Nickel is a ubiquitous metal added to jewelry and metallic substances for its hardening properties and because it is inexpensive. Estimates suggest that at least 1.1 million children in the United ...States are sensitized to nickel. Nickel allergic contact dermatitis (Ni-ACD) is the most common cutaneous delayed-type hypersensitivity reaction worldwide. The incidence among children tested has almost quadrupled over the past 3 decades. The associated morbidities include itch, discomfort, school absence, and reduced quality of life. In adulthood, individuals with Ni-ACD may have severe disabling hand eczema. The increasing rate of Ni-ACD in children has been postulated to result from early and frequent exposure to metals with high amounts of nickel release (eg, as occurs with ear piercing or with products used daily in childhood such as toys, belt buckles, and electronics).To reduce exposure to metal sources with high nickel release by prolonged and direct contact with human skin, Denmark and the European Union legislated a directive several decades ago with the goal of reducing high nickel release and the incidence of Ni-ACD. Since then, there has been a global reduction in incidence of Ni-ACD in population-based studies of adults and studies of children and young adults being tested for allergic contact dermatitis. These data point to nickel exposure as a trigger for elicitation of Ni-ACD and, further, provide evidence that legislation can have a favorable effect on the economic and medical health of a population.This policy statement reviews the epidemiology, history, and appearances of Ni-ACD. Examples of sources of high nickel release are discussed to highlight how difficult it is to avoid this metal in modern daily lives. Treatments are outlined, and avoidance strategies are presented. Long-term epidemiological interventions are addressed. Advocacy for smarter nickel use is reviewed. The American Academy of Pediatrics supports US legislation that advances safety standards (as modeled by the European Union) that protect children from early and prolonged skin exposure to high-nickel-releasing items. Our final aim for this article is to aid the pediatric community in developing nickel-avoidance strategies on both individual and global levels.
A new series of raloxifene sulfonate/sulfamate derivatives were designed and synthesized. The target compounds were tested for inhibitory effect against nucleotide pyrophosphatase/phosphodiesterase-1 ...and -3 (NPP1 and NPP3) enzymes. Furthermore, all the ten target compounds were subjected to cytotoxic studies on various cancer cell lines, and the most potent derivatives were explored for their potency against these cancer cell lines as well as F180 fibroblasts to investigate the selectivity indexes. Compound 1f exerted the highest potency against HT-29 colon cancer cell line (IC50 = 1.4 μM) with 8.43-fold selectivity towards HT-29 than F180 fibroblasts. Compound 1f exerted sub-micromolar IC50 values against NPP1 and NPP3 (IC50 = 0.29 μM and 0.71 μM, respectively). The most potent inhibitors were docked in developed homology model of NPP1 and crystal structure of NPP3. All the docked analogues manifested remarkable interactions within the active pocket of NPP1 and NPP3.
Compound 1f docked into NPP1 model (IC50 = 0.29 μM). Display omitted
•A series of raloxifene sulfonate/sulfamate derivatives were synthesized and tested for NPP1&3 inhibitory effects.•Compound 1f exerted sub-micromolar IC50 values against NPP1 and NPP3 (IC50 = 0.29 μM and 0.71 μM, respectively).•Compound 1f exerted the highest potency against HT-29 colon cancer cell line (IC50 = 1.4 μM).•Compound 1f was 8.43-fold selective towards HT-29 than F180 fibroblasts.•The binding modes were studied by molecular docking.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND
Use of universally ABO‐compatible group AB plasma for trauma resuscitation can be challenging due to supply limitations. Many centers are now using group A plasma during the initial ...resuscitation of traumatically injured patients. This study was undertaken to evaluate the impact of this practice on mortality and hospital length of stay (LOS).
STUDY DESIGN AND METHODS
Seventeen trauma centers using group A plasma in trauma patients of unknown ABO group participated in this study. Eligible patients were group A, B, and AB trauma patients who received at least 1 unit of group A plasma. Data collected included patient sex, age, mechanism of injury, Trauma Injury Severity Score (TRISS) probability of survival, and number of blood products transfused. The main outcome of this study was in‐hospital mortality differences between group B and AB patients compared to group A patients. Data on early mortality (≤24 hr) and hospital LOS were also collected.
RESULTS
There were 354 B and AB patients and 809 A patients. The two study groups were comparable in terms of age, sex, TRISS probability of survival, and total number of blood products transfused. The use of group A plasma during the initial resuscitation of traumatically injured patients of unknown ABO group was not associated with increased in‐hospital mortality, early mortality, or hospital LOS for group B and AB patients compared to group A patients.
CONCLUSION
These results support the practice of issuing thawed group A plasma for the initial resuscitation of trauma patients of unknown ABO group.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Nucleoside triphosphate diphosphohydrolase1 (NTPDase1, CD39) inhibitors have potential as novel drugs for the (immuno)therapy of cancer. They increase the extracellular concentration of ...immunostimulatory ATP and reduce the formation of AMP, which can be further hydrolyzed by ecto-5’-nucleotidase (CD73) to immunosuppressive, cancer-promoting adenosine. In the present study, we synthesized analogs and derivatives of the standard CD39 inhibitor ARL67156, a nucleotide analog which displays a competitive mechanism of inhibition. Structure-activity relationships were analyzed at the human enzyme with respect to substituents in the
N
6
- and C8-position of the adenine core, and modifications of the triphosph(on)ate chain. Capillary electrophoresis coupled to laser-induced fluorescence detection employing a fluorescent-labeled ATP derivative was employed to determine the compounds’ potency. Selected inhibitors were additionally evaluated in an orthogonal, malachite green assay versus the natural substrate ATP. The most potent CD39 inhibitors of the present series were ARL67156 and its derivatives 31 and 33 with
K
i
values of around 1 µM. Selectivity studies showed that all three nucleotide analogs additionally blocked CD73 acting as dual-target inhibitors. Docking studies provided plausible binding modes to both targets. The present study provides a full characterization of the frequently applied CD39 inhibitor ARL67156, presents structure-activity relationships, and provides a basis for future optimization towards selective CD39 and dual CD39/CD73 inhibitors.
Objective: To evaluate the morphological changes that take place in the subchondral bone and calcified cartilage zone in the experimental anterior cruciate ligament (ACL) dog model of osteoarthritis ...(OA) and analyze concomitant changes in the level of MMP-13 and cathepsin K, as well as examine the therapeutic effects of licofelone, a lipoxygenase (LO)/cyclooxygenase (COX) inhibitor, on these morphological and biochemical changes.
Methods: Experimental group 1 underwent sectioning of the ACL of the right knee with no active treatment (placebo group). Experimental groups 2 and 3 underwent sectioning of the ACL of the right knee and were administered therapeutic concentrations of licofelone (2.5 or 5.0 mg/kg/day po, respectively) for 8 weeks, beginning the day following surgery. Group 4 consisted of untreated dogs used as normal control. Specimens of subchondral bone including the calcified cartilage were selected from lesional and non-lesional areas of OA tibial plateaus. Specimens were processed for static morphometric analysis and immunohistochemical analysis for MMP-13 and cathepsin K.
Results: As indicated by a reduction in bone surface and trabecular thickness, a significant loss of subchondral bone occurred in OA dogs. These changes were associated with an increased level of MMP-13 synthesis by bone cells and an increase in the osteoclast population that stained strongly positive for cathepsin K and MMP-13. Changes were much more pronounced in the specimens taken from the lesional areas. Treatment with licofelone decreased, in a dose-dependent manner, the OA bone morphological changes at the same time it reduced the level of MMP-13 in bone cells and the number of cathepsin K and MMP-13 positive osteoclasts.
Conclusions: Increased bone loss and bone resorption is associated with the development of OA cartilage lesions. Licofelone treatment was found to prevent the morphological and biochemical changes seen in early experimental OA effectively. These findings may help explain the mechanisms by which this drug could exert its possible effect on the development of OA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Canada experienced two distinct waves of pandemic (H1N1) influenza during the 2009 pandemic, one in the spring and the second in early fall 2009. We compared the incidence of hospital admissions and ...severe outcomes (admission to intensive care unit ICU and death) during the two waves.
We reviewed data on all laboratory-confirmed cases of pandemic (H1N1) influenza that resulted in hospital admission, ICU admission or death reported to the Public Health Agency of Canada by all provinces and territories from Apr. 18, 2009, to Apr. 3, 2010.
A total of 8678 hospital admissions (including 1473 ICU admissions) and 428 deaths related to pandemic (H1N1) influenza were reported during the pandemic and post-peak period. There were 4.8 times more hospital admissions, 4.0 times more ICU admissions and 4.6 times more deaths in the second pandemic wave than in the first wave. ICU admissions and deaths as a proportion of hospital admissions declined in the second wave; there was a 16% proportional decline in ICU admissions and a 6% proportional decline in deaths compared with the first wave. Compared with patients admitted to hospital in the first wave, those admitted in the second wave were older (median age 30 v. 23 years) and more had underlying conditions (59.7% v. 47.5%). Pregnant women and Aboriginal people accounted for proportionally fewer patients who were admitted to hospital or who died in the second wave than in the first.
The epidemiologic features of the first and second waves of the 2009 pandemic differed. The second wave was substantially larger and, although the patients admitted to hospital were older and more of them had underlying conditions, a smaller proportion had a severe outcome.
Introduction
Heparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found to possess ...additional antitumor activities. Ectonucleotidases have recently been proposed as novel targets for cancer immunotherapy.
Methods and results
In the present study, we discovered that heparin and its derivatives act as potent, selective, allosteric inhibitors of the poorly investigated ectonucleotidase NPP1 (nucleotide pyrophosphatase/phosphodiesterase-1, CD203a). Structure-activity relationships indicated that NPP1 inhibition could be separated from the compounds’ antithrombotic effect. Moreover, unfractionated heparin (UFH) and different low molecular weight heparins (LMWHs) inhibited extracellular adenosine production by the NPP1-expressing glioma cell line U87 at therapeutically relevant concentrations. As a consequence, heparins inhibited the ability of U87 cell supernatants to induce CD4+ T cell differentiation into immunosuppressive Treg cells.
Discussion
NPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer.
Ectonucleoside triphosphate diphosphohydrolases (NTPDases) catalyze the hydrolysis of nucleoside tri- and di-phosphates to mono-phosphates. The products are subsequently hydrolyzed by ...ecto-5′-nucleotidase (ecto-5′-NT) to nucleosides. NTPDase inhibitors have potential as novel drugs, e.g., for the treatment of inflammation, neurodegenerative diseases, and cancer. In this context, a series of anthraquinone derivatives structurally related to the anthraquinone dye reactive blue-2 (RB-2) was synthesized and evaluated as inhibitors of human NTPDases utilizing a malachite green assay. We identified several potent and selective inhibitors of human NTPDase2 and -3. Among the most potent NTPDase2 inhibitors were 1-amino-4-(9-phenanthrylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (20, PSB-16131, IC
50
of 539 nM) and 1-amino-4-(3-chloro-4-phenylsulfanyl)phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (48, PSB-2020, IC
50
of 551 nM). The most potent NTPDase3 inhibitors were 1-amino-4-3-(4,6-dichlorotriazin-2-ylamino)-4-sulfophenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (42, PSB-1011, IC
50
of 390 nM) and 1-amino-4-(3-carboxy-4-hydroxyphenylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (33, PSB-2046, IC
50
of 723 nM). The best NTPDase2 inhibitor 20 showed a non-competitive inhibition type, while the NTPDase3 inhibitor 42 behaved as a mixed-type inhibitor. These potent compounds were found to be selective vs. other NTPDases. They will be useful tools for studying the roles of NTPDase2 and -3 in physiology and under pathological conditions.
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