Protective role of hydroxysteroid sulfotransferase in lithocholic acid—in—duced liver toxicity

Supplement of 1% lithocholic acid (LCA) in the diet for 5-9d resulted in elevated levels of the marker for liver damage AST and ALP activities in both FXR-null and wild-type female mice.The levels were clearly higher in wild-type mice than in FXR-null mice,in spite of the diminished expression of a bile salt export pump(Bsep) in the latter.Consistent with liver toxicity marker activities,serum and liver levels of bile acide,particularly LCA and tauro LCA,were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement.Marked increases in hepatic sulfating activity for LCA(5.5-fold) and hydroxysteroid sulfotransferase St2a(5.8-fold) were detected in liver of FXR-null mice.Liver St2a content was inversely correlated with levels of ALP.In contrast,microsomal LCA 6-hydroxylation was not increased and in fact lower in FXR-null mice compared in wild-type mice.Clear decreases in mRNA encoding Ntcp,Oatpl and Lst-1 transporters function in bild acid import were detected in LCA fed mice.These transporter levels are higher in FXR-null mice than in wild-type mice after 1% LCA supplement.No obvious changes were detected in the Mrp2,Mrp3 and Mrp4 mRNAs.These results indicate that hydroxysteroid sulfotransferase is reuired for protection against LCA-induced liver damage.     

Micelles of Different Morphologies—Advantages of Worm-like Filomicelles of PEO-PCL in Paclitaxel Delivery

Purpose

Worm-like and spherical micelles are both prepared here from the same amphiphilic diblock copolymer, poly(ethylene oxide)-b-poly (ε-caprolactone) (PEO [5 kDa]–PCL [6.5 kDa]) in order to compare loading and delivery of hydrophobic drugs.

Materials and Methods

Worm-like micelles of this degradable copolymer are nanometers in cross-section and spontaneously assemble to stable lengths of microns, resembling filoviruses in some respects and thus suggesting the moniker ‘filomicelles’. The highly flexible worm-like micelles can also be sonicated to generate kinetically stable spherical micelles composed of the same copolymer.

Results

The fission process exploits the finding that the PCL cores are fluid, rather than glassy or crystalline, and core-loading of the hydrophobic anticancer drug delivery, paclitaxel (TAX) shows that the worm-like micelles load and solubilize twice as much drug as spherical micelles. In cytotoxicity tests that compare to the clinically prevalent solubilizer, Cremophor^® EL, both micellar carriers are far less toxic, and both types of TAX-loaded micelles also show fivefold greater anticancer activity on A549 human lung cancer cells.

Conclusion

PEO–PCL based worm-like filomicelles appear to be promising pharmaceutical nanocarriers with improved solubilization efficiency and comparable stability to spherical micelles, as well as better safety and efficacy in vitro compared to the prevalent Cremophor^® EL TAX formulation.

     

Role of the Protease—activated Receptor—1 in Crescentic Glomerulonephritis

Objective Fibrin deposition combined with glomerular epithelial cell proliferation and monocyte/macrophage infiltration is involved in the pathogenesis of crescentic glomerulonephritis and results from local thrombin generation.In addition to its effect on procoagulation and fibrinolysis,thrombin exerts many cellular effects through a functional thrombin receptor,protease-activated receptor-1(PAR-1).The paper is To determine the role of PAR-1 in the pathogenesis of crescentic glomerulonephritis.Methods wild type and PAR-1 knockout mice in an accelerated model of anti-glomerular basement menbrane antibody nephritis were studied.Results The wild type mice exhibited severe glomerular injury 10 days after injection of sheep anti-mouse glomerular besement membrane antibody,such as thrombus formation,extracapillary proiferation as well as renal failure.APR-1 knockout mice showed significant protection from crescentic glomerulonephritis.Conclusion PAR-1 plays a critical role in the pathogenesis of crescentic glomerulonephritis and may be a new target for therapeutic intervention.     

Plasma levels and β-blocking effect of α-hydroxymetoprolol—Metabolite of metoprolol—in the dog

The plasma levels and the - blocking effect of metoprolol and its active metabolite - hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the - blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of - blockade. Because of differences in the volume of distribution, 2.0 liters/kg for - OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of - OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. - OH-Metoprolol was more slowly eliminated (t_1/27.0 hr, total body clearance 3.5 ml-kg^–1-min^–1) than metoprolol (t_1/22.0 hr, total body clearance 20.0 ml-kg^–1-min^–1). Approximately 5% of an i.v. dose of metoprolol was metabolized to - OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.     

Structure in Dehydrated Trehalose Dihydrate—Evaluation of the Concept of Partial Crystallinity

Purpose (i) To use trehalose as a model compound to evaluate the concept of crystallinity in pharmaceuticals. (ii) To understand the structural nature of dehydrated trehalose dihydrate.Materials and Methods Trehalose dihydrate was dehydrated isothermally at several temperatures below 100°C and the anhydrous product was characterized by XRD, DSC and water vapor sorption.Results XRD and DSC suggested that the dehydration product was a partially crystalline α-polymorphic form of anhydrous trehalose . An increase in the temperature of dehydration resulted in a decrease in lattice order. In agreement with earlier findings, the ordered regions in the dehydrated lattice converted to the dihydrate at much lower RH values than amorphous trehalose. However, the lattice order in the dehydrated product dictated the RH at which this conversion was initiated—the higher the lattice order the lower this RH. The structural nature of these samples can be explained based on the one-state model of crystallinity. In dehydrated trehalose, there is a continuum in lattice order ranging from highly crystalline to a completely disordered (i.e., amorphous) state.Conclusion The extent of lattice order in anhydrous trehalose was dictated by the kinetics of water removal from trehalose dihydrate. The partially crystalline nature of anhydrous trehalose produced by dehydration could be described on a continuous scale of lattice order based on the one-state model of crystallinity.     

Prevalence of hypothyroidism in Finland—a nationwide prescription study

Purpose  

The aim of this study was to estimate the 1-year prevalence of levothyroxine-treated hypothyroidism in Finland.     

Ecotoxicology of polychlorinated biphenyls in fish—a critical review

Polychlorinated biphenyls (PCBs) are widespread persistent anthropogenic contaminants that can accumulate in tissues of fish. The toxicity of PCBs and their transformation products has been investigated for nearly 50 years, but there is a lack of consensus regarding the effects of these environmental contaminants on wild fish populations. The objective of this review is to critically examine these investigations and evaluate publicly available databases for evidence of effects of PCBs in wild fish. Biological activity of PCBs is limited to a small proportion of PCB congeners [e.g., dioxin-like PCBs (DL-PCBs)] and occurs at concentrations that are typically orders of magnitude higher than PCB levels detected in wild fish. Induction of biomarkers consistent with PCB exposure (e.g., induction of cytochrome P450 monooxygenase system) has been evaluated frequently and shown to be induced in fish from some environments, but there does not appear to be consistent reports of damage (i.e., biomarkers of effect) to biomolecules (i.e., oxidative injury) in these fish. Numerous investigations of endocrine system dysfunction or effects on other organ systems have been conducted in wild fish, but collectively there is no consistent evidence of PCB effects on these systems in wild fish. Early life stage toxicity of DL-PCBs does not appear to occur at concentrations reported in wild fish embryos, and results do not support an association between PCBs and decreased survival of early life stages of wild fish. Overall, there appears to be little evidence that PCBs have had any widespread effect on the health or survival of wild fish.     

Exploring Botanicals in Indian System of Medicine—Regulatory Perspectives

Abstract

India has a rich heritage of traditional medicine constituting with its different components like Ayurveda, Siddha and Unani and traditional health care has been flourishing in this country for many centuries. Botanicals constitute of major part of these traditional medicines. With the emerging world wide interest, in adopting traditional practices, in the health care systems by exploiting their potential, the evaluation of the botanicals in these systems of medicine in India is utmost essential. Various regulations and control on use of botanicals has come up with their use in traditional medicine which will not only help to cure different ailments through indigenous resources but also will help in screening and evaluation of the natural resource in a better way to use them in traditional health care program.     

Selected risk factors of fractures in children — own observation

Bone fractures may depend on Vitamin D Receptor Gene (VDR), bone mineral density, bone turnover markers. Patients and methods. 161 patients were recruited and underwent: skeletal densitometry (DXA) method and bone turnover studies (Osteocalcin and Ntx).The study group was evaluated using restriction enzyme digestion at BsmI (rs1544410), FokI (rs2228570), ApaI (rs7975232) and TaqI (rs731236), polymorphic sites of the VDR gene. Multivariate logistic regression was used to assess factor significance. The model included variables with sex- and age-standardized parameters, VDR genotypes, and bone metabolism marker levels. Results. Factors associated with fractures were: osteocalcin concentration and Z-score BMDt. Odds Ratio (OR) values equaled: 1.01 (95%Confidence Interval (95%CI) 1.00–1.02) for osteocalcin (p=0.006), and 0.66 (95%CI 0.42-1.03; p=0.07) for Z-score BMDt. In patients with reduced bone mass, factors related to fractures were: osteocalcin (0.04) and carriage of BsmI b (0.07) or ApaI a alleles (0.08). ORs were 1.01 (95%CI 1.00–1.02) for OC, 0.29 (95%CI 0.07–1.14) for BsmI, and 2.13 (95%CI 0.91–4.99) for ApaI polymorphic allele carriage. Conclusions. Carriage of BsmI b allele reduces, while carriage of ApaI a allele and heightened osteoclacin level increase the risk of fractures in study children with reduced bone mass. VDR polymorphism, bone mineral density and bone formation’s marker — osteocalcin maybe considered as risk factor for fracure in children from Lodz region.     

The prospects of brain — computer interface applications in children

The restoring of motor functions in adults through brain-computer interface applications is widely studied in the contemporary literature. But there is a lack of similar analyses and research on the application of brain-computer interfaces in the neurorehabilitation of children. There is a need for expanded knowledge in the aforementioned area. This article aims at investigating the extent to which the available opportunities in the area of neurorehabilitation and neurological physiotherapy of children with severe neurological deficits using brain-computer interfaces are being applied, including our own concepts, research and observations.     

Assessment of Fungal Contamination in Waste Sorting and Incineration—Case Study in Portugal

Organic waste is a rich substrate for microbial growth, and because of that, workers from waste industry are at higher risk of exposure to bioaerosols. This study aimed to assess fungal contamination in two plants handling solid waste management. Air samples from the two plants were collected through an impaction method. Surface samples were also collected by swabbing surfaces of the same indoor sites. All collected samples were incubated at 27°C for 5 to 7 d. After lab processing and incubation of collected samples, quantitative and qualitative results were obtained with identification of the isolated fungal species. Air samples were also subjected to molecular methods by real-time polymerase chain reaction (RT PCR) using an impinger method to measure DNA of Aspergillus flavus complex and Stachybotrys chartarum. Assessment of particulate matter (PM) was also conducted with portable direct-reading equipment. Particles concentration measurement was performed at five different sizes (PM_0.5; PM₁; PM_2.5; PM₅; PM₁₀). With respect to the waste sorting plant, three species more frequently isolated in air and surfaces were A. niger (73.9%; 66.1%), A. fumigatus (16%; 13.8%), and A. flavus (8.7%; 14.2%). In the incineration plant, the most prevalent species detected in air samples were Penicillium sp. (62.9%), A. fumigatus (18%), and A. flavus (6%), while the most frequently isolated in surface samples were Penicillium sp. (57.5%), A. fumigatus (22.3%) and A. niger (12.8%). Stachybotrys chartarum and other toxinogenic strains from A. flavus complex were not detected. The most common PM sizes obtained were the PM₁₀ and PM₅ (inhalable fraction). Since waste is the main internal fungal source in the analyzed settings, preventive and protective measures need to be maintained to avoid worker exposure to fungi and their metabolites.     

Efficacy of preoperative embolization in management of carotid body tumours — a pilot study

Henoch The aim of the study was to evaluate the efficacy of preoperative embolization in the management of carotid body tumours. Of the 15 patients admitted to the Department of Vascular Surgery (General Surgery Unit II), Christian Medical College, Vellore, from January 1^st 2002 to December 31^st 2006 for management of carotid body tumours, 4 patients underwent preoperative embolization and were grouped together. Of the remaining 9 patients who underwent surgical excision, there were 5 with comparable tumour size and these were grouped together into the control group. Surgical outcome of both the groups were compared in terms of operating time, intraoperative blood loss, nerve injury, postoperative morbidity and mortality. There was statistically significant reduction in blood loss and duration of surgery in patients who underwent preoperative embolization. In conclusion, the preoperative embolization is effective in the management of Shamblin type III carotid body tumours.     

Altered distribution of digoxin in renal failure—a cause of digoxin toxicity?

1 Three cases are described in which renal failure was accompanied by a lowered apparent volume of distribution of digoxin. In two cases this resulted in frank digoxin toxicity and in one equivocal toxicity. In all three cases digoxin plasma levels were greater than 2 ng/ml.

2 The possible causes of the abnormal distribution of digoxin in renal failure are discussed.

3 Recommendations are outlined for the use of digoxin in patients with renal failure aimed at circumventing the problem raised by a lowered apparent volume of distribution of the drug.

     

Influence of Processing Conditions on the Physical State of Mannitol—Implications in Freeze-Drying

Purpose To study the effect of processing conditions on the physical state of mannitol during various stages of the lyophilization cycle of a protein formulation. Materials and Methods Mannitol and trehalose were used as the bulking agent and lyoprotectant, respectively. The physical state of mannitol during various stages of freeze-drying cycle, in the absence and presence of a model protein, was characterized using low temperature X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC). Results Mannitol did not crystallize even when the solution for lyophilization was cooled to −45°C at a slow cooling rate of 1°C/min. Annealing facilitated mannitol crystallization, and in the absence of the protein, a mixture of δ-mannitol and mannitol hemihydrate was obtained at both low (−18°C) and high (−8°C) annealing temperatures. However, in the presence of protein, the high annealing temperature promoted δ-mannitol crystallization and inhibited formation of mannitol hemihydrate, while the low annealing temperature facilitated the formation of mannitol hemihydrate. Interestingly, the hemihydrate in the frozen solution was retained in the final lyophile, even when the primary and secondary drying temperatures were as high as −5 and 65°C, respectively. Conclusions The presence of protein as well as the processing conditions (annealing temperature and time, primary and secondary drying temperatures) influenced the physical form of mannitol in the final lyophile. The protein promoted formation of δ-mannitol while inhibiting the formation of mannitol hemihydrate. Since the physical form of mannitol was greatly influenced by the presence of protein, it will be prudent to conduct the preliminary lyophilization cycle development studies in the presence of the protein. If mannitol hemihydrate is formed during annealing, its dehydration may require high secondary drying temperature.