The treatment effect of rivaroxaban on clot characteristics in patients who present acutely with first time deep vein thrombosis.

BACKGROUND: The acute vascular disease deep vein thrombosis (DVT) requires oral anticoagulants to prevent progression. Monitoring therapeutic efficacy of direct oral anticoagulants (DOAC), including rivaroxaban, is problematic as no reliable test is available. Advances in rheometry have led to the development of a functional coagulation biomarker using Gel Point (GP) analysis which assesses clot structure formation. The biomarker measures incipient clot formation time (TGP) and quantifies fibrin clot structure in terms of fractal dimension (df). OBJECTIVE: This study aimed to investigate clot structure formation in first time DVT and the effect of rivaroxaban treatment. METHODS: This prospective observational cohort study measured the GP and standard laboratory markers at three sample points: pre-treatment and at 20 and 60 days following 15 mg BD and 20 mg OD rivaroxaban respectively. RESULTS: Forty DVT patients (mean age 64 years [SD±14.8]; 23 males, 17 female) were recruited. The results show that DVT vs non-DVT patients did not have a significantly different GP profile (df: 1.72±0.06 vs 1.70±0.06 and TGP: 267±68 sec vs 262±73 sec) with both within the defined healthy index. In addition, rivaroxaban therapy increased TGP to 392 s (±135 s) after 20 days, and subsequently increased to 395 s (±194 s) at 60 days but did not significantly increase df (from 1.69±0.05 to 1.71±0.06). CONCLUSIONS: The results indicate in this cohort of DVT patients there was no underlying hypercoagulable effect as determined by gel point analysis. Furthermore, the anticoagulant effect of rivaroxaban prolonged clotting, suggesting a protective effect against clot formation, without significantly reducing clot microstructural properties.

Epidemiology, ecology and human perceptions of snakebites in a savanna community of northern Ghana.

BACKGROUND: Worldwide, snakebite envenomations total ~2.7 million reported cases annually with ~100,000 fatalities. Since 2009, snakebite envenomation has intermittently been classified as a very important 'neglected tropical disease' by the World Health Organisation. Despite this emerging awareness, limited efforts have been geared towards addressing the serious public health implications of snakebites, particularly in sub-Saharan Africa, where baseline epidemiological and ecological data remain incomplete. Due to poverty as well as limited infrastructure and public health facilities, people in rural Africa, including Ghana, often have no other choice than to seek treatment from traditional medical practitioners (TMPs). The African 'snakebite crisis' is highlighted here using regionally representative complementary data from a community-based epidemiological and ecological study in the savanna zone of northern Ghana. METHODOLOGY AND FINDINGS: Our baseline study involved two data collection methods in the Savelugu-Nanton District (in 2019 the district was separated into Savelugu and Nanton districts) in northern Ghana, comprising a cross-sectional study of 1,000 residents and 24 TMPs between December 2008 and May 2009. Semi-structured interviews, as well as collection of retrospective snakebite and concurrent rainfall records from the Savelugu-Nanton District Hospital and Ghana Meteorological Authority respectively over 10-years (1999-2008) were used in the study. Variables tested included demography, human activity patterns, seasonality, snake ecology and clinical reports. Complementary data showed higher snakebite prevalence during the rainy season, and a hump-shaped correlation between rainfall intensity and snakebite incidences. Almost 6% of respondents had experienced a personal snakebite, whereas ~60% of respondents had witnessed a total of 799 snakebite cases. Out of a total of 857 reported snakebite cases, 24 (~2.8%) died. The highest snakebite prevalence was recorded for males in the age group 15-44 years during farming activities, with most bites occurring in the leg/foot region. The highest snakebite rate was within farmlands, most severe bites frequently caused by the Carpet viper (Echis ocellatus). CONCLUSION: The relatively high community-based prevalence of ~6%, and case fatality ratio of ~3%, indicate that snakebites represent an important public health risk in northern Ghana. Based on the high number of respondents and long recording period, we believe these data truly reflect the general situation in the rural northern savanna zone of Ghana and West Africa at large. We recommend increased efforts from both local and international health authorities to address the current snakebite health crisis generally compromising livelihoods and productivity of rural farming communities in West Africa.

Evaluating the Antibacterial Properties of Polyacetylene and Glucosinolate Compounds with Further Identification of Their Presence within Various Carrot (Daucus carota) and Broccoli (Brassica oleracea) Cultivars Using High-Performance Liquid Chromatography with a Diode Array Detector and Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry Analyses.

Ongoing consumer concerns over using synthetic additives in foods has strongly influenced efforts worldwide to source suitable natural alternatives. In this study, the antibacterial efficacy of polyacetylene and glucosinolate compounds was evaluated against both Gram positive and Gram negative bacterial strains. Falcarinol [minimum inhibitory concentration (MIC) = 18.8-37.6 µg/mL] demonstrated the best overall antibacterial activity, while sinigrin (MIC = 46.9-62.5 µg/mL) was the most active glucosinolate compound. High-performance liquid chromatography with a diode array detector analysis showed falcarinol [85.13-244.85 µg/g of dry weight (DW)] to be the most abundant polyacetylene within six of the eight carrot (Daucus carota) cultivars investigated. Meanwhile, sinigrin (100.2-244.3 µg/g of DW) was the most abundant glucosinolate present within the majority of broccoli (Brassica oleracea) cultivars investigated using ultra performance liquid chromatography-tandem mass spectrometry analysis. The high abundance of both falcarinol and sinigrin within these respective species suggests that they could serve as potential sources of natural antibacterial agents for use as such in food products.

Should an increase in cerebral neurochemicals following head kicks in full contact karate influence return to play?

BACKGROUND: Cerebral neurochemicals are markers of traumatic brain injury (TBI). OBJECTIVES: The aim of the study was to determine whether kicks to the head (KTH) in full contact karate significantly increased serum concentrations of protein S-100B, and neurone specific enolase (NSE). Kicks to the body (KTB) were also quantified to asses muscle tissue injury. Muscle damage was assessed by analysis of serum total creatine kinase (CK). METHODS: Twenty-four full contact karate practitioners were observed and filmed during actual competition and divided into two main groups post event: (1) Kicks to the head and body group (KTH): n = 12; mean ± SD; age, 30.4 ± 6.7 years; height, 1.74 ± 0.1 m; weight, 79.1 ± 2.1 kg; and (2): Kicks to the body group (KTB): n = 12; mean ± SD; age, 28.2 ± 6.5 years; height, 1.75 ± 0.1 m; weight, 79.2 ± 1.7 kg. The KTH group received direct kicks to the head, while group KTB received kicks and punches to the body. Blood samples were taken before and immediately post-combat for analysis of serum S-100B, NSE, CK and cardiac troponin. RESULTS: Significant increases in serum concentrations of S-100B (0.12 ± 0.17 vs. 0.37 ± 0.26, µg.L(-1)) and NSE (11.8 ± 4.1 vs. 20.2 ± 9.1 ng.mL(-1)) were encountered after combat in the KTH group and CK (123 ± 53 vs. 184 ± 103 U.L(-1)) in the KTB group (all P <0.05). CONCLUSIONS: Head kicks in full contact karate cause elevation of neurochemical markers associated with damaged brain tissue. The severity of injury is related to the early post-traumatic release of protein S-100B and NSE. The early kinetics and appearance post injury can reflect intracranial pathology, and suggest S-100B and NSE are extremely sensitive prognostic markers of TBI.

Epirubicin, cisplatin and protracted venous infusion 5-Fluorouracil chemotherapy for advanced salivary adenoid cystic carcinoma.

AIMS: Adenoid cystic carcinoma (ACC) is a rare tumour that usually arises in the salivary glands. Initial management is surgery often combined with adjuvant radiotherapy. Chemotherapy is reserved for treatment of symptomatic recurrence. We evaluated the combination of epirubicin, cisplatin and protracted venous infusion 5-fluorouracil (ECF) in the management of ACC. MATERIALS AND METHODS: Patients referred for treatment of advanced, symptomatic ACC were considered. The drugs given were epirubicin 50 mg/m(2) 3-weekly, cisplatin 60 mg/m(2) 3-weekly and protracted venous infusion 5-fluorouracil 200 mg/m(2)/day. RESULTS: Eight patients (median age 46 years) received a median of five cycles of chemotherapy. All patients had had previous surgery, seven had had previous radiotherapy and one had had previous chemotherapy. One patient showed a partial response (duration 34 months) and five showed stable disease (median duration 13.6 months [6.8-15.9+ months]). Median survival was 27 months (3.5-62.3 months). CONCLUSIONS: The activity of ECF in ACC of the head and neck seems to be similar to the combination of cisplatin and 5-fluorouracil and single-agent epirubicin.

Recent insights into interactions of deferoxamine with cellular and plasma iron pools: Implications for clinical use.

Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred-fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4-8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non-transferrin-bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high-dose DFO are less desirable than continuous infusions at low doses, particularly in high-risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*-visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes.

The Global TB Drug Facility: innovative global procurement.

The Global TB Drug Facility (GDF) is a new initiative to increase access to high quality tuberculosis drugs. The GDF, a project of the Global Partnership to Stop TB, is managed by its secretariat, in the World Health Organization (WHO), Geneva. It aims to provide tuberculosis drugs to treat up to 11.6 million patients over the next 5 years and to assist countries to reach the WHO global TB control targets by 2005. The GDF was launched on 24 March 2001. Six rounds of applications have been completed, with 46 countries and non-governmental organisations (NGOs) approved for support. The GDF is not a traditional procurement mechanism. It has adopted an innovative approach to the supply of drugs, by linking demand for drugs to supply and monitoring, using partners to provide services, using product packaging to simplify drug management and linking grants to TB programme performance. This paper describes the GDF operational procedures and experience gained so far. Key achievements to date are also outlined, including the creation of a flexible supply system to meet differing programme needs, rapid establishment of procedures, reduction in TB drug prices--a catalyst for DOTS expansion in countries, standardisation of products, and collaboration with partners. The GDF is flexible enough to meet the needs of countries with a TB burden. The GDF experience could be used as an example for global procurement of drugs and commodities for other diseases, such as HIV/AIDS and malaria. In the future it is likely that the GDF will expand to include second-line drugs and diagnostic materials for TB and could assist other partnerships to develop similar mechanisms and facilities to meet country needs.

Larvae therapy and venous leg ulcers: reducing the 'yuk factor'.

When a podiatrist modified a nylon maggot therapy containment bag used to dress a wound, debridement was slower but the maggots could be more easily observed and were easier to remove. It is also more user friendly for patients and practitioners.

Mechanisms of magnesium-stimulated adhesion of osteoblastic cells to commonly used orthopaedic implants.

Poor cell adhesion to orthopaedic and dental implants may result in implant failure. Cellular adhesion to biomaterial surfaces primarily is mediated by integrins, which act as signal transduction and adhesion proteins. Because integrin function depends on divalent cations, we investigated the effect of magnesium ions modified bioceramic substrata (Al(2)O(3)-Mg(2+)) on human bone-derived cell (HBDC) adhesion, integrin expression, and activation of intracellular signalling molecules. Immunohistochemistry, flow cytometry, cell adhesion, cell adhesion blocking, and Western blotting assays were used. Our findings demonstrated that adhesion of HBDC to Al(2)O(3)-Mg(2+) was increased compared to on the Mg(2+)-free Al(2)O(3). Furthermore, HBDC adhesion decreased significantly when the fibronectin receptor alpha5beta1- and beta1-integrins were blocked by functional blocking antibodies. HBDC grown on the Mg(2+)-modified bioceramic expressed significantly enhanced levels of beta1-, alpha5beta1-, and alpha3beta1-integrins receptors compared to those grown on the native unmodified Al(2)O(3). Tyrosine phosphorylation of intracellular integrin-dependent signalling proteins as well as the expression of key signalling protein Shc isoforms (p46, p52, p66), focal adhesion kinase, and extracellular matrix protein collagen type I were significantly enhanced when HBDC were grown on Al(2)O(3)-Mg(2+) compared to the native Al(2)O(3). We conclude that cell adhesion to biomaterial surfaces is probably mediated by alpha5beta1- and beta1-integrin. Cation-promoted cell adhesion depends on 5beta1- and beta1-integrins associated signal transduction pathways involving the key signalling protein Shc and results also in enhanced gene expression of extracellular matrix proteins. Therefore, Mg(2+) supplementation of bioceramic substrata may be a promising way to improve integration of implants in orthopaedic and dental surgery.

Local lymph node assay - validation, conduct and use in practice.

The validation of alternative methods is a relatively new activity in toxicology. The local lymph node assay (LLNA), a novel method for the identification of chemicals that have the potential to cause skin sensitization, was the first test to pass through the formal regulatory validation process established in the USA under the auspices of ICCVAM, the Interagency Coordinating Committee on the Validation of Alternative Methods. ICCVAM approved the LLNA as an alternative to guinea pig tests for the identification of skin sensitisation hazards. In this report, we explore the nine recommendations made by ICCVAM and discuss their interpretation in relation to the new OECD Guideline 429, which describes the LLNA. In particular, the value and limitations of the use of statistical evaluation of data and of the inclusion of routine positive controls is examined. It is concluded that the OECD Guideline as currently written embodies the necessary flexibility to permit conduct of the LLNA in a manner necessary to meet the varying needs of regulatory agencies and toxicologists around the world.

In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimer's disease.

Salvia lavandulaefolia Vahl. (Spanish sage) essential oil and individual monoterpenoid constituents have been shown to inhibit the enzyme acetylcholinesterase in-vitro and in-vivo. This activity is relevant to the treatment of Alzheimer's disease, since anticholinesterase drugs are currently the only drugs available to treat Alzheimer's disease. Other activities relevant to Alzheimer's disease include antioxidant, anti-inflammatory and estrogenic effects. Results of in-vitro tests for these activities are reported here for S. lavandulaefolia extracts, the essential oil and its major constituents. Antioxidant activity (inhibition of bovine brain liposome peroxidation) was found in the EtOH extract of the dried herb (5 mg mL(-1)) and the monoterpenoids (0.1 M) alpha- and beta-pinene and 1,8-cineole. Thujone and geraniol had lower antioxidant effects, while camphor had no antioxidant effects. Possible anti-inflammatory activity (eicosanoid inhibition in rat leucocytes) was found in the EtOH extract (50 microg mL(-1)) and was shown by the monoterpenoids alpha-pinene and geraniol (0.2 mM), but not 1,8-cineole, thujone or camphor. Possible estrogenic activity (via induction of beta-galactosidase activity in yeast cells) was found in the essential oil (0.01 mg mL(-1)) and the monoterpenoid geraniol (0.1-2 mM). 1,8-Cineole, alpha- and beta-pinene and thujone did not exhibit estrogenic activity in this analysis. These results demonstrate that S. lavandulaefolia, its essential oil and some chemical constituents have properties relevant to the treatment of Alzheimer's disease and provide further data supporting the value of carrying out clinical studies in patients with Alzheimer's disease using this plant species.

Utilization of amino acids in growing kidney proximal tubule cell cultures.

The growth of rat kidney proximal tubule cells was monitored continuously by the cellular incorporation of [methyl-(14)C] thymidine using scintillating microplates. The radioisotope had no effect on cell proliferation over a 5 day period, neither was it extensively converted to thymine. Leibovitz L-15 medium supplemented with bicarbonate proved a good growth medium and its high levels of carbohydrates and amino acids facilitated the appearance of intermediates in the cells' metabolism of additional radioactive amino acids. Kidney proximal tubule cells had a greater potential to process amino acids than BHK-21 cells. The utilization of amino acids by proximal tubule cells differed from that of other organs. The amino acids could be classified into three classes. Members of the first type were only used for protein synthesis (arginine, lysine, histidine and tyrosine). The second class of amino acids yielded only one or two metabolites (leucine and isoleucine), while the last type gave more than two metabolites (alanine, aspartate, glycine, methionine, proline and valine).

Who are parish nurses?

This article introduces parish nursing by describing seven areas, including: the varied professional background of nurses, their educational background, the nurse as a unique person, resources to which interdisciplinary professionals and parish nurses can turn, limitations of the practice, a brief history of the profession, and types of practices.

The structure and function of the beta 2-adaptin appendage domain.

The heterotetrameric AP2 adaptor (alpha, beta 2, mu 2 and sigma 2 subunits) plays a central role in clathrin-mediated endocytosis. We present the protein recruitment function and 1.7 A resolution structure of its beta 2-appendage domain to complement those previously determined for the mu 2 subunit and alpha appendage. Using structure-directed mutagenesis, we demonstrate the ability of the beta 2 appendage alone to bind directly to clathrin and the accessory proteins AP180, epsin and eps15 at the same site. Clathrin polymerization is promoted by binding of clathrin simultaneously to the beta 2-appendage site and to a second site on the adjacent beta 2 hinge. This results in the displacement of the other ligands from the beta 2 appendage. Thus clathrin binding to an AP2-accessory protein complex would cause the controlled release of accessory proteins at sites of vesicle formation.

Effect of surface chemical modification of bioceramic on phenotype of human bone-derived cells.

In the search for methods to improve the biocompatibility of prosthetic materials, attention has recently been directed toward the potential use of surface chemical modification and its influence on cellular behavior. This in vitro study investigates the effect of surface chemistry modification of bioceramics on human bone-derived cells (HBDCs) grown on biomaterial surfaces for 2 weeks. Cells were cultured on either alumina (Al2O3), alumina doped with magnesium ions ([Mg]-Al2O3), or hydroxyapatite (HAP), as well as tissue culture polystyrene (TCPS). Expression of alkaline phosphatase (ALP), thrombospondin (Tsp), osteopontin (OP), osteocalcin (OC), osteonectin (ON/SPARC), type I collagen (Col I), and bone sialoprotein (BSP) were determined in terms of mRNAs and proteins. Protein levels for ALP, OP, OC, and BSP were significantly (p < 0. 05) greater at day 5 in HBDCs cultured on [Mg]-Al2O3 compared to those cells grown on Al2O3. At day 14 the levels of ALP, Tsp, Col I, OP, ON/SPARC, and BSP rose significantly (p < 0.05) above those occurring in HBDCs grown on Al2O3, HAP, and TCPS. This suggests that HBDCs from the same patient respond to differences in the surface chemical groups. This study confirms that the chemistry of a substratum, which facilitates cellular adhesion, will enhance cellular differentiation.

The treatment of malignancy by hyperthermia.

The use of hyperthermia for the selective destruction of tumours may be applied by a whole body, surgical perfusion or interstitial techniques. The main determinant of selectivity is tumour blood flow. The effects of hyperthermia may be augmented by step-down heating, manipulating pH changes and sensitisation by chemotherapy or specific pharmacological agents.

Antioxidant properties of S-adenosyl-L-methionine: a proposed addition to organ storage fluids.

Glutathione (GSH) depletion adversely affects the survival of organ grafts. Supplementation of commercial organ preservation solutions with GSH is complicated by the ease of oxidation of its thiol group and its ability to act as a pro-oxidant under certain conditions. Alternative sulphur-containing compounds such as S-adenosyl-L-methionine (SAM) can reduce ischaemia-reperfusion injury, possibly by acting as glutathione precursors, and are effective when added to preservation solutions. Although the antioxidant properties of GSH are known in some detail, there is little information on the ability of SAM to interact directly with reactive oxygen species (ROS) produced during ischaemia-reperfusion injury. This work compares the interaction of SAM and GSH with several ROS which may be formed during ischaemia-reperfusion. In a variety of lipid peroxidation systems, SAM and GSH had little effect except at high concentrations (5 mM) where they became pro-oxidant. Scavenging of O2.- by both species was slow. SAM was less effective than GSH at preventing damage by peroxynitrite or HOCl. In contrast, SAM was more effective than GSH in scavenging hydroxyl radicals (.OH) and in chelating iron ions to inhibit .OH generation. Unlike GSH, SAM did not stimulate .OH formation at low concentrations. The beneficial effects of SAM in preservation solutions could therefore include direct radical scavenging as well as acting as a precursor for intracellular GSH.

Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ] propenamide and related compounds.

The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.

Cloning and functional characterization of a novel dopamine receptor from Drosophila melanogaster.

A cDNA clone is described that encodes a novel G-protein-coupled dopamine receptor (DopR99B) expressed in Drosophila heads. The DopR99B receptor maps to 99B3-5, close to the position of the octopamine/tyramine receptor gene at 99A10-B1, suggesting that the two may be related through a gene duplication. Agonist stimulation of DopR99B receptors expressed in Xenopus oocytes increased intracellular Ca2+ levels monitored as changes in an endogenous inward Ca2+-dependent chloride current. In addition to initiating this intracellular Ca2+ signal, stimulation of DopR99B increased cAMP levels. The rank order of potency of agonists in stimulating the chloride current is: dopamine > norepinephrine > epinephrine > tyramine. Octopamine and 5-hydroxytryptamine are not active (< 100 microM). This pharmacological profile plus the second-messenger coupling pattern suggest that the DopR99B receptor is a D1-like dopamine receptor. However, the hydrophobic core region of the DopR99B receptor shows almost equal amino acid sequence identity (40-48%) with vertebrate serotonergic, alpha 1- and beta-adrenergic, and D1-like and D2-like dopaminergic receptors. Thus, this Drosophila receptor defines a novel structural class of dopamine receptors. Because DopR99B is the second dopamine receptor cloned from Drosophila, this work establishes dopamine receptor diversity in a system amenable to genetic dissection.

Presence of iron catalytic for free radical reactions in patients undergoing chemotherapy: implications for therapeutic management.

We investigated the kinetics of generation of iron 'catalytic' for free radical reactions in children with diagnosed acute lymphoblastic leukaemia (ALL) who received high-dose methotrexate infusions. In 76% of the chemotherapy courses studied, 'catalytic' iron appeared in plasma in the concentration range from 0.1 to 3 mumol/l. Positive correlations between maximum levels of 'catalytic' iron and plasma hepatic enzymes could be established in the majority of cases and in one subset of patients (low and medium risk ALL) mean 'catalytic' iron levels correlated well to clinically observable toxicities. The damaging potential of 'catalytic' iron was also demonstrated experimentally: oxidative damage to proteins was significantly (P < 0.05) higher in plasma samples showing the presence of 'catalytic' iron and in addition a strong correlation (r = 0.95, P < 0.02) was seen between plasma concentration of 'catalytic' iron and the ability of the plasma to stimulate lipid peroxidation. Our data show that chemotherapy releases 'catalytic' iron which may relate to toxic side effects. Hence binding this 'catalytic' iron by judicious co-administration of iron chelating agents could be beneficial in minimizing the iatrogenic adverse effects of chemotherapy of acute leukaemia.