Source characterization and health risks of BTEX in indoor/outdoor air during winters at a terai precinct of North India.

BTEX are the consistently found air contaminants in indoor and outdoor environments. In order to investigate the exposure levels of BTEX, the indoor and outdoor air was analyzed during winter season at homes located at four selected sites of Gorakhpur, Uttar Pradesh, India, which comprised residential, roadside, industrial and agricultural areas. BTEX were sampled with a low-flow pump (SKC model 220). Samples were extracted with CS2 and the aromatic fraction was subjected to GC-FID. Mean indoor concentration of BTEX was highest at the agricultural (70.9 µg m-3) followed by industrial (30.0 µg m-3), roadside (17.5 µg m-3) and residential site (11.8 µg m-3). At outdoor locations, the mean BTEX levels were highest at the roadside (22.0 µg m-3) followed by industrial (18.7 µg m-3), agricultural (11.0 µg m-3) and residential site (9.1 µg m-3). The I/O ratios were greater than 1 at all the sites except roadside site, where I/O ratios for toluene, ethylbenzene and xylene were less than unity. Poor correlation between indoor and outdoor levels at each site further indicated the dominance of indoor sources. Factor analysis followed by one-way analysis of variance depicts that the presence of BTEX compounds at all the sites indicate a mixture of vehicular and combustion activities. For benzene, the ILTCR values exceeded the safe levels, whereas ethylbenzene was nearby to the recommended level 1 × 10-6. The HQ values were above unity for agricultural (indoors) and industrial (outdoors) as an exception to all the other sites which indicted the value below unity.

Nanoscale Critical Phenomena in a Complex Fluid Studied by X-Ray Photon Correlation Spectroscopy.

The advent of high-speed x-ray photon correlation spectroscopy now allows the study of critical phenomena in fluids to much smaller length scales and over a wider range of temperatures than is possible with dynamic light scattering. We present an x-ray photon correlation spectroscopy study of critical fluctuation dynamics in a complex fluid typical of those used in liquid-liquid extraction (LLE) of ions, dodecane-DMDBTDMA with extracted aqueous Ce(NO_{3})_{3}. We observe good agreement with both static and dynamic scaling without the need for significant noncritical background corrections. Critical exponents agree with 3D Ising values, and the fluctuation dynamics are described by simple exponential relaxation. The form of the dynamic master curve deviates somewhat from the Kawasaki result, with a more abrupt transition between the critical and noncritical asymptotic behavior. The concepts of critical phenomena thus provide a quantitative framework for understanding the structure and dynamics of LLE systems and a path forward to new LLE processes.

Advancing Chemical Separations: Unraveling the Structure and Dynamics of Phase Splitting in Liquid-Liquid Extraction.

Liquid-liquid extraction (LLE), the go-to process for a variety of chemical separations, is limited by spontaneous organic phase splitting upon sufficient solute loading, called third phase formation. In this study we explore the applicability of critical phenomena theory to gain insight into this deleterious phase behavior with the goal of improving separations efficiency and minimizing waste. A series of samples representative of rare earth purification were constructed to include each of one light and one heavy lanthanide (cerium and lutetium) paired with one of two common malonamide extractants (DMDOHEMA and DMDBTDMA). The resulting postextraction organic phases are chemically complex and often form rich hierarchical structures whose statics and dynamics near the critical point were probed herein with small-angle X-ray scattering and high-speed X-ray photon correlation spectroscopy. Despite their different extraction behaviors, all samples show remarkably similar critical behavior with exponents well described by classical critical point theory consistent with the 3D Ising model, where the critical behavior is characterized by fluctuations with a single diverging length scale. This unexpected result indicates a significant reduction in relevant chemical parameters at the critical point, indicating that the underlying behavior of phase transitions in LLE rely on far fewer variables than are generally assumed. The obtained scalar order parameter is attributed to the extractant fraction of the extractant/diluent mixture, revealing that other solution components and their respective concentrations simply shift the critical temperature but do not affect the nature of the critical fluctuations. These findings point to an opportunity to drastically simplify studies of liquid-liquid phase separation and phase diagram development in general while providing insights into LLE process improvement.

Anakinra in hospitalized patients with severe COVID-19 pneumonia requiring oxygen therapy: Results of a prospective, open-label, interventional study.

OBJECTIVE: The aim of this study was to evaluate the efficacy of anakinra in patients who were admitted to hospital for severe COVID-19 pneumonia requiring oxygen therapy. METHODS: A prospective, open-label, interventional study in adults hospitalized with severe COVID-19 pneumonia was conducted. Patients in the interventional arm received subcutaneous anakinra (100 mg twice daily for 3 days, followed by 100 mg daily for 7 days) in addition to standard treatment. Main outcomes were the need for mechanical ventilation and in-hospital death. Secondary outcomes included successful weaning from supplemental oxygen and change in inflammatory biomarkers. Outcomes were compared with those of historical controls who had received standard treatment and supportive care. RESULTS: A total of 69 patients were included: 45 treated with anakinra and 24 historical controls. A need for mechanical ventilation occurred in 14 (31%) of the anakinra-treated group and 18 (75%) of the historical cohort (p < 0.001). In-hospital death occurred in 13 (29%) of the anakinra-treated group and 11 (46%) of the historical cohort (p = 0.082). Successful weaning from supplemental oxygen to ambient air was attained in 25 (63%) of the anakinra-treated group compared with 6 (27%) of the historical cohort (p = 0.008). Patients who received anakinra showed a significant reduction in inflammatory biomarkers. CONCLUSION: In patients with severe COVID-19 pneumonia and high oxygen requirement, anakinra could represent an effective treatment option and may confer clinical benefit. TRIAL REGISTRATION NUMBER: ISRCTN74727214.

Universal dynamics of coarsening during polymer-polymer thin-film spinodal dewetting kinetics.

The dewetting dynamics of a supported bilayer polymer thin film on a solid substrate is investigated using grazing incidence x-ray photon correlation spectroscopy. We find that the top layer dewets via the spinodal mechanism. The kinetics of the dewetting is studied by monitoring the time evolution of the surface diffuse x-ray scattering intensity. We study the time evolution of fluctuations about the average surface structure by measuring the two-time x-ray intensity fluctuation correlation functions. Using these two-time correlation functions we quantify the crossover from early-time diffusive dynamics to hydrodynamics. The early diffusive regime satisfies dynamic universality. The two-time correlation functions also quantify the onset of hydrodynamic effects. The hydrodynamic regime is observed during the spinodal dewetting process as these interactions are not screened.

X-ray magnetic circular dichroism and small angle neutron scattering studies of thiol capped gold nanoparticles.

X-ray magnetic circular dichroism (XMCD) and Small Angle Neutron Scattering (SANS) measurements were performed on thiol capped Au nanoparticles (NPs) embedded into polyethylene. An XMCD signal of 0.8 x 10(-4) was found at the Au L3 edge of thiol capped Au NPs embedded in a polyethylene matrix for which Superconducting Quantum Interference Device (SQUID) magnetometry yielded a saturation magnetization, M(S), of 0.06 emu/g(Au). SANS measurements showed that the 3.2 nm average-diameter nanoparticles are 28% polydispersed, but no detectable SANS magnetic signal was found with the resolution and sensitivity accessible with the neutron experiment. A comparison with previous experiments carried out on Au NPs and multilayers, yield to different values between XMCD signals and magnetization measured by SQUID magnetometer. We discuss the origin of those differences.

Immunotherapeutic effects of mangiferin mediated by the inhibition of oxidative stress to activated lymphocytes, neutrophils and macrophages.

The effect of mangiferin, a naturally occurring xanthone glucoside on cyclophosphamide-induced immunotoxicity and its mode of action in the immune system were investigated. To induce immunotoxicity, adult male Wistar rats were injected weekly with cyclophosphamide intraperitoneally at 100 mg/kg bodyweight. Mangiferin was injected intraperitoneally at 10 and 20 mg/kg daily for 14 days. Levamisole (3 mg/kg, i.p., daily for 14 days), a known immunostimulant that acts in immunosuppressive conditions was used as a standard drug. The effect of mangiferin on the primary immune response to ovalbumin (200 microg/rat, s.c.) was assessed at weekly intervals by measuring the serum ovalbumin-specific IgM levels. The organ weights and cellularity of spleen, thymus and bone marrow, haematology, T and B cell-dependent mitogen stimulation of splenocytes were assessed for the cellular response. Oxidative changes in lymphocytes, neutrophils and macrophages were measured at the end of the study. As well, the in vitro effect of mangiferin on cytotoxicity caused by H2O2 in primary lymphocytes was studied. The decrease in the lymphoid organ weights, cellular responses and antigen-specific IgM levels by cyclophosphamide treatment were significantly increased by repeated intraperitoneal administration of mangiferin. The enhanced lipid peroxidation and decreased catalase and superoxide dismutase activities found in lymphocytes, polymorphonuclear cells (PMN) and macrophages from cyclophosphamide treated rats were significantly ameliorated in mangiferin treated groups. The tissue injury caused by cyclophosphamide treatment was significantly suppressed by mangiferin as shown by the decrease in serum creatine phosphokinase (CPK) activity. In vitro experiments showed that pretreatment of lymphocytes with mangiferin protected from the toxicity induced by H2O2, further confirming the in vivo findings. From this study, it is evident that mangiferin exhibits an immunoprotective role mediated through the inhibition of reactive intermediate-induced oxidative stress in lymphocytes, neutrophils and macrophages.

Philadelphia negative, BCR-ABL positive adult acute lymphoblastic leukemia (ALL) in 2 of 39 patients with combined cytogenetic and molecular analysis.

We performed cytogenetic and molecular analysis of the BCR-ABL rearrangement by polymerase chain reaction (PCR) in 39 consecutive cases of adult acute lymphoblastic leukemia (ALL). Eleven patients had a Philadelphia (Ph) chromosome. Thirteen patients had a BCR-ABL rearrangement, involving minor breakpoint cluster region (m-bcr, situated in intron 1 of the BCR gene) in 11 cases, and major breakpoint cluster region (M-bcr, 'specific' of chronic myeloid leukemia) in the remaining two cases. All of the 12 BCR-ABL cases studied immunologically were of early B, CALLA-positive immunophenotype. The 13 BCR-ABL positive cases included the 11 Ph-positive cases, and two patients with normal karyotype at diagnosis. In the two Ph-negative BCR-positive cases, seven (patient 1) and 18 (patient 2) mitoses had been examined at diagnosis. In patient 1, Ph negativity at diagnosis could certainly be explained by the small number of mitoses analyzed, as a Ph chromosome was found at relapse. This was less probable in patient 2, who raised the issue of whether authentic Ph-negative BCR-ABL-positive ALL exists (as in the chronic myeloid leukemia model) or not. Whatever the explanation, our results suggest that molecular detection of BCR-ABL should be more widely used in B-lineage ALL.

Effect of mangiferin on hyperglycemia and atherogenicity in streptozotocin diabetic rats.

In the present study, the effect of mangiferin (a xanthone glucoside, isolated from the leaves of Mangifera indica) on the atherogenic potential of streptozotocin (STZ)-diabetes was investigated. In addition, the effect of mangiferin on oral glucose tolerance in glucose-loaded normal rats was also determined. The chronic intraperitoneal (i.p.) administration of mangiferin (10 and 20 mg/kg) once daily (o.d.) for 28 days exhibited antidiabetic activity by significantly lowering fasting plasma glucose level at different time intervals in STZ-diabetic rats. Further, mangiferin (10 and 20 mg/kg, i.p.) showed significant antihyperlipidemic and antiatherogenic activities as evidenced by significant decrease in plasma total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) levels coupled together with elevation of high-density lipoprotein cholesterol (HDL-C) level and diminution of atherogenic index in diabetic rats. In addition, the chronic administration of mangiferin (10 and 20 mg/kg, i.p.) for 14 days significantly as well as markedly improved oral glucose tolerance in glucose-loaded normal rats suggesting its potent antihyperglycemic activity. The accumulating evidences suggest that both pancreatic and extrapancreatic mechanisms might be involved in its antidiabetic or antihyperglycemic action. In conclusion, the present study demonstrates that mangiferin possesses significant antidiabetic, antihyperlipidemic and antiatherogenic properties thus suggesting its beneficial effect in the treatment of diabetes mellitus associated with hyperlipidemia and related cardiovascular complications.

Tumor targeting using polyamidoamine dendrimer-cisplatin nanoparticles functionalized with diglycolamic acid and herceptin.

Polymer mediated drug delivery system represents a novel promising platform for tumor-targeting with reduced systemic side effects and improved chemotherapeutical efficacy. In this study, we report the preparation and characterization of herceptin targeted, diglycolamic acid (DGA) functionalized polyamidoamine (PAMAM) dendrimer as a potent drug carrier for cisplatin. DGA dendrimers carrying cisplatin demonstrated enhanced anticancer activity when targeted with herceptin. In vitro cell line studies with herceptin-DGA-G4-cisplatin in HER-2 +ve and HER-2 -ve human ovarian cancer cell lines showed that these nanoparticles possessed remarkable features such as lower IC50 value, improved S-phase arrest, and enhanced apoptosis due to increased cellular uptake and accumulation than the untargeted DGA-G4-cisplatin and free cisplatin. Furthermore, in vivo results in SCID mice bearing SKOV-3 tumor xenografts, herceptin-DGA-G4-cisplatin, appeared to be more effective in inducing tumor regression as compared to free cisplatin. Collectively, these results indicate that herceptin targeted DGA functionalized PAMAM-cisplatin conjugates serve as better anti-tumor agents than individual therapeutic agents.

Mangiferin protects the streptozotocin-induced oxidative damage to cardiac and renal tissues in rats.

The role of oxidative stress in streptozotocin (STZ)-induced toxicity and its prevention by a xanthone glucoside, mangiferin was investigated. To induce diabetes mellitus, adult male Wistar rats were injected STZ intravenously at 55 mg/kg body weight. The effect of mangiferin (10 and 20 mg/kg, i.p., 28 days) was investigated in STZ-induced diabetic male rats. Insulin-treated rats (6 U/kg, i.p., 28 days) served as positive control. Diabetic rats given normal saline served as negative control. Normal rats that neither received STZ nor drugs served as normal control. On day 28, the diabetic rats showed significant increase in serum creatine phosphokinase (CPK) and total glycosylated haemoglobin. Kidney revealed tubular degeneration and decreased levels of superoxide dismutase (SOD) and catalase (CAT) with an elevation of malonaldehyde (MDA). Cardiac SOD, CAT and lipid peroxidation were significantly increased. Histopathological findings revealed cardiac hypertrophy with haemorrhages. Analysis of erythrocyte revealed significantly elevated levels of MDA with insignificant decrease in CAT and SOD. Repeated intraperitoneal injections of mangiferin (10 and 20 mg/kg) and insulin (6 U/kg) controlled STZ-induced lipid peroxidation and significantly protected the animals against cardiac as well as renal damage. From the study, it may be concluded that oxidative stress appears to play a major role in STZ-induced cardiac and renal toxicity as is evident from significant inhibition of antioxidant defence mechanism in renal tissue or a compensatory increase in antioxidant defence mechanism in cardiac tissue. Intraperitoneal administration of mangiferin exhibited significant decrease in glycosylated haemoglobin and CPK levels along with the amelioration of oxidative stress that was comparable to insulin treatment.

Liquid chromatography-tandem mass spectrometric assay with a novel method of quantitation for the simultaneous determination of bulaquine and its metabolite, primaquine, in monkey plasma.

A sensitive and selective liquid chromatography-tandem mass spectrometry method (LC-MS-MS) for the simultaneous estimation of bulaquine and primaquine has been developed and validated in monkey plasma. The mobile phase consisted of acetonitrile/ammonium acetate buffer (20 mM, pH 6) (50:50 v/v) at a flow-rate of 1 ml/min. The chromatographic separations were achieved on two spheri cyano columns (5 microm, 30 x 4.6 mm I.D.) connected in series. The quantitation was carried out using a Micromass LC-MS-MS with an electrospray source in the multiple reaction monitoring (MRM) mode. The analytes were quantified from the summed total ion value of their two most intense molecular transitions. This is another novel method leading to increased sensitivity and precision. A simple liquid-liquid extraction with 2 x 1.0 ml n-hexane/ethyl acetate/dimethyloctyl amine (90:10:0.05, v/v) was utilized. The method was validated in terms of recovery, linearity, accuracy and precision (within- and between-assay variation). The recoveries from spiked control samples were >or=90 and 50% for bulaquine and primaquine, respectively. Linearity in plasma was observed over a dynamic range of 1.56-400 and 3.91-1000 ng/ml for bulaquine and primaquine, respectively.

Impact of massive ascorbic acid supplementation on alcohol induced oxidative stress in guinea pigs.

The effects of a mega dose of ascorbic acid (AA) on alcohol induced peroxidative damages were investigated in guinea pigs. In the present study, four groups of male guinea pigs were maintained for 30 days as follows. (1) Control group (1 mg AA/100 g body wt); (2) Ethanol group (1 mg AA/100 g body wt. + 9 g ethanol/kg body wt); (3) AA group (25 mg AA/100 g body wt); (4) AA + ethanol group (25 mg AA/100 g body wt. + 9 g ethanol/kg). Results revealed that alcohol induced significant lipid peroxidation, since the lipid peroxidation products malondialdehyde (MDA), hydroperoxides and conjugated dienes were elevated. The activities of scavenging enzymes superoxide dismutase (SOD), catalase were reduced. However, supplementation of AA along with alcohol reduced the lipid peroxidation products in the liver and enhanced the activities of scavenging enzymes. Activities of glutathione peroxidase and reductase were also greater in guinea pigs given alcohol + AA in comparison with those given alcohol alone. Administration of ascorbic acid also reduced the activity of gamma-glutamyl transpeptidase (GGT), the marker enzyme of alcohol induced toxicity. The vitamin E level, which was reduced by alcohol intake, was raised by the co-administration of AA and alcohol. These studies suggest that a mega dose of AA helps in the prevention of alcohol induced oxidative stress by enhancing the antioxidant capacity and also by reducing the lipid peroxidation products.

Pharmacokinetics of centchroman in healthy female subjects after oral administration.

The pharmacokinetics of centchroman, a non-steroidal antifertility agent, were assessed in serum of eleven healthy female subjects after a single 30 mg oral dose. Maximum serum concentration (Cmax) of 55.53 (s.d., 15.45) microgram/L was attained at 5.18 (s.d., 1.78) h after oral administration. The concentration-time profile was best described by a two-compartment open model with bi-exponential disposition functions. The mean terminal elimination half-life (t1/2) was 165 (s.d., 49) h with a clearance of 6.17 (s.d., 1.67) L/h and volume of distribution of 1420 (s.d., 478) L. Comparison of the pharmacokinetic parameters of this study with those obtained after a single 60 mg oral dose did not show statistically significant differences in the rate of absorption, distribution and elimination. The Cmax and AUC0-infinity were dose-dependent. Thus, the absorption and disposition of centchroman are of first-order, reproducible and dose-dependent.

Centchroman: a new non-steroidal oral contraceptive in human milk.

Centchroman, a non-steroidal oral contraceptive drug, was given to 13 nursing mothers comprising two groups. Each participant in group I (n = 8) received a single 30 mg dose, and in group II (n = 5) each participant received a 30 mg twice a week dose for twelve weeks. Simultaneous blood and milk samples were collected and analyzed for the parent drug by high performance liquid chromatography. In the single dose study (group I), the mean +/- peak centchroman concentrations in milk and serum were 78.7 +/- 28.4 and 63.6 +/- 23.6 ng/ml with milk-to-serum (M/S) ratio of 1.4 +/- 0.9. There was no significant increase in centchroman concentrations in milk after multiple dosing (group II). However, serum concentrations reached up to 112.5 ng/ml at 6 h after the 13th dose. Average M/S ratios were insignificantly different at trough (prior to next dose) and at peak (4-6 h after dose) centchroman levels. Additionally, the breast milk and serum centchroman concentrations showed a significant correlation (r = 0.64, P < 0.01), indicating that the amount of centchroman excreted into breast milk is dependent on serum concentrations. The weekly dose (% of the maternal dose) of centchroman ingested by the breast-fed infant at peak maternal serum and milk levels was in the range of 0.4 to 11.5%, assuming a weekly milk uptake of 1.05 l/kg. There was no significant difference in the dose ingested by the infants between the two dosing groups. These levels of centchroman passing into breast milk and subsequent exposure to the infants are unlikely to be of any physiological consequence.

Optimization of contraceptive dosage regimen of Centchroman.

Centchroman (Ormeloxifene), a non-steroidal oral contraceptive, is used at a dose of 30 mg once a week. To prevent failures in the beginning of the therapy, it is recommended that a dose of 30 mg twice a week for 12 weeks be administered to build up adequate blood levels. The present study was undertaken to simplify the dosing schedule without sacrificing the purpose of twice a week dosing regimen, using modeling and measurement approaches. The drug was given to 60 female volunteers who were divided into seven groups: group I, 30 mg weekly; group II, 30 mg twice a week; group III, 30 mg twice a week for 12 weeks followed by 30 mg weekly; group IV, 30 mg twice a week for 6 weeks followed by 30 mg weekly; group V, 60 mg weekly; and groups VI and VII, single 60 mg loading dose followed by 30 mg weekly doses. The blood samples were collected and analyzed by HPLC. In group I, mean trough concentrations of centchroman and its active metabolite, 7-desmethyl centchroman, were comparable to the steady-state trough concentrations in groups III, IV, VI, and VII. The metabolite to parent drug ratio remained constant in all the groups. The pharmacokinetic parameters in group VII were comparable to those reported after a single 30 mg dose. Dosage regimen VI was more convenient and provided better pregnancy protection (Pearl index 1.18; unpublished report) than regimen III, which is currently on the market and, thus, could be effectively used for contraception.

Evaluation of interaction potential of certain concurrently administered drugs with pharmacological and pharmacokinetic profile of centchroman in rats.

Centchroman (Ormeloxifene) is a nonsteroidal, selective estrogen receptor modulator, oral contraceptive and anticancer agent, and is intended for long-term use by women. In view of its vast clinical application and the interaction of steroidal oral contraceptives with certain commonly used therapeutic agents, evaluation of interaction of certain concomitantly administered therapeutic agents (ibuprofen, rifampicin, diazepam, salbutamol, nifedipine, paracetamol, haloperidol, and tetracycline), in terms of both the postcoital contraceptive efficacy and pharmacokinetic profile, with centchroman was undertaken in female Sprague-Dawley rats. Among the representatives from each commonly used therapeutic category, interaction (pharmacokinetic) was observed with ibuprofen (60 mg/kg, twice daily), haloperidol (0.7 mg/kg, twice daily), and tetracycline (140 mg/kg, twice daily) coadministration on Days 1 through 5 postcoitum. Of these three therapeutic agents, only tetracycline interfered with the contraceptive efficacy of centchroman. It reduced the bioavailability of centchroman and its active metabolite by increasing their excretion through bile and feces. Increased metabolite excretion on tetracycline coadministration indicates the enterohepatic recirculation of the metabolite, not the parent drug. However, the effect of tetracycline was negated by the inclusion of lactic acid bacillus spores in the regimen.

Liquid chromatographic determination of a non-steroidal oral contraceptive CDRI-85/287 in rat serum.

A precise and sensitive high performance liquid chromatographic (HPLC) assay method was developed and validated for the quantitation of 2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-(2H)-1-benzo(b)pyran (compound CDRI-85/287) in rat serum. This method, applicable to 0.5 ml volumes of serum, was validated according to GLP guidelines. It involved double extraction of serum samples with a mixture of hexane and iso-propanol (98:2 v/v) at alkaline pH and the use of UV detection at 332 nm. Linearity, precision and accuracy were acceptable (5-200 ng ml-1. The absolute recovery was more than 75% and the lower limit of quantitation was 5 ng ml-1. Freeze-thaw stability studies up to four cycles showed no apparent differences in the calculated spiked concentrations. However, in-process stability evaluation showed the stability of the processed samples lasted up to 85 h.