Simulation of gold nanoparticle movement through normal and cancer cell membranes.

Gold nanoparticles (Au-NPs) have been used for a long time to target cancer cells. Different modalities have been suggested to utilize Au-NPs in cancer patients. We construct both normal and cancer cell membranes to simulate the Au-NP entry to understand better how it can penetrate the cancer cell membrane. We use molecular dynamics simulation (MDS) on both normal and cancer cell membrane models for 150 ns. At the same time, we prepared the Au-NP of spherical shape (16 nm radius) capped with citrate using MDS for 100 ns. Finally, we added the Au-NP close to the membranes and moved it using 1000 kJ mol-1 nm-1 force constant during the 7.7 ns MDS run. We analyzed the membranes in the presence and absence of the Au-NP and compared normal and cancer membranes. The results show that normal cell membranes have higher stability than cancer membranes. Additionally, Au-NP forms pore in the membranes that facilitate water and ions entry during the movement inside the lipid bilayer region. These pores are responsible for the enhanced response of Au-NP-loaded chemotherapeutic agents in cancer treatment.

An insight into synthesis and antitumor activity of citrate and gallate stabilizing gold nanospheres.

Both gallic and citrate are well-established antioxidants that show promise as new selective anti-cancer drugs. Gold nanoparticles (AuNPs) as well can be developed as flexible and nontoxic nano-carriers for anti-cancer drugs. This article evaluating the efficiency and biocompatibility of gallic acid and citrate capping gold nanoparticles to be used as anti-cancer drug. The biosafety and therapeutic efficiency of prepared nano-formulations were tested on Hela and normal BHK cell line. Gold nanospheres coated with citrate and gallate were synthesized via wet chemical reduction method. The prepared nano-formulations, citrate and gallate coated gold nanospheres (Cit-AuNPs and Ga-AuNPs), were characterized with respect to their morphology, FTIR spectra, and physical properties. In addition, to assess their cytotoxicity, cell cycle arrest and flow cytometry to measure biological response were performed. Cit-Au NPs and Ga-Au NPs were shown to significantly reduce the viability of Hela cancer cells. Both G0/G cell cycle arrest and comet assay results showed that genotoxic effect was induced in Hela cells by Cit-Au NPs and Ga-Au NPs. The results of this study showed that Cit-Au NPs and Ga-AuNPs inhibit the growth of metastatic cervical cancer cells, which could have therapeutic implications.

Quality of Life of Patients With Hidradenitis Suppurativa in Jeddah, Saudi Arabia.

Background  Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects the apocrine gland-bearing areas of the body. It initially presents as painful nodules that eventually develop into abscesses, draining sinuses, and scarring. These manifestations have physical and psychological impacts, which lead to poor quality of life. This study examined the association between quality of life and disease severity, as well as identified the areas of the body most affected by HS among patients in Saudi Arabia. Methods This cross-sectional study examined patients with HS who were seen at two dermatology outpatient clinics between December 2018 and March 2019. The patients completed a self-administered standardized questionnaire on the Dermatology Life Quality Index (DLQI). Results The average DLQI score was 15.39 ± 8.37. The majority of patients were classified as stage 3, which indicated that HS has a very large effect on quality of life. The right and left axillae were the most commonly affected areas of the body, with 80.6% of patients noting involvement. While the mean DLQI score was higher in males compared to females, there was no significant difference between the two groups (16.44 ± 9.01 vs. 13.08 ± 6.65; P = 0.248). Conclusion HS caused significant impairment in the quality of life of patients with HS in Saudi Arabia. The mean DLQI score in our study was higher than the score previously reported in the literature. Further studies may identify opportunities to provide additional awareness, care, and support for patients with HS in Saudi Arabia.

Neuroprotective effects of edaravone, a free radical scavenger, on the rat hippocampus after pilocarpine-induced status epilepticus.

PURPOSE: Edaravone (MCI-186) is a newly developed antioxidative radical scavenger for the treatment of acute cerebral infarction, exerting neuroprotective effects against ischemic insult. The neuroprotective effects of edaravone on pilocarpine-induced seizures in rats were investigated. METHODS: Rats were treated intraperitoneally with saline or edaravone (1-30 mg/kg), applied 30 min before pilocarpine hydrochloride (330 mg/kg). The onset of status epilepticus (SE) and mortality were recorded for a period of at least 3 days. The cell loss and immunoreactivities of nitric oxide synthase (NOS) in the hippocampus from control and the day 3 rats after SE, treated with saline or edaravone, were evaluated. RESULTS: Edaravone (1mg/kg) significantly prevented cell loss in the hippocampus after SE while easier inducing SE. The higher dose of drug could not induce SE significantly but tended to increase the rate of mortality. Inducible NOS (iNOS) expression was significantly decreased in the hippocampus from day 3 rats treated with 1mg/kg edaravone, compared with saline group, while neuronal NOS (nNOS) and iNOS significantly increased in the hippocampus treated with saline, compared with control group. Significant alteration of endothelial NOS (eNOS) expression in the hippocampus among control group, saline group, and edaravone group was not shown. CONCLUSIONS: Edaravone may act as a neuroprotector for the hippocampus after SE by reducing at least iNOS although the low dose of drug easier induces SE because of preventing an endogenous antiepileptic effect of NO.

Fistulotomy with or without marsupialisation of wound edges in treatment of simple anal fistula: a randomised controlled trial.

BACKGROUND: Promotion of healing of the anal wound after fistulotomy may help accelerate recovery and return to work. The present study aimed to assess the effect of marsupialisation of the edges of the laid open fistula track on wound healing after anal fistulotomy for simple anal fistula. METHODS: This was a prospective randomised trial on patients with simple anal fistula. Patients were randomly assigned to one of two groups; group I underwent anal fistulotomy and group II underwent anal fistulotomy and marsupialisation of the edges of the laid open track. Outcomes of the study were time to achieve complete wound healing, operation time, postoperative pain and complications. RESULTS: Sixty patients of mean age of 40.8 years with simple anal fistula were randomly divided into two equal groups. No significant differences between the two groups regarding operation time (16.8 vs 18.4 minutes; P = 0.054), postoperative pain score (1.6 vs 1.2; P = 0.22), and complication rates were recorded. Group II achieved complete healing in a significantly shorter duration than group I (5.1 vs 6.7 weeks; P < 0.0001). CONCLUSION: Marsupialisation of the edges of the laid open fistula track after fistulotomy resulted in quicker wound healing with similar complication and recurrence rates to lay open fistulotomy alone.

Verification of the pure alanine in PMMA tube dosimeter applicability for dosimetry of radiotherapy photon beams: a feasibility study.

Alanine dosimeters in the form of pure alanine powder in PMMA plastic tubes were investigated for dosimetry in a clinical application. Electron paramagnetic resonance (EPR) spectroscopy was used to measure absorbed radiation doses by detection of signals from radicals generated in irradiated alanine. The measurements were performed for low-dose ranges typical for single-fraction doses often used in external photon beam radiotherapy. First, the dosimeters were irradiated in a solid water phantom to establish calibration curves in the dose range from 0.3 to 3 Gy for 6 and 18 MV X-ray beams from a clinical linear accelerator. Next, the dosimeters were placed at various locations in an anthropomorphic pelvic phantom to measure the dose delivery of a conventional four-field box technique treatment plan to the pelvis. Finally, the doses measured with alanine dosimeters were compared against the doses calculated with a commercial treatment planning system (TPS). The results showed that the alanine dosimeters have a highly sensitive dose response with good linearity and no energy dependence in the dose range and photon beams used in this work. Also, a fairly good agreement was found between the in-phantom dose measurements with alanine dosimeters and the TPS dose calculations. The mean value of the ratios of measured to calculated dose values was found to be near unity. The measured points in the in-field region passed dose-difference acceptance criterion of 3% and those in the penumbral region passed distance-to-agreement acceptance criterion of 3 mm. These findings suggest that the pure alanine powder in PMMA tube dosimeter is a suitable option for dosimetry of radiotherapy photon beams.

Functional changes of aorta with massive accumulation of calcium.

The present study was undertaken to elucidate pathophysiological changes and functional alterations of the calcified artery. For this purpose, rats were treated with 500,000 units/kg vitamin D3, and tension development of isolated rat aortae was examined. Treatment of rats with vitamin D3 resulted in an increase (approx. 64-fold) in the tissue calcium. Light microscopic examination of the aorta after staining with hematoxylin-eosin and von Kossa indicated numerous plaques in the aortic media. The results indicate a massive accumulation of calcium in the aortic media. Responsiveness of the calcified tissue to norepinephrine, epinephrine, serotonin, prostaglandin F2 alpha was found to be 11-66% when compared to that of the control. Furthermore, the calcified tissue responded minimally to isoproterenol and acetylcholine, which elicited a relaxation in control aortae. Isoproterenol-induced relaxation of the calcified aorta after 100 mM KCl contracture was also diminished. In the present study we have demonstrated poor responsiveness of the calcified aorta to physiological and pharmacological substances relative to normal tissue, which implies a functional damage of the artery upon massive calcium accumulation.

Expression of the functional D-glucose transport system in Xenopus oocytes injected with mRNA of rat small intestine.

mRNA prepared from rat small intestine was injected into Xenopus oocytes. The injected oocytes showed a clear electrical response to D-glucose (Glu) in the form of membrane depolarization and conductance increase, while none was shown to D-fructose. The membrane electrical response of the injected oocytes evoked by Glu followed the Michaelis-Menten type kinetics and was dependent on the membrane potential of the oocyte. Replacing the Na+ of the bathing buffer with choline+ resulted in no response to Glu. Thus, a Glu transport system coupled to a Na+ gradient was expressed in Xenopus oocytes by injecting mRNA from rat small intestine.

Induction of muscarinic acetylcholine, serotonin and substance P receptors in Xenopus oocytes injected with mRNA prepared from the small intestine of rats.

Serotonin and muscarinic acetylcholine (ACh) receptors were clearly induced in Xenopus oocyte injected with mRNA prepared from the small intestines of rats. Their response to ACh and serotonin was composed of 4 distinct components: fast and slow depolarization, slow hyperpolarization and large membrane potential fluctuation. About three-quarters of the injected oocytes responded to substance P. The response of the injected oocytes to substance P was transient and decayed even in the presence of substance P, indicating the presence of desensitization. However, the injected oocytes showed no response to 6 other drugs analyzed: adrenaline, noradrenaline, dopamine, gamma-aminobutyric acid, glycine and glutamate.

Characterization of chitosan acetate as a binder for sustained release tablets.

A chitosan derivative as an acetate salt was successfully prepared by using a spray drying technique. Physicochemical characteristics and micromeritic properties of spray-dried chitosan acetate (SD-CSA) were studied as well as drug-polymer and excipient-polymer interaction. SD-CSA was spherical agglomerates with rough surface and less than 75 microm in diameter. The salt was an amorphous solid with slight to moderate hygroscopicity. The results of Fourier transform infrared (FTIR) and solid-state (13)C NMR spectroscopy demonstrated the functional groups of an acetate salt in its molecular structure. DSC and TGA thermograms of SD-CSA as well as FTIR and NMR spectrum of the salt, heated at 120 degrees C for 12 h, revealed the evidence of the conversion of chitosan acetate molecular structure to N-acetylglucosamine at higher temperature. No interaction of SD-CSA with either drugs (salicylic acid and theophylline) or selected pharmaceutical excipients were observed in the study using DSC method. As a wet granulation binder, SD-CSA gave theophylline granules with good flowability (according to the value of angle of repose, Carr's index, and Hausner ratio) and an excellent compressibility profile comparable to a pharmaceutical binder, PVP K30. In vitro release study of theophylline from the tablets containing 3% w/w SD-CSA as a binder demonstrated sustained drug release in all media. Cumulative drug released in 0.1 N HCl, pH 6.8 phosphate buffer and distilled water was nearly 100% within 6, 16 and 24 h, respectively. It was suggested that the simple incorporation of spray-dried chitosan acetate as a tablet binder could give rise to controlled drug delivery systems exhibiting sustained drug release.

[A trial of selective imaging for the breast mass shadow by computed radiography].

CR has ability to make many kinds of images by several imaging processings. Especially, gradation processing is more important than frequency processing to make images in CR mammography. We developed new method to image breast masses selectively with new gradation processing and tried it for 18 patients over sixty years old with breast cancer. All of breast mass shadows were separated selectively from other parenchymal shadow. So, we conclude that the auto-recognition of breast mass shadow can be possible in near future in CR system.

[A study of image processing in CR mammography; gradation processing].

CR image is made by several kinds of image processing. Gradation processing is most important to make images among them and its type can be decided by the kinds of x-ray examinations. 1.2 G gradation processing is generally recommended for CR-mammography by the CR maker, but it has not been fully studied that whether 1.2G was the ideal one or not to image masses and/or calcifications. So, we compared the image obtained by 1.2G gradation processing with one by 1.0 d gradation processing that we made about imaging sensitivity of them in 18 cases with breast cancer. 15 out of 18 cases had good mass images and all of 6 cases showed good calcified images in the latter condition due to its high declination ( = gamma). So, we have concluded that 1.0 d gradation processing was better than 1.2G in CR-mammography.

Use of spray-dried chitosan acetate and ethylcellulose as compression coats for colonic drug delivery: effect of swelling on triggering in vitro drug release.

Spray-dried chitosan acetate (CSA) and ethylcellulose (EC) were used as new compression coats for 5-aminosalicylic acid tablets. Constrained axial or radial swelling of pure CSA and EC/CSA tablets in 0.1 N HCl (stage I), Tris-HCl, pH 6.8 (stage II), and acetate buffer, pH 5.0 (stage III), was investigated. Factors affecting in vitro drug release, i.e., % weight ratios of coating polymers, dip speeds of dissolution apparatus or pH of medium or colonic enzyme (beta-glucosidase) in stage III, and use of a super disintegrant in core tablets, were evaluated. Swollen CSA gel dissolved at lower pH and became less soluble at higher pH. The mechanism of swelling was Fickian diffusion fitting well into both Higuchi's and Korsmeyer-Peppas models. EC:CSA, at 87.5:12.5% weight ratio, provided lag time rendering the tablets to reach stage III (simulated colonic fluid of patients), and the drug was released over 90% within 12 h. The system was a dual time- and pH-control due to the insolubility of EC suppressing water diffusion and the swelling of CSA in the stages I and II. The erosion of CSA gel in the stage III induced the disintegration of the coat resulting in rapid drug release. The lower dip speed and higher pH medium delayed the drug release, while a super disintegrant in the cores enhanced the drug release and no enzyme effect was observed.

Effect of lipid hydroperoxide on Xenopus oocytes and on neurotransmitter receptors synthesized in Xenopus oocytes injected with exogenous mRNA.

The effect of 13-L-hydroperoxylinoleic acid (LOOH) on both Xenopus oocytes and neurotransmitter receptors synthesized in the oocytes was studied by electrophysiological and ion flux measurement. Addition of LOOH to the incubation mixture of the oocytes raised the membrane potential and decreased the membrane resistance of the oocytes. These effects of LOOH on the oocytes were reversed within a few hours by incubation with frog Ringer solution. Addition of LOOH also caused an increase of Li+ and 45Ca2+ uptake into the oocytes. However, production of alkoxy radicals by the addition of FeCl2 to the incubation mixture containing LOOH did not accelerate the damage to the oocytes by LOOH. So essential toxicity is caused possibly by an increase in the membrane permeability resulting from disturbance of the lipid bilayer arrangement, not from production of active alkoxy radicals during decomposition of LOOH. Nicotinic acetylcholine and gamma-aminobutyric acid receptors were synthesized in Xenopus oocytes by injecting mRNA prepared from Electrophorus electricus electroplax and rat brain. LOOH noncompetitively inhibited the function of these receptors and also increased the rate of desensitization of the receptors.

Pharmacological actions of dopamine sulfoconjugate on cardiovascular system.

Pharmacological actions of dopamine 4-sulfate on the cardiovascular systems were examined and compared with those of dopamine. Dopamine 4-sulfate, used in the present study, was minimally contaminated with dopamine (less than 0.02%). Dopamine 4-sulfate at doses ranging from 0.1 to 1 mumol/kg did not elicit any appreciable changes in systemic blood pressure and heart rate of anesthetized rabbits. Contractile activity and heart rate of isolated perfused rat heart were also unaffected by the agent. Dopamine 4-sulfate at concentrations of 1 and 0.3 mM, reduced a significant contraction of isolated rabbit renal and femoral arteries, respectively, but not in the aorta. The extent of the increase in tension development induced by 1 mM dopamine 4-sulfate in the femoral artery, was almost similar to that induced by 3 microM dopamine. The maximal tension development induced by 1 mM dopamine 4-sulfate in the femoral artery occurred more slowly than that induced by 3 microM dopamine. Furthermore, dopamine 4-sulfate-induced increase in tension development, like that of dopamine itself, was inhibited by 0.3 microM phentolamine and 0.1 microM haloperidol. Any appreciable conversion of dopamine 4-sulfate into dopamine was not seen in the medium of the organ bath in vitro during the experiment. The results suggest that dopamine sulfoconjugate exerts little effect on the cardiovascular system and, if any, induces a constriction of some vascular beds without conversion into dopamine.

Minimal model to account for the membrane conductance increase and desensitization of gamma-aminobutyric acid receptors synthesized in the Xenopus oocytes injected with rat brain mRNA.

gamma-Aminobutyric acid (GABA) receptors, which translocate chloride anion with binding GABA, were synthesized in Xenopus oocytes by injecting rat brain mRNA. GABA-elicited responses in the oocytes were measured electrophysiologically by the current-clamped method. Five different measurements were made to establish the relationship between GABA concentration and the electrical responses: (1) the GABA-elicited conductance increase before desensitization; (2) the rate of desensitization of GABA receptors; (3) the rate of recovery of desensitized receptors upon removal of GABA; (4) the GABA-elicited conductance increase after desensitization equilibrium; (5) the fraction of the active form of GABA receptors after desensitization equilibrium. These results were interpreted on the basis of the minimal model proposed for nicotinic acetylcholine receptor in Electrophorus electricus electroplax [Hess, G. P., Cash, D. J., & Aoshima, H. (1983) Annu. Rev. Biophys. Bioeng. 12, 443-473]. Estimated equilibrium and rate constants in the model for GABA receptors could successfully explain the results of the five above measurements.

A survey of autologous blood collection and transfusion in Japan in 1997.

BACKGROUND: In spite of the fact that autologous blood is safest for a patient to receive, it is not generally appreciated that adverse reactions during donation and transfusion may occur. This study was conducted to assess the state and the risk of autologous blood transfusion in Japan in 1997. STUDY DESIGN AND METHODS: Results of a nation-wide questionnaire-based survey are presented. The questionnaire assessed the number of autologous blood donations, donation procedures, and the adverse reactions associated with donation, preservation, recombination erythropoietin administration and transfusion. RESULTS: Between November 1996 and October 1997, 10,697,000 ml (or 53,485 units, 200 ml = 1 unit) prestorage blood donation were made by 14,200 patients (averages; 1.9 donations/patient, 753 ml/patient, 398 ml/donation). Of these, 87% were transfused to the patients and the remainder were discarded. Using hemodilution and blood salvage intra- or postoperatively some 2,540,000 ml of blood was collected and > 70% of patient-donors received such blood. Adverse reactions were observed with 1.6% (428/26,905) of donations including 6 angina and 2 asthma attacks. There were 63 (0.2%) problems with 28,705 donations and 117 (0.5%) errors/problems reported for 24,929 units transfused; the most frequent problems were clotting on the units and breakage of the bags during storage. Hypotension using hemodilution (3.7%), coagulation (0.9%) or bacterial contamination (0.4%) using salvage were often observed. A 10-20 ml volume of autologous fresh-frozen plasma was transfused to the wrong recipient. CONCLUSION: Autologous blood transfusion accounts for at least 1.1% (2.8% estimated) of the red cell supply in Japan. Errors and adverse reactions are not infrequent in autologous blood programmes. By introducing systematic safety policies, we will be able to make autologous blood transfusion safer.

Composite film-coated tablets intended for colon-specific delivery of 5-aminosalicylic acid: using deesterified pectin.

Combinations of Eudragit RS and deesterified pectin, polygalacturonic acid (PGA), or its potassium and sodium salts, when applied as a film coat, has a potential value as a colon-specific delivery system. Dispersions of PGA in Eudragit RS were used as the film former for coating of 5-aminosalicylic acid (5-ASA) tablet cores. Drug release behavior was assessed, in vitro, under simulating conditions in term of pH and time to in vivo during their transit to the colon. Negligible drug release occurred during first 5 hr where the coated tablets were in the stomach and small intestine. After that, the pectinolytic enzymes were added into the pH 6.8 medium to simulate the in vivo condition where there is the digestion of bacteria in the colon. The release of 5-ASA from the coated tablets occurred linearly as a function of time. Drug release depended on the composition of the mixed film, as well as the ratio of Eudragit RS to PGA or its salts. The highest drug release from the coated tablets of about 40% was obtained when the ratio of Eudragit RS to potassium salt of PGA was 2.5 to 1. Drug release profiles seemed to conform to the mechanism involving the osmotically driven release and formation of channels in the film caused by dissolution of PGA salts. Channel formation was, in most cases, activated by the presence of pectinolytic enzymes, showing that the PGA in the mixed film was subjected to enzymic breakdown. In conclusion, PGA could be used as an additive in Eudragit RS films to control the release of colonic delivery system.