Efficacy of surface-functionalized Mg1−xCoxFe2O4 (0 ≤ x ≤ 1; Δx = 0.1) for hyperthermia and in vivo MR imaging as a contrast agent

Surface-functionalized Mg_1−xCo_xFe₂O₄ (0 ≤ x ≤ 1; Δx = 0.1) can be an exciting candidate as an MRI contrast agent and for thermotherapeutic applications. The figure-of-merit, T₂, relaxivity, r₂, of MRI and specific loss power, SLP, of hyperthermia depend on the structural and magnetic properties of the nanoparticles. We synthesized cobalt-substituted magnesium ferrite Mg_1−xCo_xFe₂O₄ (0 ≤ x ≤ 1 with Δx = 0.1) nanoparticles using a chemical co-precipitation method. The lattice parameter and average crystallite size increase with the increase in cobalt content. The force-constant of FTIR of the tetrahedral sites increases, and that of the octahedral sites decreases with an increase in cobalt content. The room temperature Mössbauer spectra of Mg_1−xCo_xFe₂O₄ show that the Mössbauer absorption area of the A site decreases, and the Mössbauer absorption area of the B site increases with x. The Mössbauer spectra and M–H hysteresis loops at room temperature confirmed that a transition from fast relaxation (superparamagnetic) to mixed slow/fast (superparamagnetic/ferrimagnetic) relaxation occurs with changing cobalt content. The cobalt ion tends to occupy the octahedral B site, which makes the A–B interaction stronger; therefore, we see the above transition. Cytotoxicity experiments on HeLa cells revealed that both chitosan and chitosan-coated magnesium cobalt ferrite nanoparticles are biocompatible. In the Mg_1−xCo_xFe₂O₄ series, both r₂ and SLP increase with x because of the increase in magnetization and anisotropy.

Surface-functionalized Mg_1−xCo_xFe₂O₄ (0 ≤ x ≤ 1; Δx = 0.1) can be an exciting candidate as an MRI contrast agent and for thermotherapeutic applications.     

Differences in intestinal humoral immunity between healthy volunteers from UK and Bangladesh

BACKGROUND/AIMS: Intestinal morphology has been shown to vary geographically. The impact of this variation on gut mucosal humoral immunity is not well-studied. The technique of peroral whole-gut lavage (WGL) with nonabsorbable cleansing fluid can be utilized for the study of gut immune responses in health and disease. In this study, the WGL technique was employed to compare various gut humoral immune parameters in healthy volunteers from Dhaka in Bangladesh and Edinburgh, UK. METHODS: Eleven healthy individuals (all male, age range 18-32) from Dhaka and 12 healthy individuals (4 male and 8 female, age range 23-48) from Edinburgh underwent WGL with a polyethylene glycol electrolyte-based solution drunk at a rate of 1 l/h. The first clear effluent was collected and processed. An ELISA technique was used to measure total immunoglobulins (A, M and G) and antibodies to bacterial lipopolysaccharide (LPS: endotoxin) ovalbumin and eotaxin. Immunoturbimetry and radioimmunoassy techniques were used to measure protein (albumin and alpha-1 antitrypsin) and eosinophil cationic protein (ECP), respectively, in WGL fluid (WGLF). RESULTS: The total IgA, ECP and eotaxin concentrations in WGLF from the Dhaka group were significantly higher than those of the Edinburgh group (P < 0.03, P < 0.002 and P< 0.005 respectively). The IgA antibody level against the core oligosaccharide of bacterial LPS from several Gram-negative species was significantly higher in the Dhaka group compared to the Edinburgh group (P< 0.0001). Similarly, there was generally higher level of IgA antibody response against the various different LPS core structures of Escherichia coli in the Dhaka group, in particular significantly higher against R1, R3 and R4 LPS cores (P< 0.02, P< 0.03 and P< 0.01 respectively) compared to the Edinburgh group. In contrast to antibacterial antibodies, the IgA and IgM antibodies against ovalbumin were significantly lower in the Dhaka group (P< 0.001 and P< 0.003, respectively) compared to the Edinburgh group. CONCLUSIONS: This study on gut mucosal humoral immunity from two geographically distinct populations suggests that place of residence influences gut mucosal humoral immunity. This difference in stimulation of humoral immunity of the gut might explain different rates of inflammatory bowel diseases in developing and developed countries, and also provides a major challenge for the development of mucosally presented vaccine worldwide.     

Frequency of insulin resistance in nondiabetic adult Bangladeshi individuals of different obesity phenotypes

Insulin resistance (IR) is the corner stone of metabolic obesity. This cross-sectional analytical study was aimed to find out the frequency of IR in non-diabetic adult individuals of different obesity phenotypes that would help to implement preventive measures to avoid the cardiometabolic catastrophes.MethodsTotal 955 nondiabetic adult individuals were selected and categorized into six metabolic phenotypes by metabolic syndrome criteria in each BMI group (18.5–24.9-normal weight, 25-29.9-overweight, ≥30-obese). From them, metabolically obese normal weight, metabolically obese overweight, metabolically healthy obese and metabolically unhealthy obese were selected as Obesity phenotypes (N = 616).ResultsThe frequency of IR was found to be very high (60.2%) in total nondiabetic adult obese individuals (N = 616). Highest frequency of IR was found in MUO phenotype (76.3%), lowest frequency of IR was found in MONW phenotype (37.1%) and frequency of IR in MOOW and MHO phenotypes found to be identical but significantly (p < 0.0001) less than MUO and significantly (p < 0.0001) more than MONW phenotype. Among the obesity phenotypes, females were more insulin resistant than males (67.5% vs 48.1% respectively, p < 0.05). Frequency of IR found significantly (p < 0.05) more in female than male in all obesity phenotypes except in MUO phenotype where males found to show significantly (p < 0.05) higher frequency than females. Frequency of IR was significantly higher in younger (20–39 yrs) age group than 40–60 yrs age group (63.2% vs 53.5% respectively, p < 0.05).ConclusionIR is alarmingly high (60.2%) in nondiabetic adult obese individuals. Among different obesity phenotypes, it is highest (76.3%) in MUO and lowest (37.1%) in MONW.     

Polymorphisms in DNA repair genes and therapeutic outcomes of AML patients from SWOG clinical trials

Repair of damage to DNA resulting from chemotherapy may influence drug toxicity and survival in response to treatment. We evaluated the role of polymorphisms in DNA repair genes APE1, XRCC1, ERCC1, XPD, and XRCC3 in predicting therapeutic outcomes of older adults with acute myeloid leukemia (AML) from 2 Southwest Oncology Group (SWOG) clinical trials. All patients received standard chemotherapy induction regimens. Using logistic and proportional hazards regression models, relationships between genotypes, haplotypes, and toxicities, response to induction therapy, and overall survival were evaluated. Patients with XPD Gln751C/Asp312G ('D') haplotype were more likely to have complete response (OR = 3.06; 95% CI, 1.44-6.70) and less likely to have resistant disease (OR = 0.32; 95%CI, 0.14-0.72) than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung (P = .037) and metabolic (P = .041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (OR = 0.32; 95%CI, 0.11-0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. These data from clinical trials of older patients treated for AML indicate that variants in DNA repair pathways may have an impact on both outcomes of patients and toxicities associated with treatments. With validation of results in larger samples, these findings could lead to optimizing individual chemotherapy options.     

Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters

The objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluated in vitro in (i) P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using an in situ single-pass intestinal perfusion model. [³H]Raltegravir accumulation by MDA-MDR1 (P-gp) and HEK-ABCG2-overexpressing cells was significantly enhanced in the presence of PSC833 {6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporine}, a P-gp inhibitor, or Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], a BCRP inhibitor, suggesting the inhibition of a P-gp- or BCRP-mediated efflux process, respectively. Furthermore, [³H]raltegravir accumulation by human cerebral microvessel endothelial hCMEC/D3 and mouse Sertoli TM4 cells was significantly increased by PSC833 and Ko143. In human intestinal Caco-2 cells grown on Transwell filters, PSC833, but not Ko143, significantly decreased the [³H]raltegravir efflux ratios. In rat intestinal segments, [³H]raltegravir in situ permeability was significantly enhanced by the concurrent administration of PSC833 and Ko143. In contrast, in the transporter inhibition assays, raltegravir (10 to 500 μM) did not increase the accumulation of substrate for P-gp (rhodamine-6G), BCRP ([³H]mitoxantrone), or MRP1 [2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)] by MDA-MDR1 (P-gp)-, HEK-ABCG2-, or HeLa-MRP1-overexpressing cells, respectively. Our data suggest that raltegravir is a substrate but not an inhibitor of the drug efflux transporters P-gp and BCRP. These transporters might play a role in the restriction of raltegravir permeability across the blood-brain, blood-testicular, and blood-intestinal barriers, potentially contributing to its low tissue concentrations and/or low oral bioavailability observed in the clinic setting.     

Expulsion of the gastrointestinal cestode, Hymenolepis diminuta by tolerant rats: evidence for mediation by a Th2 type immune enhanced goblet cell hyperplasia, increased mucin production and secretion

The processes underlying expulsion of Hymenolepis diminuta in rats are not known. Expression levels of mRNAs of several cytokines revealed a Th2 response that differed between worm infection levels. IL-4 protein levels decreased while IL-13 levels increased in a 50-worm infection by 30 dpi; the converse was seen with a five-worm infection. A negative correlation was found between IL-4 or IL-13 mRNA expression and worm biomass, between IL-13 protein levels and worm number or worm biomass, and between IL-4 protein levels and worm biomass in 50-worm infections. A negative correlation between IL-4 mRNA or protein expression and worm biomass was observed with five-worm infections. A strong correlation between Muc2 mRNA expression and decreased worm number or biomass in a 50-worm infection was observed. Muc2 protein, goblet cell numbers and mucin decreased in a 50-worm infection by 20 days post-infection. These changes were not seen with five-worm infections where worms are not expelled. The data show that rats infected with 50 H. diminuta mount a Th2 response leading to high levels of IL-13, increased goblet cell numbers and increased mucin2 production and release. The mucus traps the worms, which are progressively expelled from the small intestine.     

Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia

The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein- negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.     

Evaluation of conventional media for detection of colonization factor antigens of enterotoxigenic Escherichia coli.

Strains of enterotoxigenic Escherichia coli producing either colonization factor antigen (CFA) I or II were tested for expression of CFA when grown on 16 different agar media by using agglutination and coagglutination with monoclonal antibodies, mannose-resistant hemagglutination, and a salt aggregation assay. CFA was detected from the CFA-positive strains when CFA agar was used, and it was also detected when other commercially available media were used, notably nutrient agar. CFA was not detected when other commercial media such as MacConkey agar were used. The use of nutrient agar with monoclonal antibody-based coagglutination reagents offers a potentially simple and rapid method for detecting E. coli which express CFA I or II.     

Dopaminergic modulation of nitric oxide synthase activity in subregions of the rat nucleus accumbens

Nitric oxide (NO) is a gaseous neurotransmitter synthesized in the nucleus accumbens (NAc) by aspiny interneurons containing neuronal NO synthase (nNOS). nNOS activity is readily assayed using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) staining and is believed to be regulated by activation of dopamine (DA) D1- and D2-like receptors. However, the role of DA transmission in the regulation of nNOS activity in identified subregions of the NAc remains unexplored. In this study, the impact of pharmacological manipulations of D1, D2, and NMDA receptors on nNOS activity was determined using optical density measures of NADPH-d staining preformed in multiple subdivisions (core, medial shell, intermediate shell, and lateral shell) of the NAc. Awake behaving rats received systemic administration of vehicle and/or the following drugs ~25 min prior to tissue harvesting: the nNOS inhibitor N(G) -propyl-L-arginine (NPA), the D1 receptor agonist SKF 81297, the D1 receptor antagonist SCH 23390, the D2 receptor agonist quinpirole (QNP), the D2 receptor antagonist eticlopride (ETI), or the NMDA receptor antagonist 3-((±)2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP). In vehicle-treated animals, a distinct medial-lateral histochemical gradient of NADPH-d staining was observed, which was characterized by moderate staining in the core and medial shell and more robust staining in the intermediate and lateral shell. Administration of NPA, SCH 23390, QNP, and CPP attenuated staining preferentially in the intermediate and lateral shell. SKF 81297 and ETI administration consistently increased staining in the medial shell in a manner, which was attenuated following pretreatment with SCH 23390, QNP, NPA, and CPP. These observations demonstrate that nNOS activity measured in distinct subregions of the NAc is differentially modulated by DA D1 and D2 receptor activation. Moreover, these findings demonstrate for the first time that DA D1 and D2 receptor activation regulates the facilitatory influence of glutamatergic transmission on nNOS activity in the NAc medial shell via facilitation (D1) or suppression (D2) of NMDA receptor function.