A Simulated Stomach Duodenum Model Predicting the Effect of Fluid Volume and Prandial Gastric Flow Patterns on Nifedipine Pharmacokinetics From Cosolvent-Based Capsules

Nifedipine is a Biopharmaceutics Classification System class II drug displaying large variability in absorption even when administered as immediate-release soft gelatin capsules of a cosolvent formulation. This in vitro study sought to understand the reasons behind variability in nifedipine absorption, how it can be minimized, and if it can be predicted using in vitro models. A dynamic in vitro simulated stomach duodenum model was used to explore drug concentration–time profiles of nifedipine soft gelatin capsules under conditions simulating how patients take their medicines. Specifically, the effect of prandial gastric emptying patterns and fluid volume administration (250 mL vs. 50 mL water) were investigated. Significant supersaturation of nifedipine was observed. While administration of large and small water volumes gave rise to a similar C_max and area under the curve (AUC_∞), the coefficient of variation in AUC was 4.8% and 49%, respectively, which can be attributed to differences in precipitation kinetics. Fasting and fed gastric emptying patterns also gave rise to a similar AUC; however, C_max was significantly lower in the fed state. These trends are consistent with previously published in vivo results in healthy volunteers. The simulated stomach duodenum provides a good discriminative screening tool for predicting trends in drug concentration profiles of Biopharmaceutics Classification System class II drugs.     

Left ventricular rotational deformation changes by speckle tracking imaging before and 24 hours after transcatheter closure of large secundum atrial septal defects in children

Background: Large atrial septal defects (ASDs) in children cause increased volume overload of the right side of the heart which in turn lead to impairment of left ventricular (LV) performance. Aim: The aim of this study was to evaluate immediate LV rotational deformation changes in children with large ASDs post-device closure and removal of right ventricle (RV) volume overload. Patients and Methods: Twenty children who underwent transcatheter closure (TCC) of large secundum ASDs were included in the study. LV rotational deformation was assessed pre- and 24 hours post-device closure using speckle tracking imaging (STI). Results: 55% were females with mean age 6.1 ± 3.5 years. LV peak basal clockwise rotation improved significantly (−6.9 ± 2.6° before vs −10.3 ± 4.1° after TCC, P = .005), and time to peak clockwise rotation (345.1 ± 124.7 milliseconds (ms) before vs 282.2 ± 82.9 ms after closure, P = .02). There was no significant difference in apical rotational parameters including peak counterclockwise rotation (P > .05 for both). LV twist (11.3 ± 3.8° before vs 17.5 ± 7.1° after closure, P = .001) and torsion (2.1 ± 0.7°/cm before vs 3.1 ± 1.2°/cm after closure, P = .01) were significantly improved, mainly as the result of improvement of LV basal rotation. LV revealed a significant increase in LV end-diastolic volumes (P = .02) 24 hour after TCC with no significant change (P > .05) in end-systolic volumes after closure. Conclusion: Increased peak LV twisting and torsion were attributed to the improved peak systolic clockwise basal rotation after TCC of large ASDs in children.     

Effects of macrophage polarization on gold nanoparticle-assisted plasmonic photothermal therapy

Tumor associated macrophages (TAM) are key pathogenic factors in neoplastic diseases. They are known to have plasticity and can polarize into two opposing phenotypes, including the tumoricidal M1 and the protumoral M2 phenotypes with high prevalence of M2-phentoypes in patients with poor prognosis. Strategies for targeting M2-TAM may consequently increase the efficacy of therapeutic strategies for cancer treatment. Gold nanorod-assisted plasmonic photothermal therapy (PPTT) has emerged as a promising treatment for cancer but the effects of macrophage polarization parameters in the performance of this new treatment modality is still unknown. Herein, human monocytic THP-1 cells were polarized into two opposite phenotypic macrophages (M1-TAM and M2-TAM) and their response to PPTT was examined. M2-TAM exhibits a three-fold increase in AuNP uptake compared to M1-TAM. Laser irradiation results in selective killing of pro-tumoral M2-TAM after treatment with AuNPs with limited effects on anti-tumoral M1-TAM. A positive correlation between the expression of CD206 marker and the AuNP uptake may indicate the role of CD206 in facilitating AuNP uptake. Our findings also suggest that the differences in AuNP avidity and uptake between the M1-TAM and M2-TAM phenotypes may be the rationale behind the effectiveness of PPTT in the treatment of solid tumors.

A preferential uptake of gold nanoparticles by macrophages with a protumoral M2 phenotype result in efficient killing upon laser irradiation while keeping M1 phenotypes relatively undamaged.     

Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin

Variations in the gene encoding the novel protein dysbindin-1 (DTNBP1) are among the most commonly reported genetic variations associated with schizophrenia. Recent studies show that those variations are also associated with cognitive functioning in carriers with and without psychiatric diagnoses, suggesting a general role for dysbindin-1 in cognition. Such a role could stem from the protein's known ability to affect neuronal glutamate release. How dysbindin-1 might affect glutamate release nevertheless remains unknown without the discovery of the protein's neuronal binding partners and its subcellular locus of action. We demonstrate here that snapin is a binding partner of dysbindin-1 in vitro and in the brain. Tissue fractionation of whole mouse brains and human hippocampal formations revealed that both dysbindin-1 and snapin are concentrated in tissue enriched in synaptic vesicle membranes and less commonly in postsynaptic densities. It is not detected in presynaptic tissue fractions lacking synaptic vesicles. Consistent with that finding, immunoelectron microscopy showed that dysbindin-1 is located in (i) synaptic vesicles of axospinous terminals in the dentate gyrus inner molecular layer and CA1 stratum radiatum and in (ii) postsynaptic densities and microtubules of dentate hilus neurons and CA1 pyramidal cells. The labeled synapses are often asymmetric with thick postsynaptic densities suggestive of glutamatergic synapses, which are likely to be derived from dentate mossy cells and CA3 pyramidal cells. The function of dysbindin-1 in presynaptic, postsynaptic and microtubule locations may all be related to known functions of snapin.     

Pathogenic potential of Blastocystis hominis in laboratory mice

Blastocystis hominis is a ubiquitous enteric protozoan whose pathogenic potential is still controversial. This study was carried out to clarify the pathogenecity of B. hominis infection and to study the proper number of parasites for mice infection. A total of 15 albino mice were orally inoculated with B. hominis and divided according to the inoculums, 10², 10⁵, and 4 × 10⁷ B. hominis forms/100 μl saline, into three groups consisting of five mice each, GI, GII GIII, respectively. In addition with group IV (uninfected control) consisting of five mice. All mice were sacrificed 2 weeks post-infection. The results revealed that all mice of GIII and two mice of GII got the infection while all mice of GI showed a completely negative result. Histopathological examination of large intestine on highly infected group (GIII) showed that B. hominis infiltrated the lamina propria, the submucosa, and the muscle layers in the form of collection of vacuolar forms. This was accompanied by active colitis with infiltration of mixed inflammatory cells. In conclusion, this study revealed that large number of B. hominis is essential for oral infection of mice and that vacuolar forms of B. hominis can invade the lamina propria, the submucosa, and even the muscle layers.     

Genetic polymorphism of glutathione S-transferases M1 and T1 in Egyptian patients with bilharzial bladder cancer

ObjectiveTo assess the influence of glutathione S-transferases M1 and T1 (GSTM1 and T1) genotype on the risk of bladder cancer in patients with urinary bilharziasis.Materials and methodsThis study was designed as a case-control study that involved 60 individuals who were enrolled into 3 equal groups. The first one included patients with bilharzial bladder cancer, the second one had those with nonmalignant urinary bilharziasis, and the last one was the control group. All of the participants were adult males, nonsmokers, and with matched ages. All of them underwent an assessment of the serum level of the total GST concentration and the polymerase chain reaction (PCR) was used for determination of the GSTM1 and T1 genotypes.ResultsThe lower most GST enzyme concentration was reported in patients with bilharzial bladder cancer (26 ± 4.4 ng/ml) with significant difference between it and that of the second group (36.8 ± 4.1 ng/ml, P < 0.05) and that of the controls (40.4 ± 4 ng/ml, P < 0.005). The PCR results have demonstrated that the frequency of combined GSTM1 and T1 genes deletion (M1–ve T1–ve) was significantly higher in cases of bladder cancer (40%) than those of the controls (5%, P < 0.005) and those of the second group (10%, P < 0.05). The unconditional logistic regression test revealed that patients with urinary bilharziasis and combined GSTM1 and T1 genes deletion are at a significant risk for malignant transformation (OR = 6.3, P < 0.05).ConclusionsPatients with urinary bilharziasis and GSTM1–ve and T1–ve genes might be at increased risk of bladder cancer. However, larger studies are needed for confirmation of these results.