CI calculations have been compared with the experimental data. CD Cotton effects in the region 200-260 nm, which result from exciton interactions between electric dipole allowed transitions of two pyromellitdiimide chromophores in compounds 2-5, provide reliable and useful information concerning the conformation and absolute configuration of these molecules, which may be extrapolated to other oligoimide systems.

The absorption and magnetic circular dichroism (MCD) spectra of 1,8-naphthalimide are analyzed in terms of the number of contributing electronic transitions and their polarization. The experimental results are supported by semiempirical INDO/S calculations. It is demonstrated that the strongly allowed, pi --> pi naphthalene transition of the 1,8-naphthalimide chromophore located at 231 nm is perfectly suited for absolute configuration assignments of amine derivatives on the basis of the bichromophoric exciton coupling. Both degenerate (bis-1,8-naphthalimide) and nondegenerate (1,8-naphthalimide-phthalimide, 1,8-naphthalimide-phenyl, or 1,8-naphthalimide-benzoate) couplings were studied. In the latter case, the sign of the exciton Cotton effect was opposite to the sign of the degenerate exciton Cotton effect for the same absolute configuration. An extension of the application of the exciton coupling to the 264 nm pi --> pi transition of 1,9-anthraimide is also shown.

In this study we present 2 postmenopausal women who showed clinical symptoms that resembled those of a rather well-defined group of vascular dementia disorders, termed subcortical dementia (Binswanger disease, CADASIL). Patient 1 exhibited mitochondrial DNA (mtDNA) variants in the ND5 gene at position 13,708 and the Cytb gene at position 15,257. These DNA variants have been described in a number of neurologic disorders, but their pathogenetic potential is unclear. Patient 2 showed the same DNA alterations and an additional mtDNA variant at position 15,812 in the Cytb gene. The principal neurohistologic features of the 2 atrophic brains presented here include: subtotal selective neuronal cell loss in the cortex and, to a lesser degree, in the basal ganglia (claustrum, putamen, globus pallidus), sparing palaeocortex and periarchaeocortex, and a very characteristic and diagnostic feature was detachment of astrocytic processes from capillary walls resulting in pericapillary space formation. These pericapillary spaces were partially filled with macrophages. The spaces were not associated with total breakdown of the blood vessel walls as demonstrated by the absence of erythrocytes, lymphocytes, or polymorphonuclear leukocytes outside the vascular bed of the brain; progressive subcortical encephalopathy, as it is seen in subcortical dementia (Binswanger), but lacking arterial lipohyalinosis. The cerebral grey and white matter revealed cuffing of arteries and arterioles by adventitial macrophages. The neocortical and subcortical changes were accompanied by myriads of activated macrophages filled with lipids. The pathology of our 2 cases differs from that of other neurodegenerative disorders and we suggest the term of "disseminated neocortical and subcortical encephalopathy (DNSE) with widespread activation of brain macrophages".

300 patients suffering from neurodegenerative diseases distinct from Leber hereditary optic neuropathy (LHON) were screened for the presence of mitochondrial DNA mutations. We report on nine patients, eight female and one male, who all harboured mutations at positions 13,708 and 15,257 of the mitochondrial DNA. Both mutations have previously been claimed to be associated with LHON. Based on our results, these mutations occur in a number of different neurodegenerative diseases and therefore cannot be regarded as "LHON" mutations.

HeLa cells, cultured over a long period in a medium containing low doses of ethidiumbromide, were used as a model system for flow-cytometric detection of human cells with impaired mitochondrial respiratory function. Based on laserscan and flowcytometric analysis after rhodamine 123 staining, the mitochondrial membrane potential of respiratory deficient cells seems unchanged as compared to control cells. Maintenance of this membrane potential in respiration-impaired cells requires glycolytic ATP generation, as transient inhibition of glycolysis by sodium fluoride affects rhodamine 123 accumulation in ethidiumbromide-treated cells, but not in control cells. We present a protocol which allows the detection and separation of respiratory deficient cells by flow cytometry.