A critical review of uranium contamination in groundwater: Treatment and sludge disposal.

Dissolved uranium in groundwater at high concentrations is an emerging global threat to human and ecological health due to its radioactivity and chemical toxicity. Uranium can enter groundwater by geochemical reactions, natural deposition from minerals, mining, uranium ore processing, and spent fuel disposal. Although much progress has been made in uranium remediation in recent years, most published reviews on uranium treatment have focused on specific methods, particularly adsorption. This article systematically reviews the major treatment technologies, explains their mechanism and progress of uranium removal, and compares their performance under various environmental conditions. Of all treatment methods, adsorption has received much attention due to its ease of use and adaptability under various conditions. However, salinity and competition from other ions limit its application in actual field conditions. Biosorption and bioremediation are also promising methods due to their low-cost and chemical-free operation. Strong base anion exchange resins are more effective at typical groundwater pH conditions. Advanced oxidation processes like photocatalysis produce less sludge and are effective even at low uranium concentrations. Electrocoagulation shows significantly improved performance when organic ligands are added prior to treatment. The significant advantages of membrane filtration are high removal efficiency and the ability to recover uranium. While each technology has its merits and demerits, no single technology is entirely suitable under all conditions. One major area of concern with all technologies is the need to dispose of liquid and solid waste generated after treatment safely. Future research must focus on developing hybrid and state-of-the-art technologies for effective and sustainable uranium removal from groundwater. Developing holistic management strategies for uranium removal will hinge on understanding its speciation, mechanisms of fate and transport, and socio-economic conditions of the affected areas.

Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors.

Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. Methods: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. Results: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. Conclusions: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer.

Role of Hippo Pathway-YAP/TAZ Signaling in Angiogenesis.

Angiogenesis is a highly coordinated process of formation of new blood vessels from pre-existing blood vessels. The process of development of the proper vascular network is a complex process that is crucial for the vertebrate development. Several studies have defined essential roles of Hippo pathway-YAP/TAZ in organ size control, tissue regeneration, and self-renewal. Thus Hippo pathway is one of the central components in tissue homeostasis. There are mounting evidences on the eminence of Hippo pathway-YAP/TAZ in angiogenesis in multiple model organisms. Hippo pathway-YAP/TAZ is now demonstrated to regulate endothelial cell proliferation, migration and survival; subsequently regulating vascular sprouting, vascular barrier formation, and vascular remodeling. Major intracellular signaling programs that regulate angiogenesis concomitantly activate YAP/TAZ to regulate key events in angiogenesis. In this review, we provide a brief overview of the recent findings in the Hippo pathway and YAP/TAZ signaling in angiogenesis.

Phosphorylation of Mig6 negatively regulates the ubiquitination and degradation of EGFR mutants in lung adenocarcinoma cell lines.

Activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) leads to the constitutively active kinase, improves the EGFR stability and promotes malignant transformation in lung adenocarcinoma. Despite the clinical significance, the mechanism by which the increased kinase activity stabilizes the receptor is not completely understood. Using SILAC phosphoproteomic approach, we identify that Mig6 is highly phosphorylated at S256 in EGFR mutants (19del and L858R). Loss of Mig6 contributes to the efficient degradation of EGFR wildtype and mutants in lung cancer cells. Mig6 regulates the recruitment of c-Cbl to EGFR as the ablation of Mig6 enables efficient ubiquitination of the EGFR mutants through elevated recruitment of c-Cbl. We show that the cells with activating mutants of EGFR inactivate Mig6 through phosphorylation at S256. Inactivated Mig6 causes inefficient ubiquitination of EGFR, leading to defective degradation of the receptor thus contributing to the increased stability of the receptor. Taken together, we show a novel function of Mig6 in regulating the ubiquitination of EGFR.

Cavin-2 regulates the activity and stability of endothelial nitric-oxide synthase (eNOS) in angiogenesis.

Angiogenesis is a highly regulated process for formation of new blood vessels from pre-existing ones. Angiogenesis is dysregulated in various pathologies, including age-related macular degeneration, arthritis, and cancer. Inhibiting pathological angiogenesis therefore represents a promising therapeutic strategy for treating these disorders, highlighting the need to study angiogenesis in more detail. To this end, identifying the genes essential for blood vessel formation and elucidating their function are crucial for a complete understanding of angiogenesis. Here, focusing on potential candidate genes for angiogenesis, we performed a morpholino-based genetic screen in zebrafish and identified Cavin-2, a membrane-bound phosphatidylserine-binding protein and critical organizer of caveolae (small microdomains in the plasma membrane), as a regulator of angiogenesis. Using endothelial cells, we show that Cavin-2 is required for in vitro angiogenesis and also for endothelial cell proliferation, migration, and invasion. We noted a high level of Cavin-2 expression in the neovascular tufts in the mouse model of oxygen-induced retinopathy, suggesting a role for Cavin-2 in pathogenic angiogenesis. Interestingly, we also found that Cavin-2 regulates the production of nitric oxide (NO) in endothelial cells by controlling the stability and activity of the endothelial nitric-oxide synthase (eNOS) and that Cavin-2 knockdown cells produce much less NO than WT cells. Also, mass spectrometry, flow cytometry, and electron microscopy analyses indicated that Cavin-2 is secreted in endothelial microparticles (EMPs) and is required for EMP biogenesis. Taken together, our results indicate that in addition to its function in caveolae biogenesis, Cavin-2 plays a critical role in endothelial cell maintenance and function by regulating eNOS activity.

Assessing the impact of a program for late surgical intervention in early-blind children.

OBJECTIVE: Many blind children in the developing world are unable to obtain timely treatment due to lack of financial and medical resources. Can public health programs that identify and treat such children several years after the onset of blindness enhance their quality of life? The notion that visual development is subject to an early 'critical period' argues against this possibility. However, there are inadequate empirical data from humans on this issue. To address this need, we examined the quality of life of children living in India and who were treated for early-onset blindness (before one year of age), due to cataracts or corneal opacities. STUDY DESIGN: Survey study. METHODS: As part of an ongoing scientific effort named Project Prakash, we screened over 40,000 children in rural northern India to identify those suffering from early-onset blindness. They were provided eye surgeries in a tertiary care ophthalmic center in New Delhi. We subsequently surveyed 64 Prakash children, ranging in age from 5 to 22 years and obtained their responses on a multi-dimensional quality of life questionnaire. RESULTS: Nearly all of the subjects indicated that their quality of life had improved after treatment. Children reported marked enhancement in their mobility, independence, and safety, and also in social integration. Surprisingly, we found no significant correlations between quality of life metrics and factors such as age at treatment, gender, time since treatment, and pre-surgery and post-surgery acuity. CONCLUSIONS: A key question for public health policy makers is whether a program of surgical intervention for older blind children is likely to be beneficial, or if the resources are better spent on rehabilitation via vocational training and assistive devices. The marked improvements in quality of life we find in our data strongly argue for the provision of surgical care regardless of a child's age.

Development and characterisation of thermo reversible mucoadhesive moxifloxacin hydrochloride in situ ophthalmic gel.

A sustain release thermo reversible in situ gel of Moxifloxacin Hydrochloride using mucoadhesive polymer was prepared. Mucoadhesive polymer was used to obtain an ophthalmic delivery system with improved mechanical and mucoadhesive properties that will provide prolong retention time for treatment of ocular diseases. Developed formulations were evaluated for drug-excipient compatibility study, pH, Clarity, Gelation temperature study, Mucoadhesion properties and in-vitro release studies. Drug-excipient compatibility study was performed by FTIR technique. The individual IR spectra of the pure drug and polymers as well as the combination spectra of the drug and polymer were taken, which indicate no interaction between Moxifloxacin and polymers when compared with infrared spectrum of pure drug as all functional group frequencies were present. The values of other parameters obtained were in acceptable range. In vitro release tests revealed that 98% drug was released from the in situ gel containing 0.5% and 1.00% HPMC in 12 hr. provides prolonged release.

Optimization of the experimental parameters of fluticasone propionate microparticles for pulmonary delivery using a box behenken design.

The objective of this study was to examine extensively the influences of formulation and process variables on the microparticles. The microparticles were generated by the spray-drying technique using polymer chitosan, mannitol along with L-leucine. The effects of various experimental parameters such as polymer concentration, inlet temperature, and feed flow rate on particle size and production yields were evaluated by means of experimental box-behnken design. Multiple regression analysis was carried out and response surfaces were obtained. Optimized formulation and check points batches were selected by feasibility and grid search. Experimental design it was evaluated that inlet temperature and polymer concentration influence on the production yield. Feed flow rate impact on particle size. Results showed that spray drying technique yield 985 to 4060 nm indicate micro size range and production yield was found in between 27.01-52.96%. The selection of appropriate parameters yielded spray-dried microparticles characterized by narrow dimensional distribution. In our present work, prepared microparticles using the spray-drying technique and systematically estimated their feasibility for the pulmonary delivery of microparticles by careful investigations of their characteristics and aerosolization properties. Spray drying technique yield optimum size for deposition beyond the narrow airway into the alveoli and suitable for respiratory deposition.

Effects of spray drying conditions on the physicochemical properties of the Tramadol-Hcl microparticles containing Eudragit(®) RS and RL.

The preparation of Tramadol-HCL spray-dried microspheres can be affected by the long drug recrystallization time. Polymer type and drug-polymer ratio as well as manufacturing parameters affect the preparation. The purpose of this work was to evaluate the possibility to obtain tramadol spray-dried microspheres using the Eudragit(®) RS and RL; the influence of the spray-drying parameters on morphology, dimension, and physical stability of microspheres was studied. The effects of matrix composition on microparticle properties were characterized by Laser Light scattering, differential scanning calorimetry (DSC), X-ray diffraction study, FT-infrared and UV-visible spectroscopy. The spray-dried microparticles were evaluated in terms of shape (SEM), size distribution (Laser light scattering method), production yield, drug content, initial drug loding and encapsulation efficiency. The results of X-ray diffraction and thermal analysis reveals the conversion of crystalline drug to amorphous. FTIR analysis confirmed the absence of any drug polymer interaction. The results indicated that the entrapment efficiency (EE), and product yield were depended on polymeric composition and polymeric ratios of the microspheres prepared. Tramadol microspheres based on Eudragit(®) blend can be prepared by spray-drying and the nebulization parameters do not influence significantly on particle properties.

Development and in vivo evaluation of silver sulfadiazine loaded hydrogel consisting polyvinyl alcohol and chitosan for severe burns.

A new Hydrogel containing silver Sulfadiazine (SSD) was developed for enhanced burns wound healing. The hydrogel was prepared by cross-linking of PVA and Chitosan by freeze thawing method. Their gel properties, moisture retaining capacity, fluid uptake capacity, in vitro release study, in vivo burn healing effect were evaluated. Chitosan and PVA cross linking decreased gel fraction upto 70% determined the good gel properties. This cross linked hydrogel increased the Swelling ratio and Water vapour transmission rate (WVTR) which provides the sustained release of drug and moist environment for healing respectively. The hydrogel containing 7.5% of PVA, 0.75% of chitosan found to have increased gel strength, higher water vapour transmission rate and fluid uptake capacity suitable for faster healing of burns. This hydrogel also sustained the release of 1% SSD required for longer antimicrobial activity and found better in vivo burn healing capacity as compared to marketed preparation. Thus hydrogel containing 7.5% of PVA, 0.75% of chitosan and 1% SSD is a potential burns dressing with better gel properties and excellent burns healing capacity.

Endodontic-periodontal management of two rooted maxillary lateral incisor associated with complex radicular lingual groove by using spiral computed tomography as a diagnostic aid: a case report.

AIM: To present the successful endodontic and periodontal management of a two rooted maxillary lateral incisor tooth with a complex radicular lingual groove and severe periodontal destruction using spiral computed tomography as a diagnostic aid. SUMMARY: A 30-year-old male patient presented with a chief complaint of mobility and discharge of pus in an upper front tooth. Clinical examination revealed a sinus tract on the labial gingival surface and a 10-mm-deep periodontal pocket associated with maxillary left lateral incisor tooth. On the lingual side, a groove emerging from cingulum, continuing mesioapically down the lingual aspect of tooth was found. Intraoral periapical radiographs demonstrated a lateral periodontal defect around the mesial aspect and a diffuse radiolucency at the apex of maxillary left lateral incisor tooth. The sinus tract was traced with gutta-percha to the maxillary left lateral incisor that showed an accessory root surrounded by a large radiolucent area. A spiral computed tomographic scan for better understanding of the complicated root canal morphology of the tooth was performed. Based on the clinical, radiographic and spiral computed tomographic findings, a diagnosis of an endo-perio lesion in tooth 22 was made. Management consisted of conventional root canal treatment, radiculoplasty, root resection of accessory root and surgical curettage of the periodontal defect. Follow-up with radiographic examination at 3 months and 1 year was performed. At 1-year recall, the patient was asymptomatic, there was no evidence of the sinus tract and a 3-mm nonbleeding pocket was present in relation to tooth 22. Progression of hard tissue healing was observed in the periapical radiograph taken 1 year postoperatively. KEY LEARNING POINTS: The key to achieving favourable results in this particular type of developmental anomaly is accurate diagnosis and treatment planning. The health of the periapical osseous tissues appears to be the provital factor for tooth retention. A favourable outcome can only be achieved with a comprehensive treatment approach that effectively manages all local factors that are contributing to the disease process.

Targeting CYP450 modulation to decrease the risk of induced cataract in the experimental model.

BACKGROUND: Diabetes is one of the major causes of cataract. Some drugs prescribed for the treatment of diabetes are the modulators of CYP450, which may alter the risk of cataract. OBJECTIVE: To study the effect of CYP450 modulation in galactosemic cataract. MATERIALS AND METHODS: Male Sprague-Dawley suckling rats were allotted to four groups (n = 6), as follows: Group 1: Normal control, Group 2: Galactose control, Group 3: CYP450 inhibitor pretreated and Group 4: CYP450 inducer pretreated. Cataract was induced in animals of all groups except group 1 by feeding them galactose (50%), 21 days after parturition. From the eighteenth day of life, CYP450 inhibitor (nifedipine; 8.1 mg/kg) and CYP450 inducer (pioglitazone; 3.8 mg/kg) were given orally to groups 3 and 4, respectively. The maturation pattern of the cataract was observed by an operating microscope, every third day. Biochemical changes in the lenses of all groups, for example, CYP450 activity expressed as ΅M NADPH oxidized / unit time, alterations in the levels of total proteins, soluble proteins, and reduced glutathione (GSH) following the induction of cataract, were estimated. RESULTS: The microscopic examination of the lenses indicated that CYP450 inhibitor pre-treatment delayed (fourteenth day) the occurrence of cataract, while CYP450 inducer pretreatment demonstrated an early (ninth day) cataract as compared to galactose control rats (twelfth day). A significant decrease and increase in CYP450 activity was observed with the CYP450 inhibitor and inducer pre-treatment, respectively. There was no alteration in the GSH level, but a significant increase in total and soluble protein was found in groups 3 and 4 as compared to group 2. CONCLUSION: CYP450 may have a role in the initiation of cataract without any effect on the maturation pattern, as revealed by the delayed occurrence of cataract with the CYP450 inhibitor and an early onset of cataract with the CYP450 inducer.

Evaluation of the effect of Myrica sapida on bronchoconstriction and bronchial hyperreactivity.

The present investigation was undertaken to evaluate the bronchodilator and bronchial hyperreactivity of the stem bark of Myrica sapida. Experimental models studied were histamine induced bronchospasm in guinea pigs, bronchoalveolar lavage fluid (BALF) in egg albumin sensitized guinea pigs, histamine release from the lung tissues of sensitized guinea pigs and histopathological studies. Ethanolic extract of M. sapida (75 mg/kg, p.o., for 7 days) showed significant protection against histamine aerosol induced bronchospasm. Significant decrease in the total and differential leukocyte counts in BALF and prevention of egg albumin induced histamine release from chopped lung tissues of sensitized guinea pigs was observed on chronic administration of ethanolic extract of M. sapida (75 mg/kg, p.o., for 15 days). Histological examination of the section of lung from sensitized guinea pigs treated with ethanolic extract of M. sapida (75 mg/kg, p.o., for 15 days) was comparable to that of the control group. These results suggest that M. sapida possesses not only bronchodilator activity but also decreases bronchial hyperresponsiveness by decreasing the infiltration of inflammatory mediators like eosinophils, neutrophils in BALF and inhibiting histamine release from lungs of sensitized guinea pigs.

Mathematical evaluation of similarity factor using various weighing approaches on aceclofenac marketed formulations by model-independent method.

The US Food and Drug Administration's (FDA's) guidance for industry on dissolution testing of immediate-release solid oral dosage forms describes that drug dissolution may be the rate limiting step for drug absorption in the case of low solubility/high permeability drugs (BCS class II drugs). US FDA Guidance describes the model-independent mathematical approach proposed by Moore and Flanner for calculating a similarity factor (f2) of dissolution across a suitable time interval. In the present study, the similarity factor was calculated on dissolution data of two marketed aceclofenac tablets (a BCS class II drug) using various weighing approaches proposed by Gohel et al. The proposed approaches were compared with a conventional approach (W = 1). On the basis of consideration of variability, preference is given in the order of approach 3 > approach 2 > approach 1 as approach 3 considers batch-to-batch as well as within-samples variability and shows best similarity profile. Approach 2 considers batch-to batch variability with higher specificity than approach 1.

Stability Indicating RP-HPLC Estimation of Atorvastatin Calcium and Amlodipine Besylate in Pharmaceutical Formulations.

A simple, specific, accurate and stability indicating reversed phase high performance liquid chromatographic method was developed for the simultaneous determination of atorvastatin calcium and amlodipine besylate in tablet dosage forms. A phenomenex Gemini C-18, 5 µm column having 250×4.6 mm i.d. in isocratic mode, with mobile phase containing 0.02 M potassium dihydrogen phosphate:acetonitrile:methanol (30:10:60, v/v/v) adjusted to pH 4 using ortho phosphoric acid was used. The flow rate was 1.0 ml/min and effluents were monitored at 240 nm. The retention times of atorvastatin calcium and amlodipine besylate were 11.6 min and 4.5 min, respectively. The calibration curves were linear in the concentration range of 0.08-20 µg/ml for atorvastatin calcium and 0.1-20 µg/ml for amlodipine besylate. Atorvastatin calcium and amlodipine besylate stock solutions were subjected to acid and alkali hydrolysis, chemical oxidation and dry heat degradation. The degraded product peaks were well resolved from the pure drug peak with significant difference in their retention time values. The proposed method was validated and successfully applied to the estimation of atorvastatin calcium and amlodipine besylate in combined tablet dosage forms.

Stability Indicating RP-HPLC Estimation of Nebivolol Hydrochloride in Pharmaceutical Formulations.

A simple, specific, accurate and stability indicating reversed phase liquid chromatographic method was developed for the determination of nebivolol hydrochloride in tablet dosage forms. A phenomenex Gemini C-18, 5 µm column having 250×4.6 mm i.d., with mobile phase containing methanol: acetonitrile: 0.02 M potassium dihydrogen phosphate (60:30:10, v/v/v; pH 4.0) was used. The retention time of nebivolol hydrochloride was 2.6 min. The linearity for nebivolol hydrochloride was in the range of 0.2-10 µg/ml. The recovery was found to be in the range of 98.68-100.86%. The detection limit and quantification limit were found to be 0.06 µg/ml and 0.2 µg/ml, respectively. Nebivolol stock solutions were subjected to acid, alkali and neutral hydrolysis, chemical oxidation and dry heat degradation. The degraded product peaks were well resolved from the pure drug peak with significant difference in their retention time values. The proposed method was validated and successfully applied to the estimation of nebivolol hydrochloride in tablet formulations.

Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets.

We present the first analysis of the human proteome with regard to interactions between proteins. We also compare the human interactome with the available interaction datasets from yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans) and fly (Drosophila melanogaster). Of >70,000 binary interactions, only 42 were common to human, worm and fly, and only 16 were common to all four datasets. An additional 36 interactions were common to fly and worm but were not observed in humans, although a coimmunoprecipitation assay showed that 9 of the interactions do occur in humans. A re-examination of the connectivity of essential genes in yeast and humans indicated that the available data do not support the presumption that the number of interaction partners can accurately predict whether a gene is essential. Finally, we found that proteins encoded by genes mutated in inherited genetic disorders are likely to interact with proteins known to cause similar disorders, suggesting the existence of disease subnetworks. The human interaction map constructed from our analysis should facilitate an integrative systems biology approach to elucidating the cellular networks that contribute to health and disease states.

Human protein reference database--2006 update.

Human Protein Reference Database (HPRD) (http://www.hprd.org) was developed to serve as a comprehensive collection of protein features, post-translational modifications (PTMs) and protein-protein interactions. Since the original report, this database has increased to >20 000 proteins entries and has become the largest database for literature-derived protein-protein interactions (>30 000) and PTMs (>8000) for human proteins. We have also introduced several new features in HPRD including: (i) protein isoforms, (ii) enhanced search options, (iii) linking of pathway annotations and (iv) integration of a novel browser, GenProt Viewer (http://www.genprot.org), developed by us that allows integration of genomic and proteomic information. With the continued support and active participation by the biomedical community, we expect HPRD to become a unique source of curated information for the human proteome and spur biomedical discoveries based on integration of genomic, transcriptomic and proteomic data.

An evaluation of human protein-protein interaction data in the public domain.

BACKGROUND: Protein-protein interaction (PPI) databases have become a major resource for investigating biological networks and pathways in cells. A number of publicly available repositories for human PPIs are currently available. Each of these databases has their own unique features with a large variation in the type and depth of their annotations. RESULTS: We analyzed the major publicly available primary databases that contain literature curated PPI information for human proteins. This included BIND, DIP, HPRD, IntAct, MINT, MIPS, PDZBase and Reactome databases. The number of binary non-redundant human PPIs ranged from 101 in PDZBase and 346 in MIPS to 11,367 in MINT and 36,617 in HPRD. The number of genes annotated with at least one interactor was 9,427 in HPRD, 4,975 in MINT, 4,614 in IntAct, 3,887 in BIND and <1,000 in the remaining databases. The number of literature citations for the PPIs included in the databases was 43,634 in HPRD, 11,480 in MINT, 10,331 in IntAct, 8,020 in BIND and <2,100 in the remaining databases. CONCLUSION: Given the importance of PPIs, we suggest that submission of PPIs to repositories be made mandatory by scientific journals at the time of manuscript submission as this will minimize annotation errors, promote standardization and help keep the information up to date. We hope that our analysis will help guide biomedical scientists in selecting the most appropriate database for their needs especially in light of the dramatic differences in their content.