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AIMS OF THE STUDY: More than 100 cases of nephropathy over the last 10 years caused by the systemic and longer term application of Chinese snakeroot (Aristolochia fangchi) highlighted the risk of using preparations which contain a...
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AIMS OF THE STUDY: More than 100 cases of nephropathy over the last 10 years caused by the systemic and longer term application of Chinese snakeroot (Aristolochia fangchi) highlighted the risk of using preparations which contain aristolochic acids. On the other hand anecdotal evidence highlights the widespread use of Aristolochia species (Aristolochiaceae) in many regions of the world. Therefore, it was our objective to systematically assess the scientific literature available on the local and traditional use of Aristolochia spp. on a worldwide scale. Our review identifies core species which need to be investigated and which may need monitoring (esp. in national and international trade). METHODS: An extensive review of the literature available in libraries in London on the uses of species of Aristolochia was undertaken. Relevant information was extracted and entered into a database for analysis. RESULTS: Based on the assessment of 566 reference sources 685 individual sets of data were recorded. Seven species--Aristolochia indica L. (Asia), Aristolochia serpentaria L. (North America), Aristolochia debilis Sieb & Zucch. (China), Aristolochia acuminata Lam (India), Aristolochia trilobata L. (Central/South America, Caribbean), Aristolochia clematitis L. (Europe) and Aristolochia bracteolata Lam. (Africa)--are reported widely as being used medicinally. The medical uses vary, but of particular interest are uses in case of gastrointestinal problems, which is likely to result in repeated exposure to the botanical drugs by an individual. About half of all records relate to uses of Aristolochia species in Asia, one-third to the Americas, a continent which has so far received practically no attention in terms of assessing the risk of using species of Aristolochia. Of the 99 species (plus several identified at genus level only) for which we were able to summarise ethnobotanical information, preliminary phytochemical information is only available for 24 species and some of the most common ones including Aristolochia acuminata have so far not been studied phytochemically. CONCLUSIONS: Species of Aristolochia are used medicinally in many regions of the world and both from an ethnopharmacological and a public health perspective this poses a risk. A systematic assessment of the content of aristolochic acids in the most widely used species is needed to evaluate whether their uses pose a potential health risk. In China and Europe species of Aristolochia have been associated with nephropathy and it is important to evaluate whether nephropathy occurs in other parts of the world, especially India and Central America where the use of species of Aristolochia are reported to be commonly used in traditional medicine.
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Antibody-conjugated surfaces are being studied for cardiovascular implant applications to capture endothelial progenitor cells and promote endothelialization. However, despite the large amount of literature on endothelial progenit...
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Antibody-conjugated surfaces are being studied for cardiovascular implant applications to capture endothelial progenitor cells and promote endothelialization. However, despite the large amount of literature on endothelial progenitor cell capture efficiency, little effort has been made to understand acute blood responses to the modified surfaces. We hypothesize that CD34 antibody conjugation passivates surfaces against procoagulatory events, and thus improves hemocompatibility. To test this hypothesis, we subjected the modified films to hemocompatibility tests to evaluate contact activation, platelet adhesion and activation, as well as whole blood clotting response to the films. Here, we demonstrate the alteration of blood responses due to polyacrylic acid (PAAc) engraftment and subsequent antibody conjugation on biaxially stretched polycaprolactone (PCL) films. Compared to PCL, PAAc-engrafted PCL (PCL-PAAc) and CD34-antibody-conjugated films (PCL-PAAC-CD34) resulted in a four- to ninefold (p < 0.001) reduced platelet activation. PCL-PAAc, however, resulted in an increased contact activation on thromboelastography, and a poorer blood compatibility index assay (43.4% +/- 2.3% vs. 60.9% +/- 2.5%, p < 0.05). PCL-PAAC-CD34, on the other hand, resulted in delayed clot formation (r = 19.3 +/- 1.5, k = 6.8 +/- 0.6 min) and reduced platelet adhesion and activation, and yielded the highest blood compatibility index score, indicating least thrombogenicity (69.3% +/- 3.2%). Our results suggest that CD34 antibody conjugation significantly improved the hemocompatibility of PAAc-conjugated PCL.
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Stem cell transplantation for regenerative medicine has made significant progress in various injury models, with the development of modalities to track stem cell fate and migration post-transplantation being currently pursued rigo...
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Stem cell transplantation for regenerative medicine has made significant progress in various injury models, with the development of modalities to track stem cell fate and migration post-transplantation being currently pursued rigorously. Magnetic resonance imaging (MRI) allows serial high-resolution in vivo detection of transplanted stem cells labeled with iron oxide particles, but has been hampered by low labeling efficiencies. Here, we describe the use of microgel iron oxide (MGIO) particles of diameters spanning 100-750 nm for labeling human fetal mesenchymal stem cells (hfMSCs) for MRI tracking. We found that MGIO particle uptake by hfMSCs was size dependent, with 600-nm MGIO (M600) particles demonstrating three- to sixfold higher iron loading than the clinical particle ferucarbotran (33-263 versus 9.6-42.0 pg iron/hfMSC; p < .001). Cell labeling with either M600 particles or ferucarbotran did not affect either cellular proliferation or tri-lineage differentiation into osteoblasts, adipocytes, and chondrocytes, despite differences in gene expression on a genome-wide microarray analysis. Cell tracking in a rat photothrombotic stroke model using a clinical 1.5-T MRI scanner demonstrated the migration of labeled hfMSCs from the contralateral cortex to the stroke injury, with M600 particles achieving a five- to sevenfold higher sensitivity for MRI detection than ferucarbotran (p < .05). However, model-related cellular necrosis and acute inflammation limited the survival of hfMSCs beyond 5-12 days. The use of M600 particles allowed high detection sensitivity with low cellular toxicity to be achieved through a simple incubation protocol, and may thus be useful for cellular tracking using standard clinical MRI scanners.
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BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment options. As the status of the tumour immune microenvironment can affect progression of established tumours, we evaluated potential immune mechanisms associated with survival in HCC. METHODS: Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes (TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis and proliferation). RESULTS: The immune microenvironment within tumours was found to be heterogeneous, although globally more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and exclusively in areas devoid of proliferating tumour cells. NK and CD8(+) T cell densities are correlated positively with tumour apoptosis, and negatively with tumour proliferation. CONCLUSIONS: Hence, an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation....
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BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment options. As the status of the tumour immune microenvironment can affect progression of established tumours, we evaluated potential immune mechanisms associated with survival in HCC. METHODS: Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes (TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis and proliferation). RESULTS: The immune microenvironment within tumours was found to be heterogeneous, although globally more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and exclusively in areas devoid of proliferating tumour cells. NK and CD8(+) T cell densities are correlated positively with tumour apoptosis, and negatively with tumour proliferation. CONCLUSIONS: Hence, an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation.
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Adiponectin is reported to have both proinflammatory and anti-inflammatory effects. Because adiponectin circulates in isoforms of various sizes and some responses to adiponectin are isoform dependent, it was postulated that the pr...
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Adiponectin is reported to have both proinflammatory and anti-inflammatory effects. Because adiponectin circulates in isoforms of various sizes and some responses to adiponectin are isoform dependent, it was postulated that the proinflammatory effects of adiponectin may be isoform specific. To test this theory, peripheral blood mononuclear cells (PBMCs), microvascular endothelial cells (MVECs), and human glomerular mesangial cells (HMCs) were treated with high-molecular-weight (HMW) or low-molecular-weight (LMW) recombinant human adiponectin, and chemokine production was measured. The PBMCs were isolated from healthy volunteers by density gradient centrifugation of ethylenediaminetetraacetic acid (EDTA) anticoagulated whole blood through endotoxin-free Ficoll (General Electric Healthcare Bio-Sciences, Uppsala, Sweden). The MVECs were of dermal origin, and the HMCs were isolated from kidneys not suitable for transplantation. Overnight (16 h) incubation with HMW adiponectin (0.01-1 microg/mL for PBMCs; 5-20 microg/mL for MVECs and HMCs) induced a dose-dependent increase in production of monocyte chemoattractant protein-1 and interleukin-8 by PBMCs and MVECs, but it had no effect on HMC chemokine production (n=3-5). LMW adiponectin at the same concentrations did not induce chemokine production in any of the cell types tested, and it did not block cytokine-induced chemokine production by PBMCs or MVECs (n=3-5). These in vitro data suggested that the HMW adiponectin isoform is proinflammatory. To examine the possibility of a relationship between HMW adiponectin and inflammation in vivo, the urine of patients with systemic lupus erythematosus (SLE) and kidney involvement, which was shown previously to contain immunoreactive adiponectin, was examined for the presence of specific adiponectin isoforms by nondenaturing gel electrophoresis. HMW adiponectin was found in the urine of patients with active lupus nephritis. Therefore, HMW adiponectin may contribute to the renal inflammation of SLE.
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Current treatment of human autoimmune disease by autologous bone marrow stem-cell transfer is hampered by frequent disease relapses. This is most probably owing to re-emergent self-reactive lymphocytes. Gene therapy combined with ...
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Current treatment of human autoimmune disease by autologous bone marrow stem-cell transfer is hampered by frequent disease relapses. This is most probably owing to re-emergent self-reactive lymphocytes. Gene therapy combined with bone marrow stem cells has successfully introduced genes lacking in immunodeficiences. Because the bone marrow compartment has a key role in establishing immune tolerance, this combination strategy should offer a rational approach to prevent re-emergent self-reactive lymphocytes by establishing solid, life-long immune tolerance to causative self-antigen. Indeed, we have recently demonstrated the success of this combination approach to prevent and cure an experimental autoimmune disease. We suggest that this combination strategy has the potential for translation to treat human autoimmune diseases in which causative self-antigens are known.
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BACKGROUND: Perhexiline improves functional capacity in heart failure, but the mechanisms are undefined. We sought its effects on myocardial deformation in patients with viable myocardium. METHODS: Thirty-six medically-treated pat...
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BACKGROUND: Perhexiline improves functional capacity in heart failure, but the mechanisms are undefined. We sought its effects on myocardial deformation in patients with viable myocardium. METHODS: Thirty-six medically-treated patients, stable at least 6 months post-infarction with LV dysfunction and myocardial viability shown by dobutamine echo (DbE) were randomised to receive perhexiline or matching placebo for 1 year. Cardiopulmonary exercise testing and DbE were performed at baseline and follow-up. Peak-systolic strain (S) and strain rate (SR) were measured offline in 111 dysfunctional segments in the placebo and 88 in the treatment group at rest, low-dose (LDD) and peak-dose dobutamine (PDD). RESULTS: The serum perhexiline level was 0.27+/-0.7 microg/l. There was no difference in the wall motion response to dobutamine at baseline and follow-up. Resting strain and SR were similar in the two groups at baseline and follow-up. However, SR at LDD and PDD increased in the placebo group and worsened during the same period in the perhexiline group. Patients on perhexiline and placebo had a similar rate-pressure product and exercise duration at baseline (7.9+/-2.7 vs 8.7+/-3.3 min, p=NS) and follow-up (9.6+/-4.6 vs 10.1+/-3.03 min, p=NS). CONCLUSION: Perhexiline does not improve the deformation of abnormal myocardial segments in patients with ischaemic LV dysfunction.
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Marsupials are largely confined to Australasia and to Central and South America. The visual pigments that underlie the photosensitivity of the retina have been examined in a number of species from the former group where evidence f...
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Marsupials are largely confined to Australasia and to Central and South America. The visual pigments that underlie the photosensitivity of the retina have been examined in a number of species from the former group where evidence for trichromatic colour vision has been found, but none from the latter. In this paper, we report the cone opsin sequences from two nocturnal South American marsupial species, the gray short-tailed opossum, Monodelphis domestica, and the big-eared opossum, Didelphis aurita. Both are members of the Order Didelphimorphia (American opossums). For both species, only two classes of cone opsin were found, an SWS1 and an LWS sequence, and in vitro expression showed that the peak sensitivity of the SWS1 pigment is in the UV. Analysis of the Monodelphis genome confirms the absence of other classes of cone visual pigment genes. The SWS1 and LWS genes with 4 and 5 introns respectively, show the same exon-intron structure as found for these genes in all other vertebrates. The SWS1 gene shows a conserved synteny with flanking genes. The LWS gene is X-linked, as in all therian mammals so far examined, with a locus control region 1.54 kb upstream.
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BACKGROUND: The current management of thyroid lymphomas (TL) includes the combined use of chemotherapy and radiotherapy, with surgery mainly confined to diagnosis through an open biopsy following ultrasound-guided fine-needle aspi...
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BACKGROUND: The current management of thyroid lymphomas (TL) includes the combined use of chemotherapy and radiotherapy, with surgery mainly confined to diagnosis through an open biopsy following ultrasound-guided fine-needle aspiration cytology (US-FNAC). AIMS: To analyse the clinical presentation and methods of diagnosis of TL, its pitfalls and the management of these tumours presenting with compression symptoms and airway obstruction. METHODS: A retrospective review of nine patients diagnosed with TL at Guy's and St Thomas Hospital NHS Foundation Trust in London over the past 5 years. RESULTS: Nine consecutive patients were identified with the diagnosis of TL, and seven (78%) of them being women and with a mean age of 65 years. All patients presented with an anterior neck mass while four (44.4%) presented with stridor and vocal cord palsy. Two (22.2%) presented with a hoarse voice, dysphagia, and only one patient had a B symptom of weight loss. FNAC was diagnostic in three patients (33.3%) and a report of multi-nodular goitre in one patient. There was clinical suspicion of TL in three patients (33.3%). Of the three patients presenting with stridor, two had an open biopsy followed by the initiation of dexamethasone therapy and resolution of symptoms within 48 h. One patient had a partial thyroidectomy following a suspected diagnosis of multi-nodular goitre from US-FNAC. One patient required tracheostomy for airway management. CONCLUSION: Diagnosis of TL may be difficult. However, US-FNAC is useful in raising the suspicion of a TL. Open biopsy is still the definitive diagnostic tool of choice. In the emergency setting of airway obstruction, once definitive diagnosis is achieved, dexamethasone therapy and endotracheal intubation for airway management are all that is required for optimal management strategy. Surgical intervention has no role except for providing tissue for diagnosis.
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HIV-associated nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Pathogenesis involves direct infection of the glomerular and tubular epithelial cells leading to characteristic disorder. Recently, we hav...
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HIV-associated nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Pathogenesis involves direct infection of the glomerular and tubular epithelial cells leading to characteristic disorder. Recently, we have shown that HIV-1 Vpr causes hypertrophy, hyperploidy, and apoptosis. Here, we report that Vpr activates the DNA damage response resulting in the observed renal phenotype. Renal sections from the HIVAN transgenic mouse model and human biopsies both show an abundant DNA damage response.
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