High Tissue Affinity Research Articles

Mercury bioaccumulation and its toxic effects in rats fed with methylmercury polluted rice

Recent evidence indicated that methylmercury (MeHg) contaminated rice can be a significant source of MeHg human exposure, but the health implications are not known. The objective of this study was to study the kinetics, speciation, and effects of MeHg contaminated rice using a rat model. Five groups of adult Sprague-Dawley rats (n=10 in each group) were fed control rice, low (10ng/g MeHg) and high (25ng/g MeHg) MeHg contaminated rice. Two groups of the positive control were fed control rice spiked with the same levels of MeHgCl. Short-term exposure to low level of spiked MeHgCl stimulated the growth of male rats while long-term exposure to spiked MeHgCl inhibited the growth in female rats. There was no temporal variation of total mercury (THg) concentrations in the rat fecal samples from each group, and the THg concentrations significantly correlated with the inorganic Hg concentrations in the feeding rice. There were significant differences in the accumulation of THg and MeHg among different groups and different organs. THg and MeHg concentrations in the kidney were the highest among the organs examined. The blood and brain had high percentages of THg as MeHg, which indicates that MeHg can easily pass through the blood-brain barrier and has a high affinity for brain tissue. Exposure to rice containing 25ng/g MeHg decreased antioxidant function and damaged the nervous system in rats, but no significant effects were found in the group fed with rice containing 10ng/g MeHg. MeHgCys in rice is less toxic than spiked MeHgCl to rats. The toxicity of MeHg both decided by its concentration and speciation.

Bone-targeting poly(ethylene sodium phosphate).

Poly(ethylene sodium phosphate) (PEP·Na) showed excellent cytocompatibility and in vivo bone affinity. Moreover, PEP·Na did not interact with thrombin, which is a coagulation-related protein. Because immobilization of therapeutic agents and imaging probes on PEP·Na is easily performed, PEP·Na is a promising polymer for bone-targeted therapies.

Efficient brain uptake of piperine and its pharmacokinetics characterization after oral administration

1. Piperine, the major biological active component in black pepper has been associated with miscellaneous pharmacological effects, especially on central nervous system. To correlate with its neurological activity, a comprehensive pharmacokinetic profile of piperine in brain, plasma and cerebrospinal fluid after oral administration in rats was investigated in this study.2. It was noted that piperine could efficiently penetrate and homogeneously distribute into brain with similar pharmacokinetics profiles in each region. In addition, piperine concentrations in brain and plasma were found to be comparable with brain to plasma area under curve extrapolated to infinity (AUC0→∞) ratios of 0.95 and 1.10 for total concentration and unbound concentrations, respectively. Piperine also demonstrated high affinity toward brain tissue (98.4–98.5%) and plasma protein (96.2–97.8%) leading to a brain distribution volume of 36.32 ± 1.40 ml/g brain. Moreover, its efficient membrane permeability (Papp values of 5.41 ± 0.40 × 10- 5 cm/s and 4.78 ± 0.16 × 10- 5 cm/s for basolateral to apical and apical to basolateral transport in Caco-2 monolayer model) and limited hepatic metabolism (Clint of 8.15 μl/min/mg) could also contribute to its quick and high extent brain exposure.3. In summary, this study for the first time demonstrated high brain penetration potency of piperine could be resulted from its high brain tissue affinity and membrane permeability together with its limited liver metabolism.

Preoperative flurbiprofen axetil administration for acute postoperative pain: a meta-analysis of randomized controlled trials.

Non-steroidal anti-inflammatory drugs have been shown to effectively decrease postoperative pain and reduce opioid requirements. Flurbiprofen axetil is an injectable non-selective cyclooxygenase inhibitor that has a high affinity for inflammatory tissues to achieve targeted drug therapy and prolonged duration of action. This meta-analysis examined the use of preoperative flurbiprofen axetil and its impact on postoperative analgesia. An electronic literature search of the Library of PubMed, Cochrane CENTRAL, and EMBASE databases was conducted in Feb 2016. Searches were limited to randomized controlled trials. The primary outcome was pain scores. The secondary outcomes included cumulative postoperative opioid consumption and opioid-related adverse effects. A total of nine RCT studies involving 457 patients were included in this study. Compared to patients without perioperative flurbiprofen axetil, patients treated with preoperative flurbiprofen axetil had lower pain scores at 2h (SMD -1.00; 95% CI -1.57 to -0.43, P=0.0006), 6h (SMD -1.22; 95% CI -2.01 to -0.43; P=0.002), 12h (SMD -1.19; 95% CI -2.10 to -0.28; P=0.01), and 24h (SMD -0.79; 95% CI -1.31 to -0.27; P=0.003) following surgery. Preoperative flurbiprofen axetil had no significant effect on postoperative opioid consumption (SMD -13.11; 95% CI -34.56 to 8.33; P=0.23). There was no significant difference between the groups with regard to adverse effects. Compared to patients with postoperative flurbiprofen axetil, however, preoperative flurbiprofen axetil resulted in decreased pain score only at 2h after operation. Preoperative use of flurbiprofen axetil will result in significantly lower postoperative pain scores, but no difference in nausea, vomiting, and opioid consumption compared to those who did not receive flurbiprofen axetil. However, more homogeneous and well-designed clinical studies are necessary to determine whether preoperative flurbiprofen axetil administration has more efficacy than that given at the end of surgery.

Detection of colonic dysplasia in patients with ulcerative colitis using a targeted fluorescent peptide and confocal laser endomicroscopy: A pilot study.

AimTargeted molecular probes have been used to detect sporadic colonic dysplasia during confocal laser endomicroscopy (CLE) with promising results. This is a feasibility pilot study aiming to assess the potential role of CLE combined with a fluorescent-labeled peptide to stain and detect dysplasia associated with Ulcerative Colitis.MethodA phage-derived heptapeptide with predicted high binding affinity for dysplastic tissue, was synthesized and labeled with fluorescein. Eleven lesions with suspected dysplasia at endoscopy were excised from nine patients with long-standing ulcerative colitis. Specimens were sprayed with the peptide and examined by CLE. The CLE images were then compared to the corresponding histological sections.ResultsAt definitive histology, 4 lesions were diagnosed as inflammatory polyps, 6 as dysplastic lesions and one as invasive cancer. In inflammatory polyps, the fluorescence signal came from peri-cryptal spaces and crypt lumen due to passive accumulation of the peptide in these areas. Dysplasia was associated with active binding of the peptide to dysplastic colonocytes.ConclusionEx vivo staining of ulcerative colitis-associated dysplasia using a fluorescent labeled molecular probe and CLE is feasible. In vivo studies on larger populations are required to evaluate the safety and the effective contribution of molecular probes in cancer surveillance of ulcerative colitis.

Bioactive Peptides.

The increased consumer awareness of the health promoting effects of functional foods and nutraceuticals is the driving force of the functional food and nutraceutical market. Bioactive peptides are known for their high tissue affinity, specificity and efficiency in promoting health. For this reason, the search for food-derived bioactive peptides has increased exponentially. Over the years, many potential bioactive peptides from food have been documented; yet, obstacles such as the need to establish optimal conditions for industrial scale production and the absence of well-designed clinical trials to provide robust evidence for proving health claims continue to exist. Other important factors such as the possibility of allergenicity, cytotoxicity and the stability of the peptides during gastrointestinal digestion would need to be addressed. This review discusses our current knowledge on the health effects of food-derived bioactive peptides, their processing methods and challenges in their development.

Nitisinone therapy shows beneficial effects on the chondrocytes and extracellular matrix in the osteoarthropathy of alkaptonuria

Purpose: Alkaptonuria is a rare autosomal recessive form of osteoarthropathy resulting from deficiency of homogentisate 1,2 dioxygenase (HGD) causing inability to metabolise the tyrosine metabolite; homogentisic acid (HGA). HGA levels in the body become elevated and show high affinity for collagenous tissues, primarily load bearing articular cartilages, where it polymerises and deposits as a dark pigment; this process is ochronosis. Over time ochronosis causes early onset joint arthropathy, mimicking osteoarthritis (OA) in presentation but progressing much more rapidly. Recently a therapy; Nitisinone has been shown to be effective in reducing the causative molecule; HGA, therefore potentially halting the arthropathy. This study aims to examine the effect of the drug Nitisinone on cell number, ochronosis and turnover of the extracellular matrix in an in vitro model of this disease whilst also comparing with the effects of IL-1β. Methods: Cultures of immortalised human chondrocytes C20/A4 were cultured in 24 well plates in DMEM containing HGA, IL-1β, Nitisinone or a combination of these reagents for up to 9 days. The rate of pigmentation was assessed using histology and counted as a number of pigment deposits/mm3, degradation and turnover of the matrix was assessed using DMMB assay and CTX-II ELISA on cell culture supernatants. Statistical analysis was performed using Graphpad Prism by ANOVA and Newman Keuls post-hoc analysis. Results: Cultures showed a significance decrease in the number of cells after 3 days of culture when comparing cultures containing HGA, compared to any of those which didn’t (p<0.001). By day 9 of culture similar significance decreases in cell number were seen when comparing cultures containing HGA and those without; Control vs; HGA and vs HGA + IL-1β (p<0.001). The rate of pigmentation in these cultures containing HGA showed no significant differences on day 3 or 6, but by day 9 the cultures containing HGA vs those which contained HGA in combination with Nitisinone showed a significantly higher amount of pigmentation. DMMB assay revealed a significant increase in the amount of GAG in supernatants of culture containing HGA alone vs control, IL-1β, Nitisinone or HGA+IL-1β+NTBC cultures. The cultures containing a combination of HGA+IL-1β vs HGA also showed a significant increase in the amount of GAG released. By day 9 the amount of GAG detectable was not significantly different between treatment groups, although the cultures containing HGA+IL+NTBC did show a decrease in the amount of GAG compared to HGA and HGA+IL-1β. CTX-II showed no significant differences in any treatment groups across 3, 6 or 9 days. Conclusions: This model is the first to test the effect of Nitisinone on the chondrocytes and their extracellular matrix in a model of Alkaptonuria; demonstrating the combined effect on pigmentation rate, cell number and the extracellular matrix. The effect of HGA on cell number shows an early effect on chondrocytes suggesting rapid decrease in chondrocytes at day 3. This is mirrored by loss of GAG from cultures early in the presence of HGA. Nitisinone shows a significant effect in decreasing the pigmentation rate, thus preventing the advancement of disease in these patients. Our results are the first to show the effect of Nitisinone on the release of GAG’s in this in vitro model and provide useful insight into how this drug may protect cartilage in these patients; this also shows some effect of protection of GAG in the presence of IL-1β alone. It also demonstrates that when HGA, the causative molecule in AKU is compared to one of the key mediators of OA; IL-1β, the effect on the cells and their matrix is more severe - giving potential insight into why the arthritis in AKU is more severe and rapidly progressing than that in OA.

Effects of superoxide dismutase on chondrocytes in osteoarthropathy of alkaptonuria

Purpose: Alkaptonuria (AKU) is a rare autosomal recessive form of osteoarthropathy resulting from deficiency of homogentisate 1,2 dioxygenase (HGD) causing inability to metabolise the tyrosine metabolite; homogentisic acid (HGA). HGA levels in the body become elevated and show high affinity for collagenous tissues, primarily articular cartilages of load bearing joints, where it polymerises and deposits as a dark pigment; this process is ochronosis. Over time ochronosis causes rapid and early onset joint arthropathy, mimicking osteoarthritis (OA) in presentation. The ochronosis causes damage to the extracellular matrix and chondrocyte death and is reliant on the availability of oxygen radicals to proceed. One potential way to inhibit the polymerisation process is utilising antioxidants. We hypothesise that superoxide dismutase (SOD) may have a beneficial effect on chondrocytes and their extracellular matrix as well as limiting the polymerisation process in our in vitro model. This study aims to examine the effect of the superoxide dismutase on ochronosis and cell viability in an in vitro model of AKU. Methods: Cultures of immortalised human chondrocytes C20/A4 were cultured in 24 well plates in DMEM containing 0.33uM HGA/ml, 50 units of SOD/ml or a combination of both for up to 14 days. Cells were seeded at 5000/well and medium changed every 3rd day. Cell viability was assessed using trypan blue assay and expressed as number of viable cells/ml or percentage of viable cells. Statistical analysis was performed using Graphpad Prism by ANOVA and Newman-Keuls post-hoc analysis. Results: After 7 days cultures containing HGA showed a significant increase in the overall percentage of viable cells compared to control and SOD only; control vs both HGA and HGA+SOD, P<0.05 for both. The cultures containing HGA + SOD showed an increase in the overall percentage of viable cells compared to HGA only, but this was not significant. Analysis of the total number of viable cells on day 7 showed that there was no significant difference in overall total viable cell number across any of the groups; although the SOD group had the highest total number. The HGA+SOD group had a greater number of viable cells than the HGA group, although this was not significant. At day 14 cultures showed no significant difference in the percentage of viable cells across all groups, with percentage viability showing very close range across the 4 groups. The total number of viable cells was highest in the control and lowest in the SOD group.Conclusions: This model is the first to test the effect of SOD in an in vitro model of the osteoarthropathy in AKU. We demonstrate significant effects of SOD on the number of chondrocytes in this model. Prolonging the life and maintaining the number of chondrocytes in AKU, by reducing the effects of free oxygen species in tissues may be beneficial in maintaining overall cartilage health in AKU. The role of SOD in cartilage and interaction with reactive oxygen species (ROS) is well known; reduction of SOD is seen in earliest OA and results in an increase in ROS. AKU cartilage is characterised by glycosaminoglycan loss, rapid degeneration of the cartilage matrix and chondrocyte death, due to pigment formation. Whilst addition of SOD shows some chondroprotective potential in this disease, it also shows some negative effect on cell viability. These results demonstrate that antioxidant therapy, in the form of SOD, may be a beneficial treatment route in this disease. Further assessment of the role of SOD in the pigmentation process of this iconic disease is needed.

Direct dry-grinding synthesis of monodisperse lipophilic CuS nanoparticles

Copper sulfide nanoparticles, effective absorbers of near-infrared light, are recently attracting broad interest as a photothermal coupling agent for cancer therapy. Lipophilic copper sulfide nanoparticles are preferred for high performance biomedical applications due to high tissue affinity. Synthesis of lipophilic copper sulfide nanoparticles requires complicated multi-step processes under severe conditions. Here, we describe a new synthetic process, developed by direct dry-grinding of copper(II) acetylacetonate with sulfur under ambient environment at low temperature. The formed CuS nanoparticles are of uniform size, ∼10 nm in diameter, and are monodispersed in chloroform. Each covellite CuS nanocrystal surface is modified with oleylamine through hydrogen bonding between sulfur atoms and amine groups of oleylamine. The nanoparticles demonstrate near-infrared light absorption for photothermal applications. The synthetic methodology described here is more convenient and less extreme than previous methods, and should thus greatly facilitate the preparation of photothermal lipophilic copper sulfide nanomaterials for cancer therapy.

Systemic Administration of a Biopolymer‐delivered VEGF Improved Renal Hemodynamics and Microvascular Rarefaction in Renal Artery Stenosis

Elastin-like polypeptides (ELP) are drug delivery vectors that can be fused to therapeutic compounds to increase their efficacy. ELPs have high affinity for kidney tissue. We showed that the stenotic kidney in renal artery stenosis (RAS) develops progressive loss of function and renal microvascular (MV) damage associated to loss of vascular endothelial growth factor (VEGF). We designed a novel ELP-VEGF121 fusion and tested its therapeutic potential for the kidney after systemic (IV) administration. We hypothesized that IV ELP-VEGF therapy will preserve the stenotic kidney function and microcirculation. Unilateral RAS was induced in 10 pigs. After 6 weeks, stenotic kidney blood flow (RBF) and filtration (GFR) was quantified in vivo using multi-detector computed tomography. Then, pigs were randomized in placebo (RAS) or treated with a single IV infusion of ELP-VEGF121 (RAS+ELP-VEGF, 1 mg/kg, n=5 each). Pigs were observed for 4 weeks, in vivo studies repeated and then euthanized for ex vivo studies. Hypertension and degree of stenosis was similar in RVD and RVD+ELP-VEGF treated pigs. Stenotic kidney RBF and GFR were similarly reduced in all RVD animals after 6 weeks, remained attenuated in RVD at 10 weeks but were significantly improved (albeit not normalized) after IV ELP-VEGF, accompanied by ameliorated cortical and medullary vascular rarefaction A single IV administration of an ELP-VEGF121 construct improved stenotic kidney hemodynamics, filtration, and reduced cortical microvascular damage in RAS. Our study supports the therapeutic feasibility of systemic administration of a novel compound never tested before for renoprotection.

Toxicology of Organochlorines: Implications of Presence in Breast Milk

Background: Organochlorine pesticides (OCPs) are compounds that have been widely used in agriculture to control pests and also in the field of public health to control of paludism dissemination and other vectors. Currently, they are banned in most countries because they constitute a great threat to human health and ecosystems. The high affinity for adipose tissue and its slow metabolism place OCPs in the group of bioacumulative substances. Hence, OCPs passage into breast milk is high and involves a severe risk for infants. Objective: Analyze the toxicity including toxicodynamic and toxicokinetic of organochlorine (OC) and evaluate perinatal and infant toxicity after its exposure through breast milk. Methods: A desk top systematic literature research was carried out to explore the toxicity of OCPs. We conducted an extensive literature review using databases such as Web of Knowledge, Google search engine, Science Direct, Medline, Scopus, Lilacs databases and involved observational Mini-review Article Ezequiel et al.; JALSI, 2(2): xxx-xxx, 2015; Article no.JALSI.2015.006 50 studies on low-dose exposure in humans. Results: 1) OCPs constitute a real threat to ecosystems and public health. 2) They are concentrated in breast milk and breastfeeding contributes to worsen this exposure during the lactation period. 3) They have severe effects on CNS and the immune system, inducing mutagenesis, carcinogenesis, teratogenesis, metabolic and reproductive abnormalities 3) The human fetus and infant exposure to OCPs cause learning disabilities, low intelligence quotient, attention deficit and hyperactivity. Conclusions: For children, the best way to determine the risk of OC exposure is the analysis of breast milk samples and milk producing animals.

Pharmacokinetics, tissue distribution and excretion of verticinone from F. hupehensis in rats.

Verticinone, the main active component in F. hupehensis, exhibits potent antitussive and expectorant effects. Here, a LC-MS method was developed and applied to study the pharmacokinetics, tissue distribution and excretion of verticinone in rats, and its plasma protein binding in vitro. A significant gender difference in the pharmacokinetics of verticinone in rats was observed, as its absolute oral bioavailability in male and female rats was 45.8% and 2.74%, respectively. The relative bioavailability of verticinone was significantly lower in female rats as compared to male, following intragastrical (i.g.) and intravenous (i.v.) administration. After successive i.g. administration of verticinone, accumulation was observed in female rats but not in the male ones. The tissue distribution study showed that verticinone had a good tissue penetrability and a high tissue affinity in most studied tissues, except brain. After a 2 mg/kg oral dose, less than 4% of the dose was excreted as unchanged parent compound in male rats, and less than 1% in female rats, which indicated that verticinone was metabolized more extensively in female rats than in male rats.

Cholesterol-conjugated let-7a mimics: antitumor efficacy on hepatocellular carcinoma in vitro and in a preclinical orthotopic xenograft model of systemic therapy.

BackgroundA major challenge to the clinical utility of let-7 for hepatocellular carcinoma (HCC) therapy is the lack of an effective carrier to target tumours. We confirmed the high transfection efficiency of cholesterol-conjugated let-7a miRNA mimics (Chol-let-7a) in human HCC cells, as well as their high affinity for liver tissue in nude mice. However, their antitumor efficacy via systemic delivery remains unknown.MethodsWe explored the effects of Chol-let-7a on HCC in vitro and in vivo. Cell viability and mobility, let-7a abundance and the target ras genes was measured. Live-cell image and cell ultrastructure was observed. Antitumor efficacy in vivo was analyzed by ultrasonography, hispatholgogy and transmission electronic microscopy in a preclinical model of HCC orthotopic xenografts with systemic therapy.ResultsChol-let-7a inhibited the viability and mobility of HCC cells. Chol-let-7a was primarily observed in the cytoplasm and induced organelle changes, including autophagy. Mild changes were observed in the cells treated with negative control miRNA. Chol-let-7a reached HCC orthotopic tumours, significantly inhibited tumour growth, and prevented local invasion and metastasis. Compared to control tumours, Chol-let-7a-treated tumours showed more necrosis. Tumour cells showed no significant atypia, and mitoses were very rare after systemic Chol-let-7a therapy. Furthermore, let-7a abundance in orthotopic xenografts was coincident with a reduction in the expression of 3 human ras mRNAs and RAS proteins.ConclusionsChol-let-7a exerted significant antitumor effects by down-regulating all human ras genes at the transcriptional and translational levels. Chol-let-7a inhibited cell proliferation, growth, and metastasis, and mainly functioned in the cytoplasm. Chol-let-7a represents a potential useful modified molecule for systemic HCC therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-889) contains supplementary material, which is available to authorized users.

Intravenous AAV9 efficiently transduces myenteric neurons in neonate and juvenile mice.

Gene therapies for neurological diseases with autonomic or gastrointestinal involvement may require global gene expression. Gastrointestinal complications are often associated with Parkinson's disease and autism. Lewy bodies, a pathological hallmark of Parkinson's brains, are routinely identified in the neurons of the enteric nervous system (ENS) following colon biopsies from patients. The ENS is the intrinsic nervous system of the gut, and is responsible for coordinating the secretory and motor functions of the gastrointestinal tract. ENS dysfunction can cause severe patient discomfort, malnourishment, or even death as in intestinal pseudo-obstruction (Ogilvie syndrome). Importantly, ENS transduction following systemic vector administration has not been thoroughly evaluated. Here we show that systemic injection of AAV9 into neonate or juvenile mice results in transduction of 25–57% of ENS myenteric neurons. Transgene expression was prominent in choline acetyltransferase positive cells, but not within vasoactive intestinal peptide or neuronal nitric oxide synthase cells, suggesting a bias for cells involved in excitatory signaling. AAV9 transduction in enteric glia is very low compared to CNS astrocytes. Enteric glial transduction was enhanced by using a glial specific promoter. Furthermore, we show that AAV8 results in comparable transduction in neonatal mice to AAV9 though AAV1, 5, and 6 are less efficient. These data demonstrate that systemic AAV9 has high affinity for peripheral neural tissue and is useful for future therapeutic development and basic studies of the ENS.

High fat diet modulates Trypanosoma cruzi infection associated myocarditis.

Background Trypanosoma cruzi, the causative agent of Chagas disease, has high affinity for lipoproteins and adipose tissue. Infection results in myocarditis, fat loss and alterations in lipid homeostasis. This study was aimed at analyzing the effect of high fat diet (HFD) on regulating acute T. cruzi infection-induced myocarditis and to evaluate the effect of HFD on lipid metabolism in adipose tissue and heart during acute T. cruzi infection.Methodology/Principal FindingsCD1 mice were infected with T. cruzi (Brazil strain) and fed either a regular control diet (RD) or HFD for 35 days following infection. Serum lipid profile, tissue cholesterol levels, blood parasitemia, and tissue parasite load were analyzed to evaluate the effect of diet on infection. MicroPET and MRI analysis were performed to examine the morphological and functional status of the heart during acute infection. qPCR and immunoblot analysis were carried out to analyze the effect of diet on the genes involved in the host lipid metabolism during infection. Oil red O staining of the adipose tissue demonstrated reduced lipolysis in HFD compared to RD fed mice. HFD reduced mortality, parasitemia and cardiac parasite load, but increased parasite load in adipocytes. HFD decreased lipolysis during acute infection. Both qPCR and protein analysis demonstrated alterations in lipid metabolic pathways in adipose tissue and heart in RD fed mice, which were further modulated by HFD. Both microPET and MRI analyses demonstrated changes in infected RD murine hearts which were ameliorated by HFD.Conclusion/SignificanceThese studies indicate that Chagasic cardiomyopathy is associated with a cardiac lipidpathy and that both cardiac lipotoxicity and adipose tissue play a role in the pathogenesis of Chagas disease. HFD protected mice from T. cruzi infection-induced myocardial damage most likely due to the effects of HFD on both adipogenesis and T. cruzi infection-induced cardiac lipidopathy.

Development and applications of radioactive nanoparticles for imaging of biological systems.

Radioactive nanoparticles possess the ability to carry high payloads of radionuclides for noninvasive imaging of regions of interest inside the body. In this way, they can be used for nuclear imaging of systems such as normal physiology and disease states. Various methods have been developed to label nanoparticles using both radiometals and radiohalogens, for single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging in laboratory animals. The use of imaging to develop radioactive nanoparticles with long circulation times and minimal reticuloendothelial uptakes led to the design of nanoparticle constructs for imaging animal models of chronic illnesses, such as cancer and cardiovascular disease. Further improvements in targeting were made by modifying these constructs with vectors having high affinity and specificity for diseased tissue. In addition, constructs containing more than one type of imaging material afforded nanoparticles with multimodal properties, such as those designed for nuclear, magnetic resonance, and/or optical detection. Given the close relationship between diagnosis and therapy, theranostic nanoparticles have also been developed both to deliver radiotherapy and monitor response by imaging. In this article, we review the use of radionuclides to label nanoparticles for development and applications involving noninvasive detection of normal and abnormal biological functions.

GATA3 expression in metastatic urothelial carcinoma in fine needle aspiration cell blocks: A review of 25 cases

GATA binding protein 3 is a zinc finger transcription factor with high affinity for urothelial tissue and is a promising immunohistochemical marker in detection of urothelial carcinomas (UC). We studied its usefulness in metastatic high-grade UC. This study was performed on cell blocks (CB) of fine needle aspirates from 25 cases of metastatic high-grade UC in patients with previously resected high-grade UC. Immunohistochemical staining for GATA3, thrombomodulin, uroplakin, cytokeratin 7, and cytokeratin 20 was performed. Twenty-three of 25 cases of metastatic UC expressed GATA3 (92%); positive staining for cytokeratin 7 was present in 23 of 25 cases (92%), 20 of 25 (80%) stained for thrombomodulin, and 13 of 25 (52%) stained for cytokeratin 20. No case expressed uroplakin. Five hundred forty-seven non-urothelial carcinomas, including breast ductal carcinoma (77), hepatocellular carcinoma (100), colonic adenocarcinoma (81), pancreatic adenocarcinoma (28), gastric adenocarcinoma (31), endometrial carcinoma (27), ovarian serous carcinoma (27), lung adenocarcinoma (27), lung squamous cell carcinoma (26), malignant melanoma (27), renal cell carcinoma (48), and prostatic adenocarcinoma (48) in tissue microarrays were also analyzed and were GATA3 negative except for 35 of 77 (45.5%) of GATA3 positive breast ductal carcinoma. GATA3 has high sensitivity and specificity for detection of metastatic UC and thus may play an important role in diagnosing metastatic UC in CB samples.

Recent Patents on Light Based Therapies: Photodynamic Therapy, Photothermal Therapy and Photoimmunotherapy

This article reviews the more recent patents in three kinds of therapeutic strategies using the application of visible light to irradiate photosensible substances (PSs) of different natures. The light-activation of these PSs is directly responsible for the desired therapeutic effects. This group of light therapies includes photodynamic therapy (PDT), photothermal therapy (PTT) and photoimmunotherapy (PIT). Therapeutic mechanisms triggered by the activation of the PSs depend basically (though not exclusively) on the release of reactive oxygen species (ROS) and the activation of immune responses (PDT and PIT) or the local generation of heat (PTT). The main difference between PIT and PDT is that in PIT, monoclonal antibodies (MABs) are associated to PSs to improve the selective binding of the PSs to the target tissues. All these therapeutic strategies offer the possibility of destroying tumor tissue without damaging the surrounding healthy tissue, which is not achievable with chemotherapy or radiotherapy. PDT is also used as an alternative or adjuvant antimicrobial therapy together with the traditional antibiotic therapy since these organisms are unlikely to develop resistance to the ROS induced by PDT. Furthermore, PDT also induces an immune response against bacterial pathogens. The current challenge in PDT, PIT and PTT is to obtain the highest level of selectivity to act on targeted sick tissues with the minimum effects on the surrounding healthy tissue. The development of new PSs with high affinity for specific tissues, new PSs- MABs conjugates to bind to specific kinds of tumors, and new light-sensible nanoparticles with low toxicity, will increase the clinical utility of these therapies.

GW24-e1356 The histocompatibility of angiotensin converting enzyme does not promote its function on inhibitory to negative ventricular remodelling

ObjectivesRenin-angiontensin-aldosterone system (RAAS) is widely evidenced its point on inhibiting ventricular remodelling post myocardial infarction. The increasing expression of angiotensin and angiotensin-converting enzyme (ACE) post infarction and the effectiveness of...

Osteitis in the dens of axis caused by Treponema pallidum

BackgroundSyphilis has been referred to as “the great imitator” due to its ability to imitate other diseases. Untreated syphilis becomes a systemic infection that can involve almost every organ systems. Treponema pallidum has a high affinity for bone tissue, but osteitis has mainly been described in late stages of the disease. Vertebral involvement is rare, and this is to our knowledge the first case describing syphilitic spondylitis in early acquired syphilis.Case presentationWe here describe destructive osteitis in the vertebral column as the initial manifestation of early acquired syphilis in a 24-year-old caucasian homosexual male with HIV infection. The diagnosis was reached by universal bacterial PCR and DNA sequencing of the DNA product. It was confirmed by PCR specific for Treponema pallidum, immunohistochemistry and detection of increasing antibody titer.ConclusionsAs syphilis has re-emerged in Western countries and remains a worldwide common disease it is important to have in mind as a causative agent of skeletal symptoms, especially among HIV-infected individuals or men who have sex with men (MSM).