Structural investigation of borosilicate glasses containing lanthanide ions.

High level radioactive actinides are produced as a side product in reprocessing spent nuclear fuel, for which safe long-term-inert immobilizer matrices are needed. Borosilicate glasses are of great potential amongst the candidates of suitable inert materials for radioactive waste immobilization. Understanding the effects of actinide addition to a borosilicate glass matrix is of great importance in view of waste immobilization. Here we present structural studies of a simplified glass-matrix, - 55SiO2·10B2O3·25Na2O·5BaO·5ZrO2 - upon adding lanthanide (Ln-)oxides: CeO2, Nd2O3, Eu2O3, in two different concentrations 10% and 30w% each, to investigate the effects of lanthanides (Ln) taken as chemical surrogates for actinides. Neutron diffraction combined with of Reverse Monte Carlo simulations show that all investigated glass structures comprise tetrahedral SiO4, trigonal BO3 and tetrahedral BO4 units, forming mixed [4]Si-O-[3]B and [4]Si-O-[4]B linkages. 11B Magic Angle Spinning Nuclear Magnetic Resonance is indicative of simultaneous presence of trigonal BO3 and tetrahedral BO4 units, with spectral fractions strongly dependent on the Ln addition. Ln-addition promote the BO3 + O-→[BO4]- isomerization resulting in lower fraction of boron in BO3, as compared to BO4 units. Raman spectra, in full agreement with neutron diffraction, confirm that the basic network structure consists of BO3/trigonal and SiO4/BO4 tetrahedral units. Second neighbour atomic pair correlations reveal Ce, Nd, Eu to be accommodated in both Si and B sites, supporting that the borosilicate-matrix well incorporates Ln-ions and is likely to similarly incorporate actinides, opening a way to radioactive nuclear waste immobilization of this group of elements in a borosilicate glass matrix.

Ultrasound-based detection of glucocorticoid-induced impairments of muscle mass and structure in Cushing's disease.

PURPOSE: To investigate the glucocorticoid-induced impairments of muscle mass and structure in patients presenting different stages of steroid myopathy progression. METHODS: Thirty-three patients (28 women) affected by active (N = 20) and remitted (N = 13) Cushing's disease were recruited and the following variables were assessed: walking speed, handgrip strength, total body and appendicular muscle mass by bioelectrical impedance analysis (BIA), thickness and echo intensity of lower limb muscles by ultrasonography. RESULTS: The two groups of patients showed comparable values of both handgrip strength [median (interquartile range) values: active disease: 27.4 (7.5) kg vs. remitted disease: 26.4 (9.4) kg; P = 0.58] and walking speed [active disease: 1.0 (0.2) m/s vs. remitted disease: 1.1 (0.3) m/s; P = 0.43]. Also, the thickness of the four muscles and all BIA-derived sarcopenic indices were comparable (P > 0.05 for all comparisons) between the two groups. On the contrary, the echo intensity of vastus lateralis, tibialis anterior (lower portion), and medial gastrocnemius was significantly (P < 0.05 for all comparisons) higher in patients with active disease compared to patients with remitted disease. Finally, significant negative correlations were found in the whole group of patients between muscle echo intensity and muscle function assessments. CONCLUSIONS: We provided preliminary evidence that the ultrasound-derived measurements of muscle thickness and echo intensity can be useful to detect and track the changes of muscle mass and structure in patients with steroid myopathy and we suggest that the combined assessment of muscle mass, strength, and performance should be systematically applied in the routine examination of steroid myopathy patients.

Restriction Spectrum Imaging Improves Risk Stratification in Patients with Glioblastoma.

BACKGROUND AND PURPOSE: ADC as a marker of tumor cellularity has been promising for evaluating the response to therapy in patients with glioblastoma but does not successfully stratify patients according to outcomes, especially in the upfront setting. Here we investigate whether restriction spectrum imaging, an advanced diffusion imaging model, performed after an operation but before radiation therapy, could improve risk stratification in patients with newly diagnosed glioblastoma relative to ADC. MATERIALS AND METHODS: Pre-radiation therapy diffusion-weighted and structural imaging of 40 patients with glioblastoma were examined retrospectively. Restriction spectrum imaging and ADC-based hypercellularity volume fraction (restriction spectrum imaging-FLAIR volume fraction, restriction spectrum imaging-contrast-enhanced volume fraction, ADC-FLAIR volume fraction, ADC-contrast-enhanced volume fraction) and intensities (restriction spectrum imaging-FLAIR 90th percentile, restriction spectrum imaging-contrast-enhanced 90th percentile, ADC-FLAIR 10th percentile, ADC-contrast-enhanced 10th percentile) within the contrast-enhanced and FLAIR hyperintensity VOIs were calculated. The association of diffusion imaging metrics, contrast-enhanced volume, and FLAIR hyperintensity volume with progression-free survival and overall survival was evaluated by using Cox proportional hazards models. RESULTS: Among the diffusion metrics, restriction spectrum imaging-FLAIR volume fraction was the strongest prognostic metric of progression-free survival (P = .036) and overall survival (P = .007) in a multivariate Cox proportional hazards analysis, with higher values indicating earlier progression and shorter survival. Restriction spectrum imaging-FLAIR 90th percentile was also associated with overall survival (P = .043), with higher intensities, indicating shorter survival. None of the ADC metrics were associated with progression-free survival/overall survival. Contrast-enhanced volume exhibited a trend toward significance for overall survival (P = .063). CONCLUSIONS: Restriction spectrum imaging-derived cellularity in FLAIR hyperintensity regions may be a more robust prognostic marker than ADC and conventional imaging for early progression and poorer survival in patients with glioblastoma. However, future studies with larger samples are needed to explore its predictive ability.

Evaluation of Risk Factors for Laryngopharyngeal Reflux among Sikkimese Population.

Background Laryngopharyngeal reflux is a global health problem and is associated with a huge economic burden and decreased quality of life. Studies describing the epidemiology of laryngopharyngeal reflux are sparse in India and south east Asia. This study becomes significant as it is being conducted in Sikkimese population who resides in high altitude have a different lifestyle. Objective To evaluate the risk factors for laryngopharyngeal reflux among Sikkimese origin. Method Patients of Sikkimese origin visiting Ear Nose Throat outpatient department Were administered with validated questionnaire. The patients were further subjected to validate Reflux symptom Index score. Indirect laryngoscopy was performed to calculate reflux finding score. Presence of laryngopharyngeal reflux was identified with patients having reflux symptom index and reflux finding score of greater or equal to 13 or more and 7 or more. Result Out of 200 subjects analysed, there were 77(38.5%) male and 123(61.5%) female. Heartburn and regurgitation were the most common symptom among the masses. Hoarseness and frequent throat clearance were the commonest laryngopharyngeal reflux symptoms. Various risk factors were computed as mentioned in the results column. Conclusion Study on the above mentioned population differed from rest of the country in terms of dietary habits. Fermented food was found to be one of the important risk factor for the development of laryngopharyngeal reflux in the sikkimise population.

In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells.

BACKGROUND: The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk. METHODS: We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations. RESULTS: In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells. CONCLUSIONS: Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.

bHLH Transcription factors inhibitors for cancer therapy: general features for in silico drug design.

Numerous basic-helix-loop-helix (bHLH) transcription factors (TF) have been found to play important roles in tumor growth and progression. Elucidation of the common features of these TFs can pave the road to possible therapeutic intervention. The existing studies of possible inhibition of these TFs are concentrated on the development of peptides or small molecules that inhibit their dimerization or prevent their DNA binding. The bHLH TFs have striking similarity in many functionally important regions, such as the helical regions of TFs that interact with each other during dimerization and have complementary sets of residues on both sides of a dimer. These are hydrophobic residues along with anionic and cationic residues with complementary charges. Such complementarity also exists in other contact regions of the bHLH TFs. They also have a very specific set of positively charged residues on the surface, which would contact DNA. Such specificity defines a common concept for an in silico design of bHLH TFs inhibitors for a number of existing and important cancer-related TFs.

An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop regulates the activation of EGFRvIII.

EGFRvIII is a key oncogene in glioblastoma (GBM). EGFRvIII results from an in-frame deletion in the extracellular domain of EGFR, does not bind ligand and is thought to be constitutively active. Although EGFRvIII dimerization is known to activate EGFRvIII, the factors that drive EGFRvIII dimerization and activation are not well understood. Here we present a new model of EGFRvIII activation and propose that oncogenic activation of EGFRvIII in glioma cells is driven by co-expressed activated EGFR wild type (EGFRwt). Increasing EGFRwt leads to a striking increase in EGFRvIII tyrosine phosphorylation and activation while silencing EGFRwt inhibits EGFRvIII activation. Both the dimerization arm and the kinase activity of EGFRwt are required for EGFRvIII activation. EGFRwt activates EGFRvIII by facilitating EGFRvIII dimerization. We have previously identified HB-EGF, a ligand for EGFRwt, as a gene induced specifically by EGFRvIII. In this study, we show that HB-EGF is induced by EGFRvIII only when EGFRwt is present. Remarkably, altering HB-EGF recapitulates the effect of EGFRwt on EGFRvIII activation. Thus, increasing HB-EGF leads to a striking increase in EGFRvIII tyrosine phosphorylation while silencing HB-EGF attenuates EGFRvIII phosphorylation, suggesting that an EGFRvIII-HB-EGF-EGFRwt feed-forward loop regulates EGFRvIII activation. Silencing EGFRwt or HB-EGF leads to a striking inhibition of EGFRvIII-induced tumorigenicity, while increasing EGFRwt or HB-EGF levels resulted in accelerated EGFRvIII-mediated oncogenicity in an orthotopic mouse model. Furthermore, we demonstrate the existence of this loop in human GBM. Thus, our data demonstrate that oncogenic activation of EGFRvIII in GBM is likely maintained by a continuous EGFRwt-EGFRvIII-HB-EGF loop, potentially an attractive target for therapeutic intervention.

Recovery of white matter tracts in regions of peritumoral FLAIR hyperintensity with use of restriction spectrum imaging.

BACKGROUND AND PURPOSE: DTI is being increasingly used to visualize critical white matter tracts adjacent to brain tumors before neurosurgical resection. However, brain tumors, particularly high-grade gliomas, are typically surrounded by regions of FLAIR hyperintensity that include edema, which increase isotropic diffusion, degrading the ability of standard DTI to uncover orientation estimates within these regions. We introduce a new technique, RSI, which overcomes this limitation by removing the spherical, fast diffusion component introduced by edema, providing better analysis of white matter architecture. MATERIALS AND METHODS: A total of 10 patients with high-grade gliomas surrounded by FLAIR-HI that at least partially resolved on follow-up imaging were included. All patients underwent RSI and DTI at baseline (FLAIR-HI present) and at follow-up (FLAIR-HI partially resolved). FA values obtained with RSI and DTI were compared within regions of FLAIR-HI and NAWM at both time points. RESULTS: RSI showed higher FA in regions of FLAIR-HI and NAWM relative to DTI, reflecting the ability of RSI to specifically measure the slow, restricted volume fraction in regions of edema and NAWM. Furthermore, a method by time interaction revealed that FA estimates increased when the FLAIR-HI resolved by use of standard DTI but remained stable with RSI. Tractography performed within the region of FLAIR-HI revealed the superior ability of RSI to track fibers through severe edema relative to standard DTI. CONCLUSIONS: RSI improves the quantification and visualization of white matter tracts in regions of peritumoral FLAIR-HI associated with edema relative to standard DTI and may provide a valuable tool for neurosurgical planning.

Improved conspicuity and delineation of high-grade primary and metastatic brain tumors using "restriction spectrum imaging": quantitative comparison with high B-value DWI and ADC.

BACKGROUND AND PURPOSE: Restriction spectrum imaging is a sensitive DWI technique for probing separable water diffusion compartments in tissues. Here, we evaluate RSI-CMs derived from the spherically-restricted water compartment for improved tumor conspicuity and delineation from nontumor tissue and reduced sensitivity to edema compared with high-b-value DWI and ADC. MATERIALS AND METHODS: RSI was performed in 10 presurgical patients: 4 with glioblastoma, 3 with primary CNS lymphoma, and 3 with metastatic brain tumors. Multidirectional DWI data were collected at b = 500, 1500, and 4000 s/mm(2). Quantification of tumor conspicuity, edema conspicuity, and relative sensitivity to edema for RSI-CMs; DWI at b = 4000 (DWI-4000); and ADC were compared in manually drawn VOIs. Receiver operating characteristic curves were used to evaluate the sensitivity and specificity of each method for delineating tumor from normal-appearing WM. RESULTS: Significant TC was seen with both RSI-CMs and DWI-4000, but not ADC. Significant EC was seen with ADC, but not RSI-CMs or DWI-4000. Significantly greater TC was seen with RSI-CMs compared with DWI-4000. Significantly reduced RSE was seen with RSI-CMs compared with both DWI-4000 and ADC. Greater sensitivity and specificity for delineating tumor from normal-appearing WM were seen with RSI-CMs (AUC = 0.91) compared with both DWI-4000 (AUC = 0.77) and ADC (AUC = 0.66). CONCLUSIONS: RSI-CMs offer improved conspicuity and delineation of high-grade primary and metastatic brain tumors and reduced sensitivity to edema compared with high-b-value DWI and ADC.

Cerebral phaeohyphomycosis caused by Bipolaris spicifera after heart transplantation.

Phaeohyphomycosis is an increasingly recognized cause of brain abscess in both immunocompetent and immunocompromised hosts. We report a case of cerebral phaeohyphomycosis in a 55-year-old male heart transplant recipient caused by Bipolaris spicifera. We review the literature regarding the pathogenesis, epidemiology, diagnosis, and management of infections with dematiaceous fungi.

The use of remote sensing in the identification of the eco-environmental factors associated with the risk of human visceral leishmaniasis (kala-azar) on the Gangetic plain, in north-eastern India.

Human visceral leishmaniasis (VL) or kala-azar remains a major cause of mortality, particularly in the developing world. The disease is common in the internal regions of north-eastern India, which have a tropical or sub-tropical climate. In a recent study on VL in this region, the relationship between the incidence of VL and certain physio-environmental factors was explored, using a combination of a geographical information system (GIS), satellite imagery and data collected 'on the ground'. Some eco-environmental parameters were then used to map and describe the spatial heterogeneity seen in the transmission of the parasite (Leishmania donovani) that causes VL in India, and to identify those habitats, on the Gangetic plain, where the sandfly vectors might thrive. It was found that the presence of waterbodies, woodland and urban, built-up areas, soil of the fluvisol type, air temperatures of 25.0-27.5 degrees C, relative humidities of 66%-75%, and an annual rainfall of 100-<160 cm were all positively associated with the incidence of VL. A VL map was created and stratified into areas of 'risk' and 'non-risk' for the disease, based on calculations of risk indices.

Vector density and the control of kala-azar in Bihar, India.

Bihar, India has been in the grip of kala-azar for many years. Its rampant and severe spread has made life miserable in most parts of the state. Such conditions require a comprehensive understanding of this affliction. The numbers coming out of the districts prone to the disease in the north and south Ganges have provided us with several startling revelations, as there are striking uniformities on both sides, including similar vegetation, water storage facilities, house construction and little change in risk factors. The northern areas have been regularly sprayed with DDT since 1977, but eradication of the disease appears to be a distant dream. In 2007 alone, there were as many as 37,738 cases in that region. In contrast, the southern districts of Patna and Nalanda have never had the disease in its epidemic form and endemic disease has been present in only some pockets of the two districts. In those cases, two rounds of spraying with DDT had very positive results, with successful control and no new established foci. In addition, an eleven-year longitudinal study of the man hour density and house index for the vector Phlebotomus argentipes demonstrated that they were quite high in Patna and Nalanda and quite low in north Bihar. Given these facts, an attempt has been made to unravel the role of P. argentipes saliva (salivary gland) in the epidemiology of kala-azar. It was determined that patchy DDT spraying should be avoided for effective control of kala-azar.

Determinants of survival in progressive multifocal leukoencephalopathy.

BACKGROUND: We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML). METHODS: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood. RESULTS: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival. CONCLUSIONS: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.

Vector density and the control of kala-azar in Bihar, India

Bihar, India has been in the grip of kala-azar for many years. Its rampant and severe spread has made life miserable in most parts of the state. Such conditions require a comprehensive understanding of this affliction. The numbers coming out of the districts prone to the disease in the north and south Ganges have provided us with several startling revelations, as there are striking uniformities on both sides, including similar vegetation, water storage facilities, house construction and little change in risk factors. The northern areas have been regularly sprayed with DDT since 1977, but eradication of the disease appears to be a distant dream. In 2007 alone, there were as many as 37,738 cases in that region. In contrast, the southern districts of Patna and Nalanda have never had the disease in its epidemic form and endemic disease has been present in only some pockets of the two districts. In those cases, two rounds of spraying with DDT had very positive results, with successful control and no new established foci. In addition, an eleven-year longitudinal study of the man hour density and house index for the vector Phlebotomus argentipes demonstrated that they were quite high in Patna and Nalanda and quite low in north Bihar. Given these facts, an attempt has been made to unravel the role of P. argentipes saliva (salivary gland) in the epidemiology of kala-azar. It was determined that patchy DDT spraying should be avoided for effective control of kala-azar.

A report on the indoor residual spraying (IRS) in the control of Phlebotomus argentipes, the vector of visceral leishmaniasis in Bihar (India): an initiative towards total elimination targeting 2015 (Series-1).

BACKGROUND & OBJECTIVES: Visceral leishmaniasis, commonly known as kala-azar is endemic in Bihar state, India. Current vector control programme in Bihar focuses mainly on spraying the sandfly infested dwellings with DDT. The Government of India in collaboration with WHO has fixed the target 2015 for total elimination of kala-azar. The present study was carried out to see the impact of DDT and improved IEC in the containment of vector density vis-à-vis disease transmission. METHODS: Before the start of the spraying operations training was imparted to all the medical and paramedical personnel regarding the methods of spraying operations. Pre- and post-sandfly density was monitored in four selected districts. Incidences of kala-azar cases were compared for pre- and post-spray periods. Social acceptability and perceptions of households was collected through questionnaires from 500 randomly selected households in the study districts. RESULTS: House index in three study districts reduced considerably during post-spray when compared to pre-spray. Kala-azar incidence in many districts was reduced after the DDT spray. Either partial or complete refusal was reported in 14.4%, while 35% were not satisfied with the suspension concentration and coverage; and 46.6% were found satisfied with the spraying procedure. INTERPRETATION & CONCLUSION: Strengthening the IEC activities to sensitise the community, proper training of health personnel, monitoring of spray, good surveillance, proper treatment of cases and two rounds of DDT spray with good coverage in the endemic districts up to three years are essential to achieve the desired total elimination of kala-azar in Bihar state.

Emergence periodicity of Phlebotomus argentipes annandale and brunetti (Diptera: psychodidae): A laboratory study.

Phlebotomus argentipes Annandale and Brunetti (Diptera: Psychodidae) is the vector for visceral leishmaniasis in India. The aspects of its biology such as feeding and man vector contact are associated with emergence periodicity of the adult. Hence, the present study was made to find out the actual emergence period of P. argentipes. Wild caught P. argentipes were confined in the rearing pots inside laboratory. The newly emerged adults were collected at hourly intervals and released in to separate polythene bags and were held at 4°C till death. Sand flies were segregated sex-wise after the death under a microscope. The emergence of adult was observed throughout the day. However, the male preferred dawn emergence and the female the dusk. Two peaks of emergence were found in a day; first one in the morning (0900h) and the second one in the evening (1800h). The ratio of both sexes was found to be about equal. The emergence of adult was found to be 77% out of total eggs laid, which was completed within 7-10 days from the 1st day of emergence under laboratory conditions (25°C to 31°C and 70% to 75% relative humidity). This study has important bearings to find out the actual time for personal protection against biting of sand flies to prevent the transmission of Kala-azar.