• Hair as a source of ancient DNA

      Gilbert, M.T.P.; Tobin, Desmond J.; Wilson, Andrew S. (2009)
    • Hair Degradation

      Wilson, Andrew S. (2000)
    • Hair follicle bulge stem cells appear dispensable for the acute phase of wound re-epithelialization

      Garcin, C.L.; Ansell, David M.; Headon, D.J.; Paus, R.; Hardman, M.J. (2016-05)
      The cutaneous healing response has evolved to occur rapidly, in order to minimize infection and to re‐establish epithelial homeostasis. Rapid healing is achieved through complex coordination of multiple cell types, which importantly includes specific cell populations within the hair follicle (HF). Under physiological conditions, the epithelial compartments of HF and interfollicular epidermis remain discrete, with K15+ve bulge stem cells contributing progeny for HF reconstruction during the hair cycle and as a basis for hair shaft production during anagen. Only upon wounding do HF cells migrate from the follicle to contribute to the neo‐epidermis. However, the identity of the first‐responding cells, and in particular whether this process involves a direct contribution of K15+ve bulge cells to the early stage of epidermal wound repair remains unclear. Here we demonstrate that epidermal injury in murine skin does not induce bulge activation during early epidermal wound repair. Specifically, bulge cells of uninjured HFs neither proliferate nor appear to migrate out of the bulge niche upon epidermal wounding. In support of these observations, Diphtheria toxin‐mediated partial ablation of K15+ve bulge cells fails to delay wound healing. Our data suggest that bulge cells only respond to epidermal wounding during later stages of repair. We discuss that this response may have evolved as a protective safeguarding mechanism against bulge stem cell exhaust and tumorigenesis.
    • A "hair-raising" history of alopecia areata

      Broadley, David; McElwee, Kevin J. (2020-03)
      A 3500‐year‐old papyrus from ancient Egypt provides a list of treatments for many diseases including “bite hair loss,” most likely alopecia areata (AA). The treatment of AA remained largely unchanged for over 1500 years. In 30 CE, Celsus described AA presenting as scalp alopecia in spots or the “windings of a snake” and suggested treatment with caustic compounds and scarification. The first “modern” description of AA came in 1813, though treatment still largely employed caustic agents. From the mid‐19th century onwards, various hypotheses of AA development were put forward including infectious microbes (1843), nerve defects (1858), physical trauma and psychological stress (1881), focal inflammation (1891), diseased teeth (1902), toxins (1912) and endocrine disorders (1913). The 1950s brought new treatment developments with the first use of corticosteroid compounds (1952), and the first suggestion that AA was an autoimmune disease (1958). Research progressively shifted towards identifying hair follicle‐specific autoantibodies (1995). The potential role of lymphocytes in AA was made implicit with immunohistological studies (1980s). However, studies confirming their functional role were not published until the development of rodent models (1990s). Genetic studies, particularly genome‐wide association studies, have now come to the forefront and open up a new era of AA investigation (2000s). Today, AA research is actively focused on genetics, the microbiome, dietary modulators, the role of atopy, immune cell types in AA pathogenesis, primary antigenic targets, mechanisms by which immune cells influence hair growth, and of course the development of new treatments based on these discoveries.
    • Halide Control of N,N-Coordination versus N,C-Cyclometalation and Stereospecific Phenyl Ring Deuteration of Osmium(II) p-Cymene Phenylazobenzothiazole Complexes

      Needham, R.J.; Habtemariam, A.; Barry, Nicolas P.E.; Clarkson, G.; Sadler, P.J. (2017-11-09)
      We report the synthesis of halido Os(II) p-cymene complexes bearing bidentate chelating phenylazobenzothiazole (AZBTZ) ligands. Unlike the analogous phenylazopyridine (AZPY) complexes, AZBTZ-NMe2 is capable of both N,N-coordination to Os(II) and cyclometalation to form N,C-coordinated species. N,C-Coordination occurs via an azo nitrogen and an ortho carbon on the aniline ring, as identified by 1H NMR and X-ray crystallography of [Os(p-cym)(N,N-AZBTZ-NMe2)Cl]PF6 (1a), [Os(p-cym)(N,N-AZBTZ-NMe2)Br]PF6 (2a), [Os(p-cym)(N,C-AZBTZ-NMe2)Br] (2b), and [Os(p-cym)(N,C-AZBTZ-NMe2)I] (3b). The N,C-coordinated species is more stable and is not readily converted to the N,N-coordinated complex. Analysis of the crystal structures suggests that their formation is influenced by steric interactions between the p-cym and AZBTZ-NMe2 ligands: in particular, larger monodentate halide ligands favor N,C-coordination. The complexes [Os(p-cym)(N,N-Me2-AZBTZ-NH2)Cl]PF6 (4) and [Os(p-cym)(N,N-Me2-AZBTZ-NH2)I]PF6 (5) were synthesized with methyl groups blocking the ortho positions on the aniline ring, forcing an N,N-coordination geometry. 1H NMR NOE experiments confirmed hindered rotation of the arene ligand and steric crowding around the metal center. Complex 2b exhibited unexpected behavior under acidic conditions, involving regiospecific deuteration of the aniline ring at the meta position, as observed by 1H NMR and high-resolution ESI-MS. Deuterium exchange occurs only under acidic conditions, suggesting an associative mechanism. The calculated partial charges on 2b show that the meta carbon is significantly more negatively charged, which may account for the regiospecificity of deuterium exchange.
    • Halo-substituted azobenzenes adsorbed at Ag(111) and Au(111) interfaces: Structures and optical properties

      Hughes, Zak E.; Baev, A.; Prasad, P.N.; Walsh, T.R. (2017-05-19)
      The adsorption of azobenzene (AB), ortho fluoro-azobenzene (FAB) and ortho chlor-azobenzol (ClAB), in both the cis and trans isomers, at the Au(111) and Ag(111) surfaces is investigated using plane-wave density functional calculations with the revPBE-vdW-DF functional. The resulting adsorption energies and internal structures of AB adsorbed to both metal surfaces are in broad agreement with available experimental data. In the gas phase, FAB and ClAB feature a significant reduction in the energy difference between the two isomeric states, compared with AB. This relative reduction in the energy difference is still significant for the adsorbed form of FAB but is only weakly apparent for ClAB. The absorption spectra of the molecules have also been calculated, with the halogen substituents generating significant changes in the gas phase, but only a modest difference for the adsorbed molecules.
    • Health care at a crossroads in Bangladesh

      Majumder, Md A.A. (2014)
      Though Bangladesh has made tremendous strides forward in health and other socio-economic indicators in the recent past, basic needs of health still remain largely unmet and only less than half of the population has access to basic healthcare. The health spending is far below the optimum level which is needed to scale up essential health intervention. Bangladesh is also experiencing a critical and chronic shortage and imbalance of skill mix and deployment of health workforce. The important achievements in health indicators include life expectancy, infant mortality, and vaccinations. However, overall burden of mortality and morbidity in most of the key health indicators is higher compared to other regional countries. Despite remarkable progress, except child mortality, targets are not expected to be met by 2015 if the prevailing trends persist in several areas. Major reforms are needed in health and medical education to ensure quality healthcare for the population of Bangladesh.
    • Heat induced evaporative antisolvent nanoprecipitation (HIEAN) of itraconazole

      Mugheirbi, N.A.; Paluch, Krzysztof J.; Tajber, L. (2014-08)
      Itraconazole (ITR) is an antifungal drug with a limited bioavailability due to its poor aqueous solubility. In this study, ITR was used to investigate the impact of nanonisation and solid state change on drug’s apparent solubility and dissolution. A bottom up approach to the production of amorphous ITR nanoparticles (NPs), composed of 100% drug, with a particle diameter below 250 nm, using heat induced evaporative antisolvent nanoprecipitation (HIEAN) from acetone was developed. The NPs demonstrated improved solubility and dissolution in simulated gastrointestinal conditions when compared to amorphous ITR microparticles. NPs produced with polyethylene glycol (PEG) or its methoxylated derivative (MPEG) as a stabiliser enabled the production of smaller NPs with narrower particle size distribution and enhanced apparent solubility. MPEG stabilised NPs gave the greatest ITR supersaturation levels (up to 11.6 ± 0.5 μg/ml) in simulated gastric fluids. The stabilising polymer was in an amorphous state. Dynamic vapour sorption data indicated no solid state changes in NP samples with water vapour at 25 °C, while crystallisation was apparent at 50 °C. HIEAN proved to be an efficient method of production of amorphous ITR NPs, with or without addition of a polymeric stabiliser, with enhanced pharmaceutical properties.
    • Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels

      Duckles, H.; Boycott, H.E.; Al-Owais, M.M.; Elies, Jacobo; Johnson, E.; Dallas, M.L.; Porter, K.E.; Giuntini, F.; Boyle, J.P.; Scragg, J.L.; et al. (2015-02)
      Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) affords cellular protection and suppresses proliferation of vascular smooth muscle cells (VSMCs) associated with a variety of pathological cardiovascular conditions including myocardial infarction and vascular injury. However, the underlying mechanisms are not fully understood. Over-expression of Cav3.2 T-type Ca2+ channels in HEK293 cells raised basal [Ca2+]i and increased proliferation as compared with non-transfected cells. Proliferation and [Ca2+]i levels were reduced to levels seen in non-transfected cells either by induction of HO-1 or exposure of cells to the HO-1 product, carbon monoxide (CO) (applied as the CO releasing molecule, CORM-3). In the aortic VSMC line A7r5, proliferation was also inhibited by induction of HO-1 or by exposure of cells to CO, and patch-clamp recordings indicated that CO inhibited T-type (as well as L-type) Ca2+ currents in these cells. Finally, in human saphenous vein smooth muscle cells, proliferation was reduced by T-type channel inhibition or by HO-1 induction or CO exposure. The effects of T-type channel blockade and HO-1 induction were non-additive. Collectively, these data indicate that HO-1 regulates proliferation via CO-mediated inhibition of T-type Ca2+ channels. This signalling pathway provides a novel means by which proliferation of VSMCs (and other cells) may be regulated therapeutically.
    • Heparin octasaccharides inhibit angiogenesis in vivo.

      Hasan, J.; Shnyder, Steven D.; Clamp, A.R.; McGown, A.T.; Bicknell, R.; Presta, M.; Bibby, Michael C.; Double, John A.; Craig, S.; Leeming, D.; et al. (2005)
      Background: In previous experiments, we showed that heparin oligosaccharides inhibit the angiogenic cytokine fibroblast growth factor-2. Here, we present the first in vivo study of size-fractionated heparin oligosaccharides in four models of angiogenesis that are progressively less dependent on fibroblast growth factor-2. Experimental Design: Heparin oligosaccharides were prepared using size-exclusion gel filtration chromatography and characterized through depolymerization and strong anion exchange high-performance liquid chromatography. Size-defined oligosaccharides (20 mg/kg/d) were given to mice bearing s.c. sponges that were injected with fibroblast growth factor-2 (100 ng/d). After 14 days, octasaccharides and decasaccharides reduced the microvessel density to levels below control. In a second experiment, HEC-FGF2 human endometrial cancer cells that overexpress fibroblast growth factor-2 were implanted in a hollow fiber placed s.c. in vivo. Oligosaccharides were given at 20 mg/kg/d for 2 weeks and the data again showed that octasaccharides significantly reduced microvessel density around the fiber (P = 0.03). In a more complex model, where angiogenesis was induced by a broad spectrum of growth factors, including vascular endothelial growth factor, we implanted H460 lung carcinoma cells in hollow fibers and treated the animals with oligosaccharides at 20 mg/kg/d over 3 weeks. Octasaccharides reduced the microvessel density to that of control. Preliminary investigation of 6-O-desulfated heparins showed that these also had antiangiogenic activity. Results: Finally, we examined the inhibitory potential of hexasaccharides and octasaccharides given at 20 mg/kg/d and these inhibited the growth of H460 lung carcinoma in vivo. At clinically attainable concentrations, significant anticoagulation (activated partial thromboplastin time, anti-factor Xa, and anti-factor IIa) was not observed in vitro unless species containing 16 saccharide residues were investigated. Conclusions: Thus, our preclinical data show that heparin octasaccharides represent novel antiangiogenic compounds that can be given without the anticoagulant effects of low molecular weight heparin.
    • Hepatic Arterial Infusion with Oxaliplatin and 5-FU/Folinic Acid for Advanced Biliary Tract Cancer: A Phase II Study.

      Sinn, M.; Nicolaou, Anna; Gebauer, B.; Podrabsky, P.; Seehofer, D.; Ricke, J.; Dörken, B.; Riess, H.; Hildebrandt, B. (2013-08)
      Background Effective and tolerable chemotherapy with gemcitabine and cisplatin for advanced biliary tract cancer (BTC) has been established recently. However, overall prognosis is still poor, and additional therapeutic approaches are needed for patients with locally advanced, irresectable and/or pretreated tumors. Hepatic arterial infusion (HAI) of chemotherapy represents a safe and well-established treatment modality, but data on its use in patients with BTC are still sparse. Methods Patients with irresectable BTC predominant to the liver were included in a prospective, open phase II study investigating HAI provided through interventionally implanted port catheters. Intraarterial chemotherapy consisted of biweekly oxaliplatin (O) 85 mg/m2 and folinic acid (F) 170 mg/m2 with 5-FU (F) 600 mg/m2. Results Between 2004 and 2010, 37 patients were enrolled. A total of 432 cycles of HAI were applied with a median of 9 (range 1–46) cycles. Objective response rate was 16 %, and tumor control was achieved in 24 of 37 (65 %) patients. Median progression-free survival was 6.5 months (range 0.5–26.0; 95 % CI 4.3–8.7), median overall survival was 13.5 (range 0.9–50.7; 95 % CI 11.1–15.9) months. The most frequent adverse event was sensory neuropathy grade 1/2 in 10/14 patients. Conclusions Using a minimal invasive technique, repetitive HAI with OFF is feasible and results in clinically relevant tumor control with low toxicity in patients with liver predominant advanced BTC.
    • Hepatocyte-specific deletion of TIPARP, a negative regulator of the aryl hydrocarbon receptor, is sufficient to increase sensitivity to dioxin-induced wasting syndrome

      Hutin, D.; Tamblyn, L.; Gomez, A.; Grimaldi, Giulia; Soedling, H.; Cho, T.; Ahmed, S.; Lucas, C.; Kanduri, C.; Grant, D.M.; et al. (2018-10)
      The aryl hydrocarbon receptor (AHR) mediates the toxic effects of dioxin (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin; TCDD), which includes thymic atrophy, steatohepatitis, and a lethal wasting syndrome in laboratory rodents. Although the mechanisms of dioxin toxicity remain unknown, AHR signaling in hepatocytes is necessary for dioxin-induced liver toxicity. We previously reported that loss of TCDD-inducible poly(adenosine diphosphate [ADP]-ribose) polymerase (TIPARP/PARP7/ARTD14), an AHR target gene and mono-ADP-ribosyltransferase, increases the sensitivity of mice to dioxin-induced toxicities. To test the hypothesis that TIPARP is a negative regulator of AHR signaling in hepatocytes, we generated Tiparpfl/fl mice in which exon 3 of Tiparp is flanked by loxP sites, followed by Cre-lox technology to create hepatocyte-specific (Tiparpfl/flCreAlb) and whole-body (Tiparpfl/flCreCMV; TiparpEx3−/−) Tiparp null mice. Tiparpfl/flCreAlb and TiparpEx3−/− mice given a single injection of 10 μg/kg dioxin did not survive beyond days 7 and 9, respectively, while all Tiparp+/+ mice survived the 30-day treatment. Dioxin-exposed Tiparpfl/flCreAlb and TiparpEx3−/− mice had increased steatohepatitis and hepatotoxicity as indicated by greater staining of neutral lipids and serum alanine aminotransferase activity than similarly treated wild-type mice. Tiparpfl/flCreAlb and TiparpEx3−/− mice exhibited augmented AHR signaling, denoted by increased dioxin-induced gene expression. Metabolomic studies revealed alterations in lipid and amino acid metabolism in liver extracts from Tiparpfl/flCreAlb mice compared with wild-type mice. Taken together, these data illustrate that TIPARP is an important negative regulator of AHR activity, and that its specific loss in hepatocytes is sufficient to increase sensitivity to dioxin-induced steatohepatitis and lethality.
    • Hepatoprotective activity of Schouwia thebica Webb

      Maitland, Derek J.; Awaad, A.S.; Soliman, G.A. (2006)
    • Hierarchical composite structure of few-layers MoS2 nanosheets supported by vertical graphene on carbon cloth for high-performance hydrogen evolution reaction

      Zhang, Z.; Li, W.; Yuen, M.F.; Ng, T-W.; Tang, Y.; Lee, C-S.; Chen, Xianfeng; Zhang, W. (2015)
      Here we report a hierarchical composite structure composed of few-layers molybdenum disulfide nanosheets supported by vertical graphene on conductive carbon cloth (MDNS/VG/CC) for high-performance electrochemical hydrogen evolution reaction (HER). In the fabrication, 3D vertical graphene is first prepared on carbon cloth by a micro-wave plasma enhanced chemical vapor deposition (MPCVD) and then few-layers MoS2 nanosheets are in-situ synthesized on the surface of the vertical graphene through a simple hydrothermal reaction. This integrated catalyst exhibits an excellent HER electrocatalytic activity including an onset potential of 50 mV, an overpotential at 10 mA cm(-2) (eta(10)) of 78 mV, a Tafel slop of 53 mV dec(-1), and an excellent cycling stability in acid solution. The excellent catalytic performance can be ascribed to the abundant active edges provided by the vertical MoS2 nanosheets, as well as the effective electron transport route provided by the graphene arrays on the conductive substrate. Moreover, the vertical graphene offers robust anchor sites for MoS2 nanosheets and appropriate intervals for electrolyte infiltration. This not only benefits hydrogen convection and release but also avoids the damaging or restacking of catalyst in electrochemical processes.
    • High pancreatic n-3 fatty acids prevent STZ-induced diabetes in fat-1 mice: inflammatory pathway inhibition

      Nicolaou, Anna; Bellenger, J.; Bellenger, S.; Bataille, A.; Massey, Karen A.; Rialland, M.; Tessier, C.; Kang, J.X.; Narce, M. (2011)
      Because of confounding factors, the effects of dietary n-3 polyunsaturated fatty acids (PUFA) on type 1 diabetes remain to be clarified. We therefore evaluated whether fat-1 transgenic mice, a well-controlled experimental model endogenously synthesizing n-3 PUFA, were protected against streptozotocin (STZ)-induced diabetes. We then aimed to elucidate the in vivo response at the pancreatic level. Beta-Cell destruction was produced by multiple low-doses STZ (MLD-STZ). Blood glucose level, plasma insulin level, and plasma lipid analysis were then performed. Pancreatic mRNA expression of cytokines, the monocyte chemoattractant protein, and GLUT2 were evaluated as well as pancreas nuclear factor (NF)-kB p65 and inhibitor of kB (IkB) protein expression. Insulin and cleaved caspase-3 immunostaining and lipidomic analysis were performed in the pancreas. STZ-induced fat-1 mice did not develop hyperglycemia compared with wild-type mice, and Beta-cell destruction was prevented as evidenced by lack of histological pancreatic damage or reduced insulin level. The prevention of Beta-cell destruction was associated with no proinflammatory cytokine induction (tumor necrosis factor-alpha, interleukin-1Beta, inducible nitric oxide synthase) in the pancreas, a decreased NF-kB, and increased IkB pancreatic protein expression. In the fat-1-treated mice, proinflammatory arachidonic-derived mediators as prostaglandin E2 and 12-hydroxyeicosatetraenoic acid were decreased and the anti-inflammatory lipoxin A4 was detected. Moreover, the 18-hydroxyeicosapentaenoic acid, precursor of the anti-inflammatory resolvin E1, was highly increased. Collectively, these findings indicate that fat-1 mice were protected against MLD-STZ-induced diabetes and pointed out for the first time in vivo the beneficial effects of n-3 PUFA at the pancreatic level, on each step of the development of the pathology-inflammation, Beta-cell damage-through cytokine response and lipid mediator production.
    • High performance liquid chromatography (HPLC) in the investigation of gout in paleopathology.

      Swinson, D.J.; Snaith, J.; Buckberry, Jo; Brickley, M.B. (2010)
      Gout is a disease caused by the abnormal accumulation of uric acid in the body, which can result in sodium urate crystals forming tophi at joints, with associated erosion of bone and cartilage. Only two examples of tophi have been reported from archaeological individuals, and the diagnosis of gout based on dry bone manifestations can be difficult. This paper presents preliminary results of a new technique to aid the diagnosis of gout in palaeopathology, namely high performance liquid chromatography (HPLC). Five archaeological skeletons with suspected gout (diagnosed using visual and radiological analysis) and three controls were analysed. Two of the gouty individuals had a white powder in their erosive lesions. HPLC showed the presence of uric acid in bone in four of the five individuals with evidence of gouty arthritis and was negative for uric acid in bone from the three controls. The white powder was also positive for uric acid. With reliance on the presence of articular erosions, cases of gout will be missed in archaeological human bone. HPLC measurement of uric acid could prove useful in the differential diagnosis of erosive arthropathy in archaeology. It may also be useful in identifying individuals with an increased body pool of uric acid, linked to conditions included in the term `metabolic syndrome¿. As a result, HPLC uric acid measurement also has the potential to provide additional information on health and lifestyle in past communities.
    • High Performance Liquid Chromatography Assay Method for Simultaneous Quantitation of Formoterol and Budesonide in Symbicort Turbuhaler

      Assi, Khaled H.; Chrystyn, Henry; Tarsin, W. (2006)
      A sensitive and rapid high performance liquid chromatography method has been developed and used for the simultaneous determination of formoterol and budesonide in Symbicort Turbuhaler when assessing the aerodynamic characteristics of the emitted dose using Pharmacopoeial methods. This capability results in both time and cost saving. The mobile phase composition was acetonitrile-5 mM sodium dihydrogen orthophosphate, pH 3 (60: 40% v/v), and was passed at 1.5 ml min-1 through a C18 column with a UV detection (wavelength 214 nm). The method was shown to give good analytical performance in terms of linearity, precision (using phenylpropanolamine as an internal standard), sensitivity and solution stability. The intra-day precision for both formoterol and budesonide were 0.75% and 1.11%, respectively (n = 10). The limit of quantitation for formoterol was 10 ¿g L-1 and for budesonide was 120 ¿g L-1, and the limit of detection were 3 and 30 ¿g L-1, for both formoterol and budesonide, respectively. The method has been applied to determine the content of the emitted dose and the fine particle dose of Symbicort Turbuhaler.
    • High resolution imaging of bio-molecular binding studies using a widefield surface plasmon microscope

      Jamil, M. Mahadi Abdul; Youseffi, Mansour; Twigg, Peter C.; Britland, Stephen T.; Liu, S.; See, C.W.; Zhang, J.; Somekh, M.G.; Denyer, Morgan C.T. (2008)
      Surface plasmon microscopes are mostly built around the prism based Kretschmann configuration. In these systems, an image of a sample can be obtained in terms of an intensity map, where the intensity of the image is dependent on the coupling of the light into the surface plasmons. Unfortunately the lateral resolution of these systems relies on the ability of plasmons to propagate along the metallised layer and is usually limited to a few microns unless special measures are taken. The widefield surface plasmon microscope (WSPR), used here enables surface plasmon imaging at significantly higher lateral resolutions than prism based systems. In this study we demonstrate the functionality of the WSPR by imaging a sequence of binding events between micro-patterned extracellular matrix proteins and their specific antibodies. Using the WSPR system a change in contrast was observed with each binding event. Images produced via the WSPR system were analyzed and compared qualitatively and quantitatively. Consequently, we confirm that the WSPR microscope described here can be used to study sequential monomolecular layer binding events on a micron scale. These results have significant implications in the development of new micron scale bioassays.