Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. ...Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of x(c)--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The x(c)- cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine.
We report multicolor optical imaging and polarimetry observations of the afterglow of the first TeV-detected gamma-ray burst (GRB), GRB 190114C, using the RINGO3 and MASTER II polarimeters. ...Observations begin 31 s after the onset of the GRB and continue until ∼7000 s postburst. The light curves reveal a chromatic break at ∼400-500 s, with initial temporal decay = 1.669 0.013 flattening to ∼ 1 postbreak, which we model as a combination of reverse and forward shock components with magnetization parameter RB ∼ 70. The observed polarization degree decreases from 7.7% 1.1% to 2%-4% 52-109 s postburst and remains steady at this level for the subsequent ∼2000 s at a constant position angle. Broadband spectral energy distribution modeling of the afterglow confirms that GRB 190114C is highly obscured (Av,HG = 1.49 0.12 mag; cm−2). We interpret the measured afterglow polarization as intrinsically low and dominated by dust -in contrast to the P > 10% measured previously for other GRB reverse shocks-with a small contribution from polarized prompt photons in the first minute. We test whether first- and higher-order inverse Compton scattering in a magnetized reverse shock can explain the low optical polarization and subteraelectronvolt emission but conclude that neither is explained in the reverse shock inverse Compton model. Instead, the unexpectedly low intrinsic polarization degree in GRB 190114C can be explained if large-scale jet magnetic fields are distorted on timescales prior to reverse shock emission.
Aims
To examine prescribed psychotropic medicine use on a given day in Australia (25 September 2018; World Pharmacists Day), with a focus on psychotropic polypharmacy.
Methods
We used a 10% sample of ...individual‐level nationwide dispensing claims to examine psychotropic medicine use on a given day. We estimated the prevalence of psychotropic medicine use in all ages stratified by age and sex. We also calculated the observed vs expected (had medicines been randomly combined) prevalence of psychotropic combinations used. We focused on combinations of clinical significance as well combinations of psychotropics with medicines prescribed to manage cardiovascular risk and disease.
Results
Serotonin reuptake inhibitors, serotonin–noradrenalin reuptake inhibitors/noradrenaline reuptake inhibitors, tricyclic antidepressants and gabapentinoids dominated psychotropic use. The use of any psychotropic as a proportion of people in the Australian population increased with age, peaking at the 85–89 year age group and declining thereafter. Combinations of medicines from the same subclass generally occurred at lower than expected frequencies. However, combinations including atypical antipsychotics occurred more frequently than expected; e.g. 7.4× with anticonvulsants and 2.2× with other atypical antipsychotics. This was also the case for combinations of sedatives, e.g. anxiolytic with hypnotic benzodiazepines (3.8×). Lipid‐lowering drugs and antidiabetic medicines were combined with psychotropics at frequencies close to those expected had they been randomly combined.
Conclusion
Psychotropic use in older adults and certain psychotropic combinations that are not well supported with evidence remain prevalent and greater consideration of the drivers of this potentially inappropriate prescribing is required.
Summary
Background The seventh amendment of the European Union (EU) Cosmetics Directive (March 2005) and the Detergents Regulations of the EU (October 2005) are now legal requirements in Europe. ...Cosmetic products and detergents must be labelled for 26 individual named fragrances, when present at concentrations of > 10 parts per million (p.p.m.) in leave‐on products and > 100 p.p.m. in rinse‐off products.
Objectives To make an assessment of the exposure pattern to fragrance of the U.K. consumer and to determine the frequency with which the constituent fragrances of fragrance mix I (FM I) and fragrance mix II (FM II) are included in products currently sold in the U.K.
Methods A study of perfumed cosmetic and household products available on the shelves of U.K. retailers was carried out in January 2006. Products were included if ‘parfum’ or ‘aroma’ was listed among the ingredients. Three hundred products were surveyed and any of the 26 listed fragrances named on the label were recorded.
Results The top six most frequently labelled fragrances were linalool (190; 63%), limonene (189; 63%), citronellol (145; 48%), geraniol (126; 42%), butyl phenyl methyl propional (Lilial™) (126; 42%) and hexyl cinnamal (125; (42%). One of these, geraniol, is present in FM I and two others, citronellol and hexyl cinnamal, in FM II, thus tested as part of the British Standard patch test series. The frequencies of other constituents of FM I were as follows: eugenol, 80 (27%); hydroxycitronellal, 52 (17%); isoeugenol, 27 (9%); cinnamic alcohol, 25 (8%); amyl cinnamal, 22 (7%); cinnamal, 17 (6%); Evernia prunastri (oak moss absolute), 13 (4%). The other constituents of FM II occurred as follows: coumarin, 90 (30%); hydroxyisohexyl‐3‐cyclohexene carboxaldehyde (Lyral™), 88 (29%); citral, 74 (25%); farnesol, 23 (8%). Linalool (n = 46; 66%) was the most frequently found fragrance in 70 personal care products (soap, shampoo, shower gel). Linalool (n = 47; 80%) and limonene (n = 45; 76%) were the most frequent in 59 products for men (e.g. aftershave). Limonene (n = 29; 51%) predominated in 57 household products (washing‐up liquid, detergent). Limonene (n = 43; 98%) and linalool (n = 42; 95%) were the most frequent fragrances in 44 perfumes for women. Alpha‐isomethyl ionone (n = 28; 72%) was the most frequent in 39 cosmetics (foundation, lipstick, etc). Citronellol predominated (n = 15; 88%) in 17 deodorants and limonene (n = 9; 64%) was the commonest in 14 dental products (toothpaste and mouthwash). Thirty‐four products (11%) contained none of the listed fragrances but were labelled as containing ‘parfum’ or ‘aroma’.
Conclusions There is ongoing consumer exposure to the most frequent sensitizers in FM I: E. prunastri, isoeugenol and the cinnamon fragrances cinnamal and cinnamic alcohol. Hydroxyisohexyl‐3‐cyclohexene carboxaldehyde (Lyral™) is present at significant concentrations in almost one‐third of products. Linalool and limonene, fragrance terpenes which are significant allergens in their oxidized state, are the most frequent fragrances encountered by individuals living in the U.K. The current exposure pattern of the U.K. consumer suggests that we should add oxidized limonene and oxidized linalool to the test series for patients suspected to have fragrance allergy.
The Engineering Field Testing Platform (EFTP) was designed to provide an opportunity for technology developers (TDs) to test non-sewered sanitation prototypes in the eThekwini Municipal Area ...(Durban), South Africa. Between 2017 and 2020, 15 sanitation systems were tested in informal settlements, peri-urban households, and other ‘real world’ settings. This paper illustrates the lessons learned from establishing and managing this testing platform. Costs and timelines for testing are dependent on several factors, including the aims of testing, the development stage of the prototype, whether testing takes place in a community or household setting and if a testing site is shared between prototypes. Timelines were routinely underestimated, particularly for community engagement and commissioning of prototypes to reach steady-state operation. Personnel accounted for more than half of the EFTP’s costs. The presence of the municipality as a platform partner was vital to the success of testing, both for gaining political support and for enabling access to testing sites. It is noted that working in communities, with test sites in public spaces, requires technical and social sensitivity to context. It was important to ensure testing supported future municipal decision-making on service provision, as well as longer-term development within communities. The high number of stakeholders, locally and internationally, raised management challenges common to any large project. However, the EFTP added value to TDs, the eThekwini Municipality, and communities requiring improved sanitation services; this was amplified through the platform approach.
Evidence for the changing regimens of acetylcysteine Chiew, Angela L.; Isbister, Geoffrey K.; Duffull, Stephen B. ...
BJCP. British journal of clinical pharmacology/British journal of clinical pharmacology,
March 2016, Letnik:
81, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Paracetamol overdose prior to the introduction of acetylcysteine was associated with significant morbidity. Acetylcysteine is now the mainstay of treatment for paracetamol poisoning and has ...effectively reduced rates of hepatotoxicity and death. The current three‐bag intravenous regimen with an initial high loading dose was empirically derived four decades ago and has not changed since. This regimen is associated with a high rate of adverse effects due mainly to the high initial peak acetylcysteine concentration. Furthermore, there are concerns that the acetylcysteine concentration is not adequate for ‘massive’ overdoses and that the dose and duration may need to be altered. Various novel regimens have been proposed, looking to address these issues. Many of these modified regimens aim to decrease the rate of adverse reactions by slowing the loading dose and thereby decrease the peak concentration. We used a published population pharmacokinetic model of acetylcysteine to simulate these modified regimens. We determined mean peak and 20 h acetylcysteine concentrations and area under the under the plasma concentration–time curve to compare these regimens. Those regimens that resulted in a lower peak acetylcysteine concentration have been shown in studies to have a lower rate of adverse events. However, these studies were too small to show whether they are as effective as the traditional regimen. Further research is still needed to determine the optimum dose and duration of acetylcysteine that results in the fewest side‐effects and treatment failures. Indeed, a more patient‐tailored approach might be required, whereby the dose and duration are altered depending on the paracetamol dose ingested or paracetamol concentrations.
The study assessed the suitability of two effluent types, namely anaerobic filtered (AF) and horizontal flow constructed wetland (HFCW) effluent for Moistube irrigation (MTI). Secondary to this, the ...study determined the plugging coefficients (α) on MTI for the respective effluents. The feed water was supplied from a raised tank (3.5 m), and mass-flow rates were recorded at 15 min intervals using an electronic balance. The effluent feed water concentrations and experimental room temperature (25 °C ± 1 °C) were continuously monitored and kept constant. Hermia's models based on the Formula: see text coefficient was used to select the best fitting fouling mechanism model and, consequently, the plugging coefficients. In addition, microbial colony analysis and scanning electron microscopy (SEM) analysis was carried out to assess the composition of the deposited sediment (DS) and adhered bacterial film (ABF) onto the MTI lateral. The study revealed that MTI pore blocking was a complex phenomenon described by complete pore-blocking model (Formula: see text ≥ 0.50). Discharge followed an exponential decay with early fouling observed on AF effluent because of a high concentration of total suspended solids (TSS) and dissolved organic matter (DOM). Discharge declined by 50% after 20 and 10 h of intermittent operation for AF and HFCW effluent, respectively. The α for each effluent (foulant) were Formula: see text = 0.07 and Formula: see text = 0.05, respectively, for AF and HFCW. The microbial analysis revealed bacterial aggregation structures that contributed to pore blocking. SEM imaging revealed complete surface coverage by deposited sediment. It is concluded that water quality determines the operation life span of MTI, and the two effluents promote accelerated MTI pore fouling or blocking. Continuous use without flushing the MTI will promote membrane degradation and reduced discharge efficiency. Additional filtration can potentially mitigate the membrane degradation process.
The early afterglow of GRB 190829A Dichiara, S; Troja, E; Lipunov, V ...
Monthly notices of the Royal Astronomical Society,
03/2022, Letnik:
512, Številka:
2
Journal Article
Recenzirano
ABSTRACT
GRB 190829A at z = 0.0785 is the fourth closest long GRB ever detected by the Neil Gehrels Swift observatory, and the third confirmed case with a very high-energy component. We present our ...multiwavelength analysis of this rare event, focusing on its early stages of evolution, and including data from Swift, the MASTER global network of optical telescopes, ALMA, and ATCA. We report sensitive limits on the linear polarization of the optical emission, disfavouring models of off-axis jets to explain the delayed afterglow peak. The study of the multiwavelength light curves and broad-band spectra supports a model with at least two emission components: a bright reverse shock emission, visible at early times in the optical and X-rays and, later, in the radio band; and a forward shock component dominating at later times and lower radio frequencies. A combined study of the prompt and afterglow properties shows many similarities with cosmological long GRBs, suggesting that GRB 190829A is an example of classical GRBs in the nearby universe.
We report on the results of the extensive multi-wavelength campaign from optical to GeV γ-rays of the 2014 periastron passage of PSR B1259−63, which is a unique high-mass γ-ray emitting binary system ...with a young pulsar companion. Observations demonstrate the stable nature of the post-periastron GeV flare and prove the coincidence of the flare with the start of rapid decay of the Hα equivalent width, usually interpreted as a disruption of the Be stellar disc. Intensive X-ray observations reveal changes in the X-ray spectral behaviour happening at the moment of the GeV flare. We demonstrate that these changes can be naturally explained as a result of synchrotron cooling of monoenergetic relativistic electrons injected into the system during the GeV flare.
Uveal melanoma is a rare, but deadly, form of eye cancer that arises from melanocytes within the uveal tract. Although advances have emerged in treatment of the primary tumour, patients are still ...faced with vision loss, eye enucleation and lethal metastatic spread of the disease. Approximately 50% of uveal melanoma patients develop metastases, which occur most frequently in the liver. Metastatic patients encounter an extremely poor prognosis; as few as 8% survive beyond 2 years. Understanding of the genetic underpinnings of this fatal disease evolved in recent years with the identification of new oncogenic mutations that drive uveal melanoma pathogenesis. Despite this progress, the lack of successful therapies or a proven
standard-of-care
for uveal melanoma highlights the need for new targeted therapies. This review focuses on the recently identified
CYSLTR2
oncogenic mutation in uveal melanoma. Here, we evaluate the current status of uveal melanoma and investigate how to better understand the role of this
CYSLTR2
mutation in the disease and implications for patients harbouring this mutation.
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