A novel thermoresponsive nano carrier matrix of hyaluronic acid, methotrexate and chitosan to target the cluster of differentiation 44 receptors in tumors.

Major challenges in current cancer chemotherapy include drug resistance, low efficacy and non-selectivity, resulting in undesirable side effects. In this study, we demonstrate a solution to these challenges that involves a dual targeting approach for tumors that overexpress CD44 receptors. The approach employs a nano-formulation (tHAC-MTX nano assembly), fabricated from hyaluronic acid (HA), the natural ligand for CD44, conjugated with methotrexate (MTX) and complexed with the thermoresponsive polymer 6-O-carboxymethylchitosan (6-OCMC) graft poly(N-isopropylacrylamide) [6-OCMC-g-PNIPAAm]. The thermoresponsive component was designed to have a lower critical solution temperature of 39 °C (the temperature of tumor tissues). In-vitro drug release studies reveal faster release of the drug at the higher temperatures of the tumor tissue likely due to the conformation changes in the thermoresponsive component of the nano assembly. Drug release was also enhanced in the presence of hyaluronidase enzyme. Higher cellular uptake and greater cytotoxicity of the nanoparticles were demonstrated in cancer cells that overexpress CD44 receptors suggesting a receptor binding and cellular uptake mechanism. Such nano-assemblies which incorporate multiple targeting mechanisms have the potential to improve efficacy and decrease side effects of cancer chemotherapy.

A Review on Exploring the Opportunities of Polymer Drug Conjugated Systems for Targeted Cancer Treatment.

Polymeric drug conjugates (PDCs) for cancer therapy have been a hot research topic for the past three decades. Successful examples of PDC conjugates have demonstrated sustained drug release action with decreased systemic toxicity and enhanced tumor retention effect (EPR) via active as well as passive targeting mechanisms. Therefore, the PDC approach has now become a keystone of the drug delivery system for cancer and other diseases. In recent years, several PDCs have successfully made up to the clinical trials. The approach aids targeted delivery of the anticancer drugs to the tumor site without disturbing the healthy cells. The selection of the over-expressed receptor and the receptor-ligand plays a vital role in designing the receptor-targeting PDC so that it is able to distinguish between the healthy cell and the tumor cell. Continuous efforts are being made in research and development toward an active targeted PDC delivery system to revolutionize cancer treatment despite the controversy built due to heterogeneity in tumor models. This review highlights the chemistry aspects involved in the preparation of PDCs that deal with novel molecular tumor targets and strategies used for the development of targeted PDCs for delivering the drug payload via active or passive targeting. Furthermore, it sheds light on the challenges faced by targeted PDCs as novel drug delivery systems.

Novel derivatives of arabinogalactan, pullulan & lactobionic acid for targeting asialoglycoprotein receptor: Biomolecular interaction, synthesis & evaluation.

Targeted-drug administration to liver reduces side effects by minimising drug distribution to non-target organs and increases therapeutic efficacy by boosting drug concentration in target cells. In this study, arabinogalactan-(AG), pullulan-(PL) and lactobionic acid-(LA) were selected as natural ligands to target asialoglycoprotein receptor-(ASGPR-1) present on hepatocytes. In silico docking studies were performed and binding affinities of novel ligands viz. palmitoylated AG-(PAG), lauroylated AG-(LAG), palmitoylated PL-(PPL), lauroylated PL-(LPL) and lactobionic acid-adipic acid dihydrazide conjugate-(LAD) were compared with AG, PL and LA. These novel ligands were successfully synthesized and characterized. The ligands were incorporated into drug loaded nanostructured lipid carriers-(NLCs) for surface functionalization. HepG2 cellular internalization of hepatocyte-targeted NLCs was studied using fluorescence microscopy and LAD-decorated-drug loaded NLCs giving maximum cellular uptake were studied using confocal microscopy. Toxicity potential of LAD-decorated NLCs was assessed in vivo. Molecular docking results suggested that among the ligands, order of binding affinity was found to be LAD>PAG > PPL > LPL > LAG. Acute toxicity studies revealed hemocompatibility and absence of organ toxicity for ligand LAD. Additionally, the results establish proof-of-concept of enhanced targeting efficacy of novel ASGPR targeting ligands. These ligands can be used for surface modification of nanocarriers for future targeted delivery in treating various liver disorders.

Metal tolerance in plants: Molecular and physicochemical interface determines the "not so heavy effect" of heavy metals.

An increase in technological interventions and ruthless urbanization in the name of development has deteriorated our environment over time and caused the buildup of heavy metals (HMs) in the soil and water resources. These heavy metals are gaining increased access into our food chain through the plant and/or animal-based products, to adversely impact human health. The issue of how to restrict the entry of HMs or modulate their response in event of their ingress into the plant system is worrisome. The current knowledge on the interactive-regulatory role and contribution of different physical, biophysical, biochemical, physiological, and molecular factors that determine the heavy metal availability-uptake-partitioning dynamics in the soil-plant-environment needs to be updated. The present review critically analyses the interactive overlaps between different adaptation and tolerance strategies that may be causally related to their cellular localization, conjugation and homeostasis, a relative affinity for the transporters, rhizosphere modifications, activation of efflux pumps and vacuolar sequestration that singly or collectively determine a plant's response to HM stress. Recently postulated role of gaseous pollutants such as SO2 and other secondary metabolites in heavy metal tolerance, which may be regulated at the whole plant and/or tissue/cell is discussed to delineate and work towards a "not so heavy" response of plants to heavy metals present in the contaminated soils.

Superfluid density from magnetic penetration depth measurements in Nb-Cu 3D nano-composite films.

Superconductivity in 3D Nb-Cu nanocomposite granular films have been studied with varying thickness for two different compositions, Nb rich with 88 at% of Nb and Cu rich with 46 at% of Nb. For both compositions, the superconducting transition temperature (Tc) decreases with decreasing film thickness. For any thickness, doubling the Cu content in the films decreases the Tc by about 2 K. To explore if phase fluctuations play any role in superconductivity in these 3D films, the superfluid stiffness (JS) of the films was measured using low frequency two-coil mutual inductance (M) technique. Interestingly, the measurement of M in magnetic fields showed two peaks in the imaginary component of M for both Nb rich and Cu rich films. The two peaks were associated with the pair-breaking effect of the magnetic field on the intra and inter-granular coupling in these films consisting of random network of superconductor (S) and normal metal (N) nano-particles. Furthermore, JS was seen to decrease with decreasing film thickness and increasing Cu content. However, for all films studied JS remained higher than the superconducting energy gap (∆) indicating that phase fluctuations do not play any role in superconductivity in the film thickness and composition range investigated. Our results indicate that an interplay of quantum size effects (QSE) and superconducting proximity effect (SPE) controls the Tc with composition in these 3D nano-composite films.

Changes in the Inner Retinal Cells after Intense and Constant Light Exposure in Sprague-Dawley Rats.

Light insult causes photoreceptor death. Few studies reported that continuous exposure to light affects horizontal, Müller and ganglion cells. We aimed to see the effect of constant light exposure on bipolar and amacrine cells. Adult Sprague-Dawley rats were exposed to 300 or 3000 lux for 7 days in 12-h light: 12-h dark cycles (12L:12D). The latter group was then exposed to 24L:0D for 48 h to induce significant damage. The same animals were reverted to 300 lux and reared for 15 days in 12L:12D cycles. They were sacrificed on different days to find the degree of retinal recovery, if any, from light injury. Besides photoreceptor death, continuous light for 48 h resulted in downregulation of parvalbumin in amacrine cells and recoverin in cone bipolar cells (CBC). Rod bipolar cells (RBC) maintained an unaltered pattern of PKC-α expression. Upon reversal, there were increased expressions of parvalbumin in amacrine cells and recoverin in CBC, while RBC showed an increasing trend of PKC-α expression. The data show that damage in bipolar and amacrine cells after exposure to intense, continuous light can be ameliorated upon reversal to normal LD cycles to which the animals were initially acclimated to.

Systemic lidocaine versus ultrasound-guided transversus abdominis plane block for postoperative analgesia: A comparative randomised study in bariatric surgical patients.

BACKGROUND AND AIMS: The multimodal analgesia strategies to minimise opioid-related side effects are highly desirable in bariatric surgical procedures. We evaluated the efficacy of ultrasound-guided transversus abdominis plane (USG-TAP) block and intravenous lidocaine for postoperative analgesia in obese patients undergoing laparoscopic bariatric surgery. METHODS: We studied 56 patients with body mass index >35 kg/m2. They were randomly allocated to Lidocaine group (Group A) and USG-TAP group (Group B). Group A patients were given intravenous Lidocaine (1.5 mg/kg) bolus followed by (1.5 mg/kg/h) infusion. Group B patients were given ultrasound-guided bilateral TAP block using 20 cc of 0.375% ropivacaine each side. Postoperative numeric rating pain scale score (NRS) hours were compared. Other parameters compared were total fentanyl requirement, sedation score, postoperative nausea vomiting (PONV) score and patient satisfaction score. A P value < 0.05 was considered statistically significant. RESULTS: The patient in the Group A had lower resting NRS score (P < 0.05) postoperatively and less fentanyl consumption (P < 0.001) than in Group B. The difference in the sedation scores (P = 0.161) and PONV (P = 0.293) score was found to be statistically insignificant between Group A and B. The difference between the two groups was statistically significant with respect to patient satisfaction score with majority of patients having an excellent patient satisfaction score in Group A as compared to Group B. CONCLUSION: Intravenous Lidocaine as part of multimodal analgesic technique in obese patients undergoing laparoscopic bariatric surgery improves pain score and reduces opioid requirement as compared to USG-TAP Block.

An Ex Vivo Evaluation of Moxifloxacin Nanostructured Lipid Carrier Enriched In Situ Gel for Transcorneal Permeation on Goat Cornea.

The study was designed to fabricate the moxifloxacin nanostructured lipid carriers (MOX-NLCs) loaded in situ gel for opthalmic application to improve the corneal permeation and retention and also subside the toxic effect associated with intracameral injection of moxifloxacin in endophthalmitis treatment. Initially, Box-Behnken design was used to optimize the various factors significantly affecting the final formulation attributes. MOX-NLCs with particle size 232.1 ± 9.2 nm, polydispersity index 0.247 ± 0.031, zeta potential -16.3 ± 1.6 mV, entrapment efficiency 63.1 ± 2.4%, and spherical shape was achieved. The optimized MOX-NLCs demonstrated the Higuchi release kinetics with highest regression coefficient. Besides this, FTIR, differential scanning calorimetry, and X-ray diffraction results suggested that MOX had excellent compatibility with excipients. Furthermore, the results of ex-vivo permeation study demonstrated 2-fold higher permeation (208.7 ± 17.6 µg), retention (37.26 ± 2.83 µg), and flux (9.57 ± 0.73 µg/cm2 h) compared with free MOX in situ gel. In addition, MOX-NLCs exhibited normal corneal hydration and did not show any sign of structural damage to the corneal tissue as confirmed by histology. Therefore, the findings strongly suggest that MOX-NLCs in situ gel with higher permeation and retention can be a better alternative strategy to prevent and treat the endophthalmitis infection.

Prevalence of Antiretroviral Therapy Use among HIV/AIDS Patients in a District Hospital.

INTRODUCTION: Prevention of Human Immunodeficiency Virus infection is a high priority for the government of Nepal, so the government has been scaling up Anti Retroviral Therapy centers throughout the country. The objective of our study was to find out the prevalence of people living with Human Immunodeficiency Virus infection on Anti Retroviral Therapy service. METHODS: This descriptive cross-sectional study was done in Lamjung district hospital, from May 2017 till August 2017 after taking ethical clearance from the institutional review committee. The study was done in 96 patients and convenience sampling was done. The data collected was entered in Microsoft Excel and analyzed in Statistical Packages for Social Sciences version 17.0, point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data. RESULTS: Out of the total 109 patients enrolled at the hospital, 85 (78%) were on ongoing Anti Retroviral Therapy. The predominant age group among patients using Anti Retroviral Therapy was 25-34 years 27 (31.7%) and the five most common clinical manifestation/opportunistic infections were fever 40 (47.1%), diarrhea 34 (40%), fatigue/generalized weakness 32 (37.6%), loss of appetite 25 (29.4%) and headache 18 (21.2%) among them. Out of total patients, 14 (12.8%) of our patients were under 14 years of age. We found 71 (83.6%) of the patients continued the original first-line regimen and in 14 (16.5%) one or two drugs were substituted in the original regimen. CONCLUSIONS: Our study showed a similar prevalence of people living with Human Immunodeficiency Virus infection on Anti Retroviral Therapy service with the other studies done within Nepal.

Experimental oral iron administration: Histological investigations and expressions of iron handling proteins in rat retina with aging.

Iron is implicated in age-related macular degeneration (AMD). The aim of this study was to see if long-term, experimental iron administration with aging modifies retinal and choroidal structures and expressions of iron handling proteins, to understand some aspects of iron homeostasis. Male Wistar rats were fed with ferrous sulphate heptahydrate (500mg/kg body weight/week, oral; elemental iron availability: 20%) from 2 months of age onward until they were 19.5 month-old. At 8, 14 and 20 months of age, they were sacrificed and serum and retinal iron levels were detected by HPLC. Oxidative stress was analyzed by TBARS method. The retinas were examined for cell death (TUNEL), histology (electron microscopy) and the expressions of transferrin, transferrin receptor-1 [TFR-1], H- and L-ferritin. In control animals, at any age, there was no difference in the serum and retinal iron levels, but the latter increased significantly in 14- and 20 month-old iron-fed rats, indicating that retinal iron accumulation proceeds with progression of aging (>14 months). The serum and retinal TBARS levels increased significantly with progression of aging in experimental but not in control rats. There was significant damage to choriocapillaris, accumulation of phagosomes in retinal pigment epithelium and increased incidence of TUNEL+ cells in outer nuclear layer and vacuolation in inner nuclear layer (INL) of 20 month-aged experimental rats, compared to those in age-matched controls. Vacuolations in INL could indicate a long-term effect of iron accumulation in the inner retina. These events paralleled the increased expression of ferritins and transferrin and a decrease in the expression of TFR-1 in iron-fed rats with aging, thereby maintaining iron homeostasis in the retina. As some of these changes mimic with those happening in eyes with AMD, this model can be utilized to understand iron-induced pathophysiological changes in AMD.

Uninhibited biosynthesis and release of phytosiderophores in the presence of heavy metal (HM) favors HM remediation.

Production of phytosiderophore (PS) has been causally related to iron-deficiency tolerance in cereals. However, PS can also chelate heavy metal and thus may represent a viable phytoextraction strategy on contaminated soils. Two separate experiments were conducted to assess the affect of heavy metal on phytosiderophore biosynthesis and their release in the rhizosphere of wheat. Root exudates were collected from 10-day-old wheat seedlings raised on Fe-deficient nutrient solution in the presence of 2.5, 5.0, and 10 mM concentration of different heavy metals (Cd, Pb, and Ni) for 3-day period, for the phytosiderophore and the heavy metal analysis. Plant uptake of respective heavy metal was positively correlated with the heavy metal concentration of the nutrient solution. Phytosiderophore release was positively influenced in the presence of the heavy metal. Increasing concentration of Cd, Pb, and Ni showed positive correlation with the PS release until 5 mM concentration followed by a decline at 10 mM. However, a higher induction of PS release was measured in wheat seedlings treated with Cd and Pb than Ni. Further, transcript expression analysis of nicotianamine synthase (NAS) and nicotianamine amino transferase (NAAT), involved in phytosiderophore biosynthesis, was done in roots of 10-day-old Fe-deficient wheat subjected to 2.5, 5.0, and 10 mM of Cd, Pb, and Ni. Both NAS and NAAT were expressed not only under Fe deficiency but also in the presence of Cd, Pb, and Ni. Sequencing of partial cDNA of NAS revealed a nucleotide length of 998 bp, while multiple sequence alignment of NAS with HvNAS revealed 92% sequence similarity. This study irrevocably shows that phytosiderophore biosynthesis and release are not impaired in the presence of heavy metal and that phytosiderophore mediates the uptake of toxic heavy metal.

Probing occurrence of phenylpropanoids in Morinda citrifolia in relation to foliar diseases.

Accumulation of phenolic compounds in cell walls of different plant organs leading to increased lignification is an early defence response of plants against biotic stress. The aim of this work was to delineate occurrence of cell wall-bound (CWB) phenolic compounds in Morinda citrifolia leaves. Alkaline hydrolysis of the cell wall material of leaf tissues yielded 4-coumaric acid (4-CA) as the major bulk of the phenolic compounds in all Morinda germplasms. Next in line was 4-hydroxybenzoic acid. Other phenolics identified were vanillic acid, 4-hydroxybenzaldehyde, vanillin and ferulic acid. Concentrations of all the CWB phenolics were highest in the germplasm CHN-5, followed by the germplasm CHN-1. Incidentally, these two Morinda germplasms recorded lowest incidence of foliar diseases. Significantly higher amounts of 4-CA in combination with other phenolics may be the reasons for lowest incidence of foliar diseases in CHN-5 and CHN-1 germplasms of M. citrifolia.

Localised leishmaniasis of oral mucosa: report of an unusual clinicopathological entity.

The term leishmaniasis comprises of a group of diseases caused by different species of a protozoan called Leishmania. There are three main clinical forms of leishmaniasis: visceral leishmaniasis, cutaneous leishmaniasis, and mucocutaneous leishmaniasis. Exclusive involvement of the mucosa is very rare. We present a case of mucosal leishmaniasis located in the oral cavity. The only manifestation of leishmaniasis disease in the described case was the appearance of an oral lesion. Treatment was provided in the form of antimoniates (oral miltefosine and systemic sodium stibogluconate). A review of literature is made on the subject.

Alveolar bone graft with Platelet Rich Plasma in cleft alveolus.

INTRODUCTION: Cleft of the lip, palate and alveolus are the commonest congenital anomaly to affect the orofacial region. Currently, there is great interest in the alveolar bone grafting procedures that involve use of platelet-rich-plasma (PRP), to enhance bone formation and specifically to promote bone graft healing. MATERIALS AND METHODS: 20 patients with residual alveolar cleft, in the age group of 9-29 years, having unilateral or bilateral cleft lip and palate were selected. They were randomly assigned in either group A (with PRP) or group B (without PRP). RESULTS: Primary healing was observed in 90% patients in group A. Secondary healing was seen in 30% patients in group B. There was no graft rejection in group A but was seen in one patient (10%) in group B. Pain and swelling persisted longer in group B then group A. Bone grafts with added PRP presented with increased bone density (1028.00 ± 11.30 HU) in comparison to grafts without PRP (859.50 ± 27.73 HU) at end of 6-month postoperative. However, the mean bone density (as determined by the Dentascan image analyzer software) was 1.04 times more in the PRP group than non PRP group at 3-month and 1.2 times more at 6 months. CONCLUSION: We conclude that on preliminary investigations, PRP seems to enhance bone formation in alveolar clefts when admixed with autologous cancellous bone harvested from the iliac crest.

Laser vs bur for bone cutting in impacted mandibular third molar surgery: A randomized controlled trial.

BACKGROUND: The aim of this study was to assess the feasibility of Er: YAG laser in bone cutting for removal of impacted lower third molar teeth and compare its outcomes with that of surgical bur. MATERIALS & METHODS: The study comprised 40 subjects requiring removal of impacted mandibular third molar, randomly categorized into two equal groups of 20 each, who had their impacted third molar removed either using Er: YAG laser or surgical bur as per their group, using standard methodology of extraction of impacted teeth. Clinical parameters like pain, bleeding, time taken for bone cutting, postoperative swelling, trismus, wound healing and complications were compared for both groups. OBSERVATION & RESULT: Clinical parameters like pain, bleeding and swelling were lower in laser group than bur group, although the difference was statistically not significant. However, postoperative swelling showed significant difference in the two groups. Laser group required almost double the time taken for bone cutting with bur. Trismus persisted for a longer period in laser group. Wound healing and complications were assessed clinically and there was no significant difference in both the groups. CONCLUSION: Based on the results of our study, the possibility of bone cutting using lasers is pursued, the osteotomy is easily performed and the technique is better suited to minimally invasive surgical procedures. The use of Er: YAG laser may be considered as an alternative tool to surgical bur, specially in anxious patients.

Crouzon syndrome with primary optic nerve atrophy and normal brain functions: A case report.

BACKGROUND: This report and review of literature aimed to assess an unusual case of Crouzon syndrome characterized by distinctive disfigurement of craniofacial skeletal and soft tissue structures with primary optic nerve atropy. METHODS: We present a case of a 12-year-old girl with Crouzon syndrome displaying classic facial abnormalities with reduced vision and hearing loss. CONCLUSION: Crouzon syndrome should be managed as early as possible as it results in airway obstruction, decreased vision, mental retardation and poor cosmetic appearance.

Reconstruction of ramus-condyle unit with transport distraction osteogenesis: Report of eight cases and review of literature.

BACKGROUND/AIMS: This report and review of literature aimed to assess the feasibility of condylar distraction in humans and its esthetic and functional outcome. METHODS: We present a case series of eight TMJ ankylosis patients, where after a gap arthroplasty, ramus condyle unit was reconstructed using transport distraction to analyze its feasibility, esthetic and functional outcome and success. RESULTS: All patients had satisfactory mouth opening, and minimal pain in their follow-up period. CONCLUSION: Condylar transport distraction osteogenesis holds promise for successful TMJ reconstruction and should be the method of choice as it does not involve secondary surgery or need for an alloplast.

Wide alveolar cleft and midface distraction: Report of a case.

BACKGROUND: Cleft lip and palate patients often present wide alveolar cleft and midface hypoplasia. Closure of such wide alveolar clefts may be difficult using bone graft. Traditional orthognathic surgery for midface advancement shows relapse. Distraction osteogenesis (DO) as a modality for midface advancement has shown good results with external distractors. Use of internal distractor (ID) further improves patient compliance, causes minimal discomfort and offers the advantage of limiting relapse. The purpose of this study was to evaluate the versatility of intraoral distracters in midface advancement in cases with alveolar cleft. METHOD: A 16 years old young girl with midface deficiency and alveolar cleft visited our outpatient clinic for aesthetic improvement and midface distraction was planned. After Le Fort I osteotomy, internal distractor was fixed. A latency period of 5 days was allowed and then distraction was started at the rate of 1 mm per day in two installments. Evaluation was done for closure of cleft, ease of the procedure, stability, and complications. Lateral cephalograms were evaluated at three stages: predistraction; post-distraction; and 1 year post-distraction. RESULTS: Complete closure of alveolar cleft was observed with 17 mm midface advancement and bone formation at the pterygomaxillary region. Maxillary position improved in relation to the cranial base. The results were stable even at 1 year follow-up. CONCLUSION: Distraction osteogenesis using intraoral distractors was successful in alveolar cleft closure, as well as midface advancement in terms of stability of results and patient compliance with minimal complications.