Synthesis and Pharmacological Characterization of Metronidazole-Oxadiazole Derivatives.

Background: The use of antibiotics with or without prescription is increasing worldwide. With certain limitations, metronidazole (MTZ) is extensively used as an antibacterial and antiparasitic drug. Derivatives of 1,2,4-oxadiazole (ODZ) are used to modify the chemical structure of drugs. The present study aimed to synthesize new MTZ-ODZ derivatives that could potentially lead to new medications. Methods: The reaction of MTZ with ethyl chloroacetate and potassium carbonate anhydrous was used to produce compound 7. This compound was treated with hydrazine hydrate in methanol to obtain compound 8. Carbon disulfide and potassium hydroxide were then added to obtain compound 9, which was then mixed with various α-haloketones to obtain compounds 10a to 10f. Subsequently, the structures of the new MTZ-ODZ derivatives were determined. Results: All new compounds exhibited excellent activity against all tested organisms. The synthesized compounds showed a significant radical scavenging activity. The IC50 value for compounds 10a, 10b, 10c, 10d, 10e, and 10f was 70.42±0.15, 70.52±0.54, 85.21±0.85, 80.10±0.46, 82.52±0.13, and 70.45±0.12 g/mL, respectively. In terms of antigiardial activity, the IC50 value for compounds 10a,10b, 10c, and 10d ranged from 1.31±0.11 µM to 2.26±0.49 µM. In contrast, the IC50 for MTZ was 3.71±0.27 µM. Compound 10f showed the highest antigiardial activity with an IC50 value of 0.88±0.52 µM. Conclusion: Most of the MTZ-ODZ derivatives showed high radical scavenging activity in the benzene ring due to the activation of certain groups, such as OCH3, NO2, and OH. The results suggest that the newly synthesized compounds could be used as an antiparasitic drug.

Microelectrode clusters enable therapeutic deep brain stimulation without noticeable side-effects in a rodent model of Parkinson's disease.

BACKGROUND: Deep Brain Stimulation (DBS) is an established treatment for motor symptoms in Parkinson's disease (PD). However, side effects often limit the usefulness of the treatment. NEW METHOD: To mitigate this problem, we developed a novel cluster of ultrathin platinum-iridium microelectrodes (n = 16) embedded in a needle shaped gelatin vehicle. In an established rodent PD-model (6-OHDA unilateral lesion), the clusters were implanted in the subthalamic area for up to 8 weeks. In an open field setting, combinations of microelectrodes yielding therapeutic effects were identified using statistical methods. Immunofluorescence techniques were used for histological assessments of biocompatibility. RESULTS: In all rats tested (n = 5), we found subsets of 3-4 microelectrodes which, upon stimulation (160 Hz, 60 µs pulse width, 25-40 µA/microelectrode), prompted normal movements without noticeable side effects. Other microelectrode subsets often caused side effects such as rotation, dyskinesia and tremor. The threshold (per microelectrode) to elicit normal movements strongly depended on the number of activated microelectrodes in the selected subset. The histological analysis revealed viable neurons close to the electrode contacts, minor microglial and astrocytic reactions and no major changes in the vasculature, indicating high biocompatibility. COMPARISON TO EXISTING METHODS AND CONCLUSION: By contrast to the continuous and relatively large stimulation fields produced by existing DBS electrodes, the developed microelectrode cluster enables a fine-tuned granular and individualized microstimulation. This granular type of stimulation pattern provided powerful and specific therapeutic effects, free of noticeable side effects, in a PD animal model.

Ice coating -A new method of brain device insertion to mitigate acute injuries.

BACKGROUND: Reduction of insertion injury is likely important to approach physiological conditions in the vicinity of implanted devices intended to interface with the surrounding brain. NEW METHODS: We have developed a novel, low-friction coating around frozen, gelatin embedded needles. By introducing a layer of thawing ice onto the gelatin, decreasing surface friction, we mitigate damage caused by the implantation. RESULTS AND COMPARISON WITH EXISTING METHODS: The acute effects of a transient stab on neuronal density and glial reactions were assessed 1 and 7 days post stab in rat cortex and striatum both within and outside the insertion track using immunohistochemical staining. The addition of a coat of melting ice to the frozen gelatin embedded needles reduced the insertion force with around 50 %, substantially reduced the loss neurons (i.e. reduced neuronal void), and yielded near normal levels of astrocytes within the insertion track 1 day after insertion, as compared to gelatin coated probes of the same temperature without ice coating. There were negligible effects on glial reactions and neuronal density immediately outside the insertion track of both ice coated and cold gelatin embedded needles. This new method of implantation presents a considerable improvement compared to existing modes of device insertion. CONCLUSIONS: Acute brain injuries following insertion of e.g. ultra-flexible electrodes, can be reduced by providing an outer coat of ultra-slippery thawing ice. No adverse effect of lowered implant temperature was found, opening the possibility of locking fragile electrode construct configurations in frozen gelatin, prior to implantation into the brain.

A new prodrug and bioactivity evaluation of methotrexate based on Chitosan.

Methotrexate (MTX) is the most important drug used in the treatment of several kinds of cancers, such as colon cancer. However, this drug can cause a reduction in the target tissue bioavailability. It is administered orally and absorbed quickly. This study aimed to produce an anti-colon cancer prodrug based on MTX via loading it into a biopolymer compound. Chitosan (CS) was extracted from scales of local fish by utilizing a previously published protocol. The MTX was then transformed to Methotrexate - imidazole and loaded into CS to prepare Chitosan - Methotrexate (CS-MTX) conjugates as colon cancer prodrugs. Fourier-transform infrared (FTIR), UV-visible spectroscopy, and 1H-NMR were used to analyse the structure of the prepared compounds. The prepared compounds were also tested for hemolytic activity. Chemical stability was studied using 0.2 M from the different buffer types with a pH of 1.2 and 7.4 over different periods about 240 min and kept in an incubator at 37 °C. The loading percentage was measured by hydrolysing the amide bond in basic media followed by the measurement of the absorbency at 273 nm. Three types of cancer cells, MCF-7, MDA-MB-231, and MDA-MB-453, were used to test the anticancer effects of CS-MTX by using tetrazolium bromide (MTT) assay. The results indicated that the viability of human breast cancer cell lines decreased because of the use of CS-MTX. This study also showed that CS-MTX was less toxic than the original drug. Therefore, it may be measured for additional biological analyses and medical applications. The results presented here showed that the new compound is remarkably stable in comparison with MTX and has longer half-life (t ½). Therefore, the CS-MTX has promising strategies through minimising the side effects of anti-colon tumour drugs.

Synthesis and Biological Evaluation of Three New Chitosan Schiff Base Derivatives.

Recently, chemical modifications of chitosan (CS) have attracted the attention of scientific researchers due to its wide range of applications. In this research, chitin (CH) was extracted from the scales of Cyprinus carpio fish and converted to CS by three chemical steps: (i) demineralization, (ii) deprotonation, and (iii) deacetylation. The degree (measured as a percentage) of deacetylation (DD %) was calculated utilizing the acid-base titration method. The structure of CS was characterized by Fourier transform infrared (FT-IR) spectroscopy and thermogravimetric analysis (TGA). Three new CS Schiff bases (CSSBs) (CS-P1, CS-P2, and CS-P3) were synthesized via coupling of CS with 2-chloroquinoline-3-carbaldehyde, quinazoline-6-carbaldehyde, and oxazole-4-carbaldehyde, respectively. The newly prepared derivatives were verified, structurally, by nuclear magnetic resonance (1H and 13C NMR) and FT-IR spectroscopy. Antimicrobial activity was evaluated for the prepared compounds against both "Gram-negative" and "Gram-positive" bacteria, namely, Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, and Streptococcus mutans, in addition to two kinds of fungi, Candida albicans and Aspergillus fumigates. Cytotoxicity of the synthesized CSSBs was evaluated via a MTT screening test. The results indicated a critical activity increase of the synthesized compound rather than CS generally tested bacteria and fungi and the absence of cytotoxic activity. These findings suggested that these new CSSBs are novel biomaterial candidates with enhanced antibacterial and nontoxic characteristics for applications in areas of both biology and medicine.

Synthesis of a Di-Mycoloyl Tri-Arabinofuranosyl Glycerol Fragment of the Mycobacterial Cell Wall, Based on Synthetic Mycolic Acids.

Fragments of mycobacterial cell walls such as arabinoglycerol mycolate and dimycoloyl diarabinoglycerol, comprising complex mixtures of mycolic acids, have immunostimulatory and antigenic properties. A related di-mycoloyl tri-arabinofuranosyl glycerol fragment has been isolated from cell wall hydrolysates. An effective stereoselective synthesis of tri-arabinofuranosyl glycerol, followed by coupling with stereochemically defined mycolic acids of different structural classes, to provide unique di-mycoloyl tri-arabinofuranosyl glycerols is now described.

The synthesis of mycobacterial dimycoloyl diarabinoglycerol based on defined synthetic mycolic acids.

Complex mixtures of natural dimycoloyl diarabinoglycerols isolated from mycobacteria have been shown to be both potent immune signalling agents and potentially valuable antigens in the serodiagnosis of mycobacterial infections. We now report the highly stereocontrolled synthesis of diacyl l-glycerol-(1'→1)-ß-d-arabinofuranosyl-α-d-arabinofuranosides based on simple fatty acids and single defined synthetic mycolic acids. NMR analysis confirmed that the synthetic core was identical to that in natural mixtures.

Clinical presentation of atrial myxomas does it differ in left or right sided tumor?

OBJECTIVE: This paper reports a 20 years' experience in the management of atrial myxomas at our institution. Apart from presenting our experience of their clinical presentation, surgical management, post-operative complication, and long-term follow-up we investigated any correlation between left and right sided tumor with their symptom of presentation. MATERIALS AND METHODS: The data were retrospectively collected for patients between the period 1995 and 2015 from the hospital database. The follow-up was conducted by questionnaire received from the patients describing their current status. RESULTS: Fifty four consecutive patients underwent surgical resection for atrial myxomas. The mean age was 62 years (standard deviation [SD]: ±14 years) with a larger number of female (55.5%) patients. The most common location for the tumor was the left atrium (70.3%) with the atrial septum being the most common (63%) site of attachment. The tumors presented in a variety of ways, namely, as shortness of breath (37.03%), transient ischemic attack (24.07%), and chest pains (22.2%) being the more common modes of presentation. Left heart tumors presented 6 years earlier with more severe shortness of breath as compared to right-sided tumors. Post-operative atrial fibrillation occurred in 22.2% of patients. Concomitant surgical procedures were required in 26% of patient. The median length of post-operative hospital stay was 6 days (IQR: 5; 9). There were 2 (3.7%) in-hospital mortalities and 4 (7.4%) later deaths at 2, 3, 7, and 15 years, respectively. Long-term follow-up actuarial Kaplan-Meire survival for the whole group was 92.6 ± 3.6% at 20 years with a significant reduction in the severity of shortness of breath. CONCLUSION: Cardiac myxoma is the most common form of the cardiac tumor with a slight female preponderance. Left-sided tumors present earlier than right-sided tumors with more severe shortness of breath. Excellent long-term results can be achieved with surgical intervention for cardiac myxomas, including any concomitant interventions. In particular, a sustained reduction in shortness of breath is observed.

Long-Term Outcome of Interrupted Arch Repair With Direct Anastomosis and Homograft Augmentation Patch.

BACKGROUND: This study analyzed outcomes of interrupted aortic arch (IAA) repair using a standardized technique to interpret the role of the arch repair on late outcomes in a complex and heterogeneous group of patients. METHODS: This single institution study covered the period from 1988 to 2015. A total of 120 cases of IAA were divided into four groups: IAA with ventricular septal defect (VSD) (n = 38), IAA with a Norwood or Damus-Kaye-Stansel procedure (n = 41), IAA with truncus arteriosus (n = 24), and a miscellaneous group (n = 17). Arch repair was performed using a standard technique of direct anastomosis with homograft patch augmentation. RESULTS: IAAs were predominantly type B (n = 81, 68%), and type A (n = 34, 28%), with a significant association of type B with truncus arteriosus and of type A with an aortopulmonary window (p < 0.01). Survival was similar in all groups. The incidence of catheter or surgical reintervention was 18% (confidence interval [CI], 10% to 25%) at 5 years and 18% (CI, 10% to 25%) at 10 years, with catheter reintervention more common and occurring before 18 months. Surgical reintervention occurred in 7% (CI, 2% to 13%) at 5 and 10 years and at 10 years the reintervention rate was lower in the group with truncus arteriosus (0%) and in the group with a Norwood or Damus-Kaye-Stansel procedure (5%). There was no bronchial obstruction or aortic aneurysm. The Cox proportional hazard model showed that weight at surgery <2.5 kg and era of surgery were predictive of outcome, with surgical mortality rates in all variants dropping to 8.3% in the last 15 years of the study. CONCLUSIONS: Repair of IAA using direct anastomosis and patch augmentation is applicable to all variants and provides good long-term arch patency. Survival is strongly associated with weight at surgery.

Preparation and Bioactivity Assessment of Chitosan-1-Acetic Acid-5-Flurouracil Conjugates as Cancer Prodrugs.

5-fluorouracil (5-FU) is a specific anti-cancer agent that is generally used to treat gastrointestinal, colorectal, and breast cancer. In this work, chitosan (CS) was extracted from local fish scales using an established method. 5-FU was then converted to 1-acetic acid-5-fluorouracil (FUAC) and reacted with this CS to prepare chitosan-1-acetic acid-5-fluorouracil (CS-FUAC) conjugates as a colon-specific prodrug. All compounds were characterized by Proton nuclear magnetic resonance (¹H-NMR), Fourier-transform infrared (FTIR), and UV-visible spectroscopy. The synthesized compound was subjected to a chemical stability study in phosphate buffer (0.2 M, pH 7.4) and in KCl/HCl buffer (0.2 M, pH 1.2) at different time intervals (0-240 min) and incubation at 37 °C. This revealed a significantly greater stability and a longer half-life for the CS-FUAC than for FUAC. Hemolytic activity results indicated a much lower toxicity for CS-FUAC than for 5-FU and supported consideration of CS-FUAC for further biological screening and application trials. The percentage of FUAC in the conjugates was determined by subjecting the prodrug to treatment in basic media to hydrolyze the amide bond, followed by absorbency measurements at 273 nm. The cytotoxicity studies of the conjugates were also evaluated on human colorectal cancer cell line (HT-29), which showed that the conjugates are more cytotoxic than the free drug. Therefore, CS-FUAC conjugates can be considered to represent potential colon-specific drug delivery agents, with minimal undesirable side effects, for colon cancer therapy.

Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of Mycobacterium tuberculosis.

The cell wall of mycobacteria is characterised by glycolipids composed of different classes of mycolic acids (MAs; alpha-, keto-, and methoxy-) and sugars (trehalose, glucose, and arabinose). Studies using mutant Mtb strains have shown that the structure of MAs influences the inflammatory potential of these glycolipids. As mutant Mtb strains possess a complex mixture of glycolipids, we analysed the inflammatory potential of single classes of mycolate esters of the Mtb cell wall using 38 different synthetic analogues. Our results show that synthetic trehalose dimycolate (TDM) and trehalose, glucose, and arabinose monomycolates (TMM, GMM, and AraMM) activate bone marrow-derived dendritic cells in terms of the production of pro-inflammatory cytokines (IL-6 and TNF-α) and reactive oxygen species, upregulation of costimulatory molecules, and activation of NLRP3 inflammasome by a mechanism dependent on Mincle. These findings demonstrate that Mincle receptor can also recognise pentose esters and seem to contradict the hypothesis that production of GMM is an escape mechanism used by pathogenic mycobacteria to avoid recognition by the innate immune system. Finally, our experiments indicate that TMM and GMM, as well as TDM, can promote Th1 and Th17 responses in mice in an OVA immunisation model, and that further analysis of their potential as novel adjuvants for subunit vaccines is warranted.

Preparation of the tri-arabino di-mycolate fragment of mycobacterial arabinogalactan from defined synthetic mycolic acids.

An efficient synthetic approach to tri-arabino di-mycolates, using structurally defined synthetic α-, keto and methoxy mycolic acids is described.

Supercritical carbon dioxide extraction of Triognella foenum graecum Linn seeds: Determination of bioactive compounds and pharmacological analysis

Objective To investigate the effect of temperature and pressure on supercritical CO

Is Mitral Valve Repair Superior to Mitral Valve Replacement in Elderly Patients? Comparison of Short- and Long-Term Outcomes in a Propensity-Matched Cohort.

BACKGROUND: Because of demographic changes, a growing number of elderly patients present with mitral valve (MV) disease. Although mitral valve repair (MV-repair) is the "gold standard" treatment for MV disease, in elderly patients, there is controversy about whether MV-repair is superior to mitral valve replacement. We reviewed results after MV surgery in elderly patients treated over the past 20 years. METHODS AND RESULTS: Our in-hospital database was explored for patients who underwent MV surgery between 1994 and 2015. Survival data, obtained from the National Health Service central register, were complete for all patients. Of 1776 patients with MV disease, 341 were aged ≥75 years. Patients with repeat cardiac surgery, endocarditis, and concomitant aortic valve replacement were excluded. This yielded 221 MV-repair and 120 mitral valve replacement patients. Concomitant procedures included coronary artery bypass grafting in 135 patients (39.6%) and tricuspid valve surgery in 50 patients (14.7%). Thirty-day mortality was 5.4% (MV-repair) versus 9.2% (mitral valve replacement, P=0.26). Overall 1- and 5-year survival was 90.7%, 74.2% versus 81.3%, 61.0% (P<0.01). Median survival after MV-repair was 7.8 years, close to 8.5 years (95% CI: 8.2-9.4) in the age-matched UK population (ratio 0.9). Rate of re-operation for MV-dysfunction was 2.3% versus 2.5% (mitral valve replacement, P=1.0). After propensity matching, patients after MV-repair still had improved survival at 1, 2, and 5 years (93.4%, 91.6%, 76.9% versus 77.2%, 75.2%, 58.7%, P=0.03). CONCLUSIONS: Excellent outcomes can be achieved after MV surgery in elderly patients. Long-term survival is superior after MV-repair and the re-operation rate is low. MV-repair should be the preferred surgical approach in elderly patients.

Embedded Ultrathin Cluster Electrodes for Long-Term Recordings in Deep Brain Centers.

Neural interfaces which allow long-term recordings in deep brain structures in awake freely moving animals have the potential of becoming highly valuable tools in neuroscience. However, the recording quality usually deteriorates over time, probably at least partly due to tissue reactions caused by injuries during implantation, and subsequently micro-forces due to a lack of mechanical compliance between the tissue and neural interface. To address this challenge, we developed a gelatin embedded neural interface comprising highly flexible electrodes and evaluated its long term recording properties. Bundles of ultrathin parylene C coated platinum electrodes (N = 29) were embedded in a hard gelatin based matrix shaped like a needle, and coated with Kollicoat™ to retard dissolution of gelatin during the implantation. The implantation parameters were established in an in vitro model of the brain (0.5% agarose). Following a craniotomy in the anesthetized rat, the gelatin embedded electrodes were stereotactically inserted to a pre-target position, and after gelatin dissolution the electrodes were further advanced and spread out in the area of the subthalamic nucleus (STN). The performance of the implanted electrodes was evaluated under anesthesia, during 8 weeks. Apart from an increase in the median-noise level during the first 4 weeks, the electrode impedance and signal-to-noise ratio of single-units remained stable throughout the experiment. Histological postmortem analysis confirmed implantation in the area of STN in most animals. In conclusion, by combining novel biocompatible implantation techniques and ultra-flexible electrodes, long-term neuronal recordings from deep brain structures with no significant deterioration of electrode function were achieved.

NEUROMODULATORY EFFECTS OF THYMOQUINONE IN EXTENUATING OXIDATIVE STRESS IN CHLORPROMAZINE TREATED RATS.

The present study was undertaken to evaluate the possible protective effect of thymoquinone on chlorpromazine induced catalepsy, locomotor activity and cerebral oxidative stress in rats. The rats were divided into four groups, each group containing eight animals. The animals were evaluated after repeated administration of chlorpromazine (CPZ) 30 min before the administration of thymoquinone (TQ) for 21 days. Catalepsy was assessed using block method whereas the locomotor activity was assessed using acceleratory rotarod and actophotometer. Markers of oxidative stress parameters (LPO, GSH, GPx, GR, GST and CAT) were evaluated in the brain of rats. The cataleptic scores were significantly increased in CPZ treated rats when compared with normal control rats. Oral administration of TQ (5 and 10 mg/kg) significantly decreased cataleptic scores when compared with chlorpromazine (CPZ) treated rats. The muscle coordination and spontaneous locomotor activity was significantly decreased in CPZ treated rats when compared with normal control rats. Treatment with TQ significantly improved the muscle coordination and spontaneous locomotor activity when compared with CPZ treated rats. TQ treated rats significantly reduced the elevated levels of lipid peroxidation (LPO), increased levels of antioxidant enzymes i.e., reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and catalase (CAT) when compared with CPZ treated rats. The results clearly suggest that supplementation with TQ can be used to preclude CPZ induced extrapyramidal side effects and may find a role in reducing the oxidative stress.

Influence of thermomechanical processing on biomechanical compatibility and electrochemical behavior of new near beta alloy, Ti-20.6Nb-13.6Zr-0.5V.

This paper presents the results for the effect of different methods of thermomechanical processing on the mechanical properties and electrochemical behavior of metastable ß alloy Ti-20.6Nb-13.6Zr-0.5V (TNZV). The thermomechanical processing included hot working, solution heat treatments at different temperatures, and cooling rates in addition to aging. The thermomechanical processing conditions used in the study resulted in attainment of a wide range of microstructures with varying spatial distributions and morphologies of elongated/equiaxed α, ß phases, or martensite, as a result of which several tensile properties were achieved. Aging treatment led to an increase in hardness, elastic modulus, and tensile strength and a decrease in ductility (elongation). Electrochemical tests indicated that the TNZV alloy undergoes spontaneous passivation due to spontaneous formation of an oxide film in the environment of the human body. Because the air-cooled samples possessed high hardness and also a fine grain size, they showed a lower corrosion rate than the samples treated under other conditions.

Review of Minimally Invasive Aortic Valve Surgery.

Minimally invasive aortic valve surgery (MIAVS) has been developed for the last 20 years. The improvements in techniques have permitted cardiac surgeons to perform aortic valve replacement safely and efficiently with minimally incisions. Patients have become older and have multiple comorbidities and this is expected to grow in number. Less-invasive procedures are known to reduce the number of complications, together with smaller incisions, less pain, less blood loss and reduced length of hospital stay. Selective preoperative planning with computed tomography is key to the pre-investigation stage. Hybrid and staged procedures with interventional cardiologists are part of the armamentarium and may be appealing for the present and near future. Despite the nature of demanding procedures and longer learning curve with increased cardiopulmonary bypass times, the outcomes are comparable with same quality as conventional open surgery. Patient recovery is the ultimate purpose of these approaches.

Levodopa-induced dyskinesia is strongly associated with resonant cortical oscillations.

The standard pharmacological treatment for Parkinson's disease using the dopamine precursor levodopa is unfortunately limited by gradual development of disabling involuntary movements for which the underlying causes are poorly understood. Here we show that levodopa-induced dyskinesia in hemiparkinsonian rats is strongly associated with pronounced 80 Hz local field potential oscillations in the primary motor cortex following levodopa treatment. When this oscillation is interrupted by application of a dopamine antagonist onto the cortical surface the dyskinetic symptoms disappear. The finding that abnormal cortical oscillations are a key pathophysiological mechanism calls for a revision of the prevailing hypothesis that links levodopa-induced dyskinesia to an altered sensitivity to dopamine only in the striatum. Apart from having important implications for the treatment of Parkinson's disease, the discovered pathophysiological mechanism may also play a role in several other psychiatric and neurological conditions involving cortical dysfunction.