Recent trends of stem cell therapies in The management of orthopedic surgical challenges.

Emerged health-related problems especially with increasing population and with the wider occurrence of these issues have always put the utmost concern and led medicine to outgrow its usual mode of treatment, to achieve better outcomes. Orthopedic interventions are one of the most concerning hitches, requiring advancement in several issues, that show complications with conventional approaches. Advanced studies have been undertaken to address the issue, among which stem cell therapy emerged as a better area of growth. The capacity of the stem cells to renovate themselves and adapt into different cell types made it possible to implement its use as a regenerative slant. Harvesting the stem cells, particularly mesenchymal stem cells is easier and can be further grown in vitro. In this review, we have discussed orthopedic-related issues including bone defects and fractures, non-unions, ligament and tendon injuries, degenerative changes, and associated conditions, which require further approaches to execute better outcomes, and the advanced strategies that can be tagged along with various ways of application of mesenchymal stem cells. It aims to objectify the idea of stem cells, with a major focus on the application of Mesenchymal stem cells (MSCs) from different sources in various orthopedic interventions. It also discusses the limitations, and future scopes for further approaches in the field of regenerative medicine. The involvement of mesenchymal stem cells may transition the procedures in orthopedic interventions from predominantly surgical substitution and reconstruction to bio-regeneration and prevention. Nevertheless, additional improvements and evaluations are required to explore the effectiveness and safety of mesenchymal stem cell treatment in orthopedic regenerative medicine.

Effect of an Autotaxin Inhibitor, 2-(4-Chlorophenyl)-7-methyl-8-pentylimidazo[1,2-a] Pyrimidin-5(8H)-one (CBT-295), on Bile Duct Ligation-Induced Chronic Liver Disease and Associated Hepatic Encephalopathy in Rats.

The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy. Interestingly, LPA levels were significantly increased in the plasma, liver, and brain of rats following bile duct ligation. Subsequently, we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced biliary cirrhosis and neuropsychiatric symptoms associated with hepatic encephalopathy. CBT-295 showed good oral bioavailability and favorable pharmacokinetic properties. CBT-295 exhibited a significant reduction in inflammatory cytokines like TGF-ß, TNF-α, and IL-6 levels, also reduced bile duct proliferation marker CK-19, and lowered liver fibrosis, as evident from reduced collagen deposition. The reversal of liver fibrosis with CBT-295 led to a reduction in blood and brain ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation induced by ammonia, which is characterized by a significant reduction in brain cytokine levels. It improved neuropsychiatric symptoms such as locomotor activities, cognitive impairment, and clinical grading scores associated with hepatic encephalopathy. The improvement in hepatic encephalopathy observed with the ATX inhibitor could be the result of its hepatoprotective action and its ability to attenuate neuroinflammation. Therefore, inhibition of ATX-LPA signaling can be a multifactorial approach for the treatment of chronic liver diseases.

Functional medium entropy alloys for joint replacement: An atomistic perspective of material deformation and a correlation to wear, corrosion, and biocompatibility.

The present study adopts a multi-facet approach to design bio inspired concentrated alloys for potential application as articulating surfaces in joint replacements. A series of equiatomic, Nb rich and Ti rich TiMoNbZr based medium entropy alloys (MEAs) were processed via arc melting and their mechanical, in-vitro corrosion, wear, and in vitro and in vivo biocompatibility were investigated. Equiatomic MEA had primarily bcc with minor hcp phases where the single bcc was achieved with the addition of Nb. The single bcc Nb rich alloy resulted in 13 % elongation, much higher than equiatomic or Ti rich alloy. All the MEAs showed comparatively higher yield strength due to the climb of edge dislocations which is the main rate limiting mechanism at 300 K, as evident molecular dynamics (MD) simulation. The locally fluctuating energy landscape promotes kinks on edge dislocation, and at local minima nanoscale segments gets pinned. Upon yielding the entangled kink leaves a trail of vacancies/interstitials and escapes via climb motion to render high yield strength. The higher corrosion and pitting resistance of Nb enriched alloys can be attributed to the stable ZrO2, Nb2O5, TiO2, and MoO3 oxides, high polarization resistance (106-105 Ωcm-2), and low defect densities (1016-1018). In vitro cell-materials interaction using MC3T3-E1 showed bioinert but cytocompatible nature of the MEAs. The wear rate of the MEAs was in the range of 7-9 × 10-5 mm3N-1m-1. The wear debris did not show any tissue necrosis when implanted in rabbit femur rather new bone regeneration can be seen around the particles. STATEMENT OF SIGNIFICANCE: In the present work, a noble Nb enriched MEAs with superior mechanical, in vitro wear, corrosion and cytocompatibility properties was designed for articulating surfaces in joint replacement.

Biomaterials-Based Strategies to Enhance Angiogenesis in Diabetic Wound Healing.

Amidst the present healthcare issues, diabetes is unique as an emerging class of affliction with chronicity in a majority of the population. To check and control its effects, there have been huge turnover and constant development of management strategies, and though a bigger part of the health care area is involved in achieving its control and the related issues such as the effect of diabetes on wound healing and care and many of the works have reached certain successful outcomes, still there is a huge lack in managing it, with maximum effect yet to be attained. Studying pathophysiology and involvement of various treatment options, such as tissue engineering, application of hydrogels, drug delivery methods, and enhancing angiogenesis, are at constantly developing stages either direct or indirect. In this review, we have gathered a wide field of information and different new therapeutic methods and targets for the scientific community, paving the way toward more settled ideas and research advances to cure diabetic wounds and manage their outcomes.

Autologous bone marrow-derived cells with placental extract for healing excisional cutaneous wounds in animal model.

Topical wound-healing potential of autologous bone marrow-derived nucleated cells along with placental extract was evaluated in comparison with buffy coat of autologous blood on full-thickness cutaneous wounds in the thoracolumbar region of 15 clinically healthy New Zealand rabbits. Three wounds of 2 × 2 cm, one on the right side of the body and two on the left side of the midline were created on the dorsal lumbar region of each rabbit under xylazine-ketamine anaesthesia. The wounds of each animal were randomly assigned to one of the three treatments: topical application of autologous bone marrow-derived cells with placental extract (group I), application of buffy coat in the autologous plasma with placental extract (group II) and autologous plasma with placental extract as control (group III). Wounds were observed for 30 days macroscopically and for granulation tissue formation, histomorphological and histochemical evaluation. Time of appearance of granulation tissues and filling of wound beds were faster in group I followed by group II and group III animals, respectively. Histomorphological findings exhibited an earlier disappearance of inflammatory reaction, better epithelialisation, significantly maximum neovascularisation, fibroplasias and collagenation in group I followed by group II and group III animals, respectively. Histochemical findings also depicted maximum number of robust, thick, interwoven type of collagen fibres, stout, highly tortuous and interwoven network of elastin fibres and numerous mesh war form of reticulin fibres within the dermal component were present in group I when compared with group II and III animals. Experiment conclude that single application of autologous bone marrow-nucleated cells with placental extract topically could be a novel option for faster healing in complicated non healing wounds both in human beings and animals.

Evaluation of autologous bone marrow in wound healing in animal model: a possible application of autologous stem cells.

A study was conducted to evaluate the potential of autologous bone marrow-derived cells in comparison with buffy coat of autologous blood for rapid cutaneous wound healing in rabbit model. Three square full-thickness skin excisional wounds were created in 15 selected experimental animals (rabbit) divided randomly into three groups. The wound was treated with autologous bone marrow cells in plasma (group 1), buffy coat of blood in plasma (group 2) and autologous plasma as control (group 3). Wounds were observed for 30 days for granulation tissue formation, biochemical, histomorphological and histochemical evaluation. In this study, granulation tissue appeared significantly lesser in wounds of group 3 animals followed by group 2 and 1 animals. Neovascularisation, granulation tissue formation, denser, thicker and better arranged collagen fibres, reticulin fibres and elastin fibres formation was more in group 1 as compared with other groups. It was concluded that the application of bone marrow-derived nucleated cells into the wound margins resulted in early and significantly faster rate of complete healing as compared with buffy coat of autologous blood and autologous plasma (control). This approach may be beneficial in various surface wounds that heal at a slower rate and recommended for healing of various complicated wound in future.

Biological analysis of an innovative biodegradable antibiotic eluting bioactive glass/gypsum composite bone cement for treating experimental chronic MRSA osteomyelitis.

A multi-barrier antibiotics loaded biodegradable composite bone cement for resolving chronic osteomyelitis has been studied to understand the physico-mechanical properties, drug loading/eluting efficiency, and different merits and demerits prior to clinical application. After successful induction of bone infection in 28 rabbits using methicillin-resistant Staphylococcus aureus (MRSA) strains, calcium sulfate/bioactive glass based composite cement was implanted in 12 defects to assess its performance over parenteral therapy with microscopic and radiological examination for 90 days. The composite cement revealed acceptable physico-mechanical properties and controlled drug elution kinetics. Furthermore, the antibiotics concentrations in bone up to 42 days were sufficient to kill MRSA without eliciting adverse drug reactions. The striking feature of platelets aggregation by composite cement could assist bone healing. The controlled degradation with simultaneous entrapment of composite cement within the osteoid tissues and complete repair of infected cortical defects (holes) in rabbit tibia at 6 weeks indicated the excellent anti-infective and osteoconductive properties of composite cement. Thus, the animal study demonstrated the superiority of composite over injectable antibiotic therapy based on infection resolution and bone regeneration. We thereby conclude that the composite cement can be effectively applied in the treatment of resistant cases of chronic osteomyelitis.

Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy.

Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin-lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1ß (interleukin-1ß), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1ß, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH4CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.

Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor.

Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 µM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint  = 15.6 µl/min/mg; T1/2  = 113.2 min) with solubility of 4.82 µM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.

Ratiometric pH Sensing, Photophysics, and Cell Imaging of Nonaromatic Light-Emitting Polymers.

Here, four nontraditional fluorescent polymers (NTFPs) of varying N,N-dimethyl-2-propenamide (DMPA) and butyl prop-2-enoate (BPE) mole ratios, i.e., 2:1 (NTFP1), 4:1 (NTFP2), 8:1 (NTFP3), and 16:1 (NTFP4), are prepared via random polymerization in water. The maximum fluorescence enhancement of NTFP3 makes it suitable for ratiometric pH sensing, Cu(II) sensing, and pH-dependent cell imaging of Madin-Darby canine kidney (MDCK) cells. The oxygen donor functionalities of NTFP3 involved in binding and sensing with Cu(II) ions are studied by absorption, emission, electron paramagnetic resonance, Fourier transform infrared (FTIR), and O1s/Cu2p X-ray photoelectron spectroscopies (XPS). The spectral responses of the ratiometric pH sensor within 1.5-11.5 confirm 22 and 44 nm red shifts in absorption and ratiometric emission, respectively. The striking color changes from blue (436 nm) to green (480 nm) via an increase in pH are thought to be the stabilization of the charged canonical form of tertiary amide, i.e., -C(O-)═N+(CH3)2, realized from the changes in the absorption/fluorescence spectra and XPS/FTIR analyses. The through-space n-π* interactions in the NTFP3 aggregate, N-branching-associated rigidity, and nonconventional intramolecular hydrogen bondings of adjacent NTFP3 moieties in the NTFP3 aggregate contribute to aggregation-enhanced emissions (AEEs). Here, structures of NTFP3, NTFP3 aggregate, and Cu(II)-NTFP3; absorption; n-π* interactions; hydrogen bondings; AEEs; and binding with Cu(II) are ascertained by density functional theory, time-dependent density functional theory, and reduced density gradient calculations. The excellent limits of detection and Stern-Volmer constants of NTFP3 are 2.24 nM/0.14234 ppb and 4.26 × 103 M-1 at pH = 6.5 and 0.95 nM/0.06037 ppb and 4.90 × 103 M-1 at pH = 8.0, respectively. Additionally, the Stokes shift and binding energy of NTFP3 are 13,636 cm-1/1.69 eV and -4.64 eV, respectively. The pH-dependent MDCK cell imaging ability of noncytotoxic NTFP3 is supported via fluorescence imaging and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

Macro-to-micro porous special bioactive glass and ceftriaxone-sulbactam composite drug delivery system for treatment of chronic osteomyelitis: an investigation through in vitro and in vivo animal trial.

A systematic and extensive approach incorporating in vitro and in vivo experimentation to treat chronic osteomyelitis in animal model were made using antibiotic loaded special bioactive glass porous scaffolds. After thorough characterization for porosity, distribution, surface charge, a novel drug composite were infiltrated by using vacuum infiltration and freeze-drying method which was subsequently analyzed by SEM-EDAX and studied for in vitro drug elution in PBS and SBF. Osteomyelitis in rabbit was induced by inoculation of Staphylococcus aureus and optimum drug-scaffold were checked for its efficacy over control and parenteral treated animals in terms of histopathology, radiology, in vivo drug concentration in bone and serum and implant-bone interface by SEM. It was optimized that 60P samples with 60-65% porosity (bimodal distribution of macro- to micropore) with average pore size ~60 µm and higher interconnectivity, moderately high antibiotic adsorption efficiency (~49%) was ideal. Results after 42 days showed antibiotic released higher than MIC against S. aureus compared to parenteral treatment (2 injections a day for 6 weeks). In vivo drug pharmacokinetics and SEM on bone-defect interface proved superiority of CFS loaded porous bioactive glass implants over parenteral group based on infection eradication and new bone formation.

Antidiabetic activity of resveratrol, a known SIRT1 activator in a genetic model for type-2 diabetes.

In the present study, resveratrol, a polyphenolic SIRT1 activator was evaluated for its SIRT1 activation in an in vitro fluorescent based assay (EC(50) : 7 µM). The efficacy of resveratrol was also evaluated in ob/ob mice for its antidiabetic and associated metabolic effects. Mice aged 5-8 weeks were included in four groups; control and resveratrol at 5, 15, 50 mg/kg, b.i.d. and were dosed orally. After 4 weeks of drug treatment, body weights were noted and random blood glucose and insulin was estimated for the antidiabetic effect. Animals were also subjected to the oral glucose tolerance test to observe any improvement in the glucose excursion. Triglycerides, total cholesterol, adiponectin and free fatty acid levels were also estimated. The results showed that resveratrol exhibited significant antihyperglycemic activity with an improvement in the insulin levels compared with the control mice. There was also a significant improvement observed in the glucose excursion in the oral glucose tolerance test performed for 120 min; although an insignificant improvement in the triglycerides, total cholesterol, adiponectin and free fatty acid levels was observed at different doses of resveratrol tested. The present findings suggest that resveratrol is an antihyperglycemic agent and drugs similar to resveratrol can be considered as an effective therapeutic adjuvant for the current treatment of diabetes mellitus.

Surface characteristics of titanium dental implants with improved microdesigns: An in vivo study of their osseointegration performance in goat mandible.

Current trends in endosseous implant research are focused on the modification of microdesign of implants to achieve early and strong osseointegration. This study compares the influence of zinc doped hydroxyapatite (ZnHAp) coated, hydrothermally treated (HT) and machined Ti6Al4V (control) implants on osseointegration. The surface characterisation and microbial affinity test for implants were performed. Twenty seven (27) cylinders (3 types in each animal) were placed in the mandible of 9 black Bengal goats. Bone-implant interface was examined with histological, radiological parameters and scanning electron microscopy at 6, 12, and 24 weeks post-implantation. Surface roughness alterations of bone-separated implants were analysed by non-contact profilometer with time. The ZnHAp coated implants revealed direct and early bone-implant contact but high bacterial adherence and coating cracks. Low bacterial affinity and early strong bony integration was observed with HT implants. Poor bacterial affinity and delayed but strong fixation was evident with control implants. Based on the results of laboratory and animal experiments, we conclude that the hydrothermal modification of titanium implant is the more suitable way to achieve safe and effective osseointegration than the other two implant types for endosseous application.

Development of new localized drug delivery system based on ceftriaxone-sulbactam composite drug impregnated porous hydroxyapatite: a systematic approach for in vitro and in vivo animal trial.

PURPOSE: Present investigation deals with an extensive approach incorporating in vitro and in vivo experimentation to treat chronic osteomyelitis, using hydroxyapatite porous scaffolds. MATERIALS AND METHODS: Hydroxyapatite was synthesized in the laboratory by wet chemical method, different porous scaffolds have been fabricated. In vitro studies include variation of porosity with interconnectivity, pore-drug interfacial studies by SEM-EDAX and drug elution studies (by HPLC) both in contact with PBS and SBF at approximately 37 degrees C. In vivo trials were based on experimental osteomyelitis in rabbit model induced in tibia by Staphylococcus aureus. Characterizations included observation of histopathology, radiology and estimation of drug in both bone and serum for 42 days by HPLC method and subsequent bone-biomaterial interface by SEM. RESULTS: It was established that lower pore percentage with a distribution of mainly micro-pores were found to be superior over the higher pore percentage both in vitro and in vivo. The criteria was matched with the 50N50H samples which had 50-55% porosity with an average pore size approximately 110 microm, having higher interconnectivity (10-100 microm), moderately high adsorption efficiency (approximately 50%) when loaded with CFS (drug combinations consisting of irreversible b-lactamase inhibitor and b-lactam antibiotic). CFS release from HAp implants were faster in PBS than SBF. Further, both the results of in vitro and in vivo drug elution after 42 days showed release higher than minimum inhibitory concentration of CFS against Staphylococcus aureus. In vivo studies also proved the superiority of CFS loaded HAp implants than parenteral group based on eradication of infection and new bone formation. CONCLUSIONS: HAp based porous scaffold loaded with CFS and designed porosity (in terms of micro- and macro-porosity, interconnectivity) was found to be an ideal delivery system which could locally, sustainably release the composite antibiotic in reliable manner both in terms of in vitro drug elution behaviour in contact with SBF and in vivo animal trial.

Fluorescent Guar Gum-g-Terpolymer via In Situ Acrylamido-Acid Fluorophore-Monomer in Cell Imaging, Pb(II) Sensor, and Security Ink.

The nonconventional purely aliphatic scalable and reusable fluorescent guar gum (GRGM)-grafted-acrylic acid-co-3-(N-isopropylacrylamido)propanoic acid (NIPAPA)-co-N-isopropylacrylamide (GRGM-grafted-1, i.e., 2), was synthesized via grafting of the optimum amount of GRGM and N-H functionalized in situ protrusion of acrylamido-acid fluorophore-monomer, i.e., NIPAPA, in multi C-C/N-C/O-C coupled solution polymerization of two non-emissive monomers in water. The intrinsically fluorescent noncytotoxic 2 envisaged the excellent potentials in sensing and removal of Pb(II), security ink, logic function, and imaging of both cancer and normal cells. The emission intensities of 2 elevated in concentrated solutions and solid state because of concentration-enhanced emission and aggregation-induced enhanced emission (AIEE) characteristics of 2. Additionally, the emission efficiency of 2 elevated considerably with increasing GRGM contents and temperatures. The structure of 2, in situ attached fluorophore-monomer, AIEE, cell-imaging ability, and the superadsorption mechanism were studied employing 1H/13C NMR, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, atomic absorption spectroscopy, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, dynamic light scattering, high-resolution transmission electron microscopy, fluorescence imaging, and fluorescence lifetime, along with measuring isotherms, kinetics, and thermodynamic parameters. The location, geometries, and electronic-structures of fluorophore, along with absorption and emission properties, of 2 were explored via density functional theory (DFT), time-dependent DFT, and natural transition orbital analyses. In solution, cyan light-emitting 2 envisaged an average 1.22 ns lifetime in CHCl3. The limit of detection and the maximum adsorption capacity were 2.94 × 10-7 M and 1100.25 mg g-1 at pH 7.0, 303 K, and 1000 ppm, respectively.

Perovskite solar cell for photocatalytic water splitting with a TiO2/Co-doped hematite electron transport bilayer.

Hydrogen production using a photoelectrochemical (PEC) route promises to be a clean and efficient way of storing solar energy for use in hydrogen-powered fuel cells. Iron oxide (α-Fe2O3) is best suited to be used as a photoelectrode in PEC cells for solar hydrogen production due to its favorable band gap of ∼2.2 eV. Herein, chemical solution deposition was used for the preparation of a series of Co-doped Fe2O3 thin films on a titania buffer layer at different doping concentrations (3.0, 7.0 and 10.0 at%). The maximum anodic photocurrent reached up to 3.04 mA cm-2 by optimizing the balance between the doping concentrations, enhanced donor density, light absorbance, and surface roughness. The optical properties show that the light absorbance tendency switches to the higher wavelength with the further increment of Co beyond 3.0%. Finally, synthesized photosensitive perovskite CH3NH3PbI3 materials were added as a surface treatment agent on the photoelectrode to enhance the photocurrent absolute value. This inorganic nanostructured perovskite CH3NH3PbI3 (MAPbI3) coated on the Co-doped hematite photoanode achieved an overall solar-to-hydrogen conversion efficiency of 2.46%. Due to its low temperature processing, stability, and enhance efficiency, this perovskite coated TiO2/Co-doped hematite multilayer thin film solar cell has high potential to be applied in industry for hydrogen production.

Combination of dipeptidylpeptidase IV inhibitor and low dose thiazolidinedione: preclinical efficacy and safety in db/db mice.

Thiazolidinediones (TZDs) are currently the most efficacious class of oral antidiabetics. However, they carry the burden of weight gain and haemodilution, which may lead to cardiovascular complications. The present study was designed to ascertain whether a combination of dipeptidyl peptidase IV (DPP IV) inhibitor with low dose of a thiazolidinedione absolves TZD associated weight gain and oedema without compromising its efficacy. In this study, we examined the efficacy and safety of lower dose (1 mg/kg/day) of rosiglitazone, a thiazolidinedione, in combination with 5 mg/kg/day dose of LAF-237 (vildagliptin), a known DPP IV inhibitor, in aged db/db mice after 14 days of treatment and compared the combination with therapeutic dose (10 mg/kg) of rosiglitazone. The combination therapy showed similar efficacy as that of 10 mg/kg/day rosiglitazone in lowering random blood glucose (53.8%, p<0.001 and 54.3%, p<0.001 respectively), AUC ((0-120) min) during oral glucose tolerance test (OGTT) (38.6 %, p<0.01; 38.3%, p<0.01 respectively) and triglyceride levels (63.9% and 61% respectively; p<0.01). Plasma active glucagon like peptide-1 (GLP-1) and insulin levels were found to be elevated significantly (p<0.01 and p<0.05 respectively) in both LAF-237 and combination treated groups following oral glucose load. LAF-237 alone had no effect on random glucose and glucose excursion during OGTT in severely diabetic db/db mice. Interestingly, the combination treatment showed no significant increase in body weight as compared to the robust weight gain by therapeutic dose of rosiglitazone. Rosiglitazone at 10 mg/kg/day showed significant reduction (p<0.05) in haematocrit, RBC count, haemoglobin pointing towards haemodilution associated with increased mRNA expression of Na(+), K(+)-ATPase-alpha and epithelial sodium channel gamma (ENaCgamma) in kidney. The combination therapy escaped these adverse effects. The results suggest that combination of DPP IV inhibitor with low dose of thiazolidinedione can interact synergistically to represent a therapeutic advantage for the clinical treatment of type 2 diabetes without the adverse effects of haemodilution and weight gain associated with thiazolidinediones.

Biological analysis of an innovative biodegradable antibiotic eluting bioactive glass/gypsum composite bone cement for treating experimental chronic MRSA osteomyelitis / 药物分析学报

A multi-barrier antibiotics loaded biodegradable composite bone cement for resolving chronic osteo-myelitis has been studied to understand the physico-mechanical properties,drug loading/eluting effi-ciency,and different merits and demerits prior to clinical application.After successful induction of bone infection in 28 rabbits using methicillin-resistant Staphylococcus aureus(MRSA)strains,calcium sulfate/bioactive glass based composite cement was implanted in 12 defects to assess its performance over parenteral therapy with microscopic and radiological examination for 90 days.The composite cement revealed acceptable physico-mechanical properties and controlled drug elution kinetics.Furthermore,the antibiotics concentrations in bone up to 42 days were sufficient to kill MRSA without eliciting adverse drug reactions.The striking feature of platelets aggregation by composite cement could assist bone healing.The controlled degradation with simultaneous entrapment of composite cement within the osteoid tissues and complete repair of infected cortical defects(holes)in rabbit tibia at 6 weeks indicated the excellent anti-infective and osteoconductive properties of composite cement.Thus,the animal study demonstrated the superiority of composite over injectable antibiotic therapy based on infection reso-lution and bone regeneration.We thereby conclude that the composite cement can be effectively applied in the treatment of resistant cases of chronic osteomyelitis.

Efficacy and safety of montelukast as monotherapy in children with mild persistent asthma.

OBJECTIVE: To study the efficacy and tolerability of montelukast as monotherapy in the treatment of mild persistent bronchial asthma. DESIGN: Open, non-comparative, prospective, 12-month study. SETTING: Asthma clinic in urban multi-speciality trust hospital. METHODS: Children (age 3-11 yrs) with mild persistent asthma, not on any prophylactic drugs were enrolled consecutively (from January to December 2003) and started on 4 mg (2-4 yrs) or 5mg (<4 yrs) montelukast for a period of 12 weeks. Efficacy was assessed by improvements in clinical score, peak expiratory flow rates (PEFR), spirometry measurements and reduction in reliever drug requirement after 4 and 12 weeks of therapy. Side effects were also judged after 12 weeks of therapy. RESULTS: 50 children (mean age 5.41 +/-2.11 years) completed the study. There was association with positive family history (92%), allergic rhinitis (64%), exercise induced asthma (40%), cough variant asthma (24%), seasonal asthma (80%) and high IgE (12%) levels. Clinical scores, viz, activity, wheeze and cough, improved effectively from (1.64 +/-0.5253) at baseline to (0.7 +/-0.7071) and (1.72 +/-0.701) to (0.92 +/-0.6952) and (1.5 +/-0.6145) to (0.88 +/-0.8241) respectively after 12 weeks of therapy. Significant clinical improvement (p >0.001) was also noted after 4 weeks of therapy. Peak expiratory flow rates (done in 19 cases) documented improvement from (120.21 +/-12.23) at baseline to (135.41 +/-23.34) after 12 weeks. FEV1 / FVC (done in 11 cases) improved from (71.44 +/-1.35%) to (87.10 +/-8.34%) after 12 weeks. Mean improvement in all the parameters demonstrated P value less than >.001. A total of 19 of 50 cases showed mild side-effects as anorexia (16%), elevated liver function tests (18%) and headache (10%). CONCLUSION: The clinical outcome showed significant improvement (p < 0.01) after 4 and 12 weeks.

Understanding osteomyelitis and its treatment through local drug delivery system.

Chronic osteomyelitis is a major challenge in bone surgery. Conventional use of antibiotics is not an effective way to control the malaise due to so many reasons. Determination of optimal treatment strategy becomes difficult for the orthopaedic surgeons and as a consequence, the patients suffer not only from therapeutic failure but also due to adverse side effects of antibiotics and financial loss due to additional stay at hospitals. A wide application of carrier systems, as a medium for local delivery of antibiotics, is being used experimentally and clinically for the treatment of osteomyelitis. This kind of delivery system provides sustained higher concentration of antibiotics at the infection site with reduced possibility of toxicity. This review highlight etiology and pathophysiology of osteomyelitis, current therapeutic options with their limitations, and potentiality of biomaterial based carrier materials impregnated with antibiotics as local delivery approach.