Purpose
To describe the characteristics of Japanese patients with hydroxychloroquine (HCQ) retinopathy developing within 3 years of treatment outset.
Study design
Retrospective case series
Methods
...Three patients with HCQ retinopathy developing within 3 years of treatment outset have been identified in Japan since HCQ became available in 2015. Their medical charts, containing optical coherence tomography (OCT), fundus autofluorescence imaging, and visual field tests, were reviewed.
Results
The treatment durations and cumulative doses until onset were 29–36 months and 182–326 g, respectively. The first patient had possible pre-existing maculopathy, although the abnormalities were ambiguous. The second and third patients had impaired renal function. The patients did not complain of severe visual disturbance at diagnosis, but visual field loss and disruption of the outer retinal segments consisting of a parafoveal pattern in the first case and a pericentral pattern (localized, 8 or more degrees from the center of the fovea) in the second and third cases were clearly observed on OCT. Even after HCQ discontinuation, their retinopathy showed slight progression on the visual field tests and OCT images. A blood sample was obtained from 1 patient on the day after HCQ discontinuation, and the whole blood level of HCQ was measured using validated liquid chromatography-tandem mass spectrometry. The HCQ level 27 h after the last dose was high, at 2240 ng/mL (suggested threshold > 1733 ng/mL).
Conclusion
Ophthalmologic screening from the initiation of HCQ treatment detected 3 cases of HCQ retinopathy developing within 3 years of treatment outset, including a patient with a high blood level of HCQ.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Vaccination is widely used to control foot-and-mouth disease (FMD), but maternal antibodies may interfere with the response to vaccination in calves. This study, conducted on a regularly vaccinated ...Malaysian dairy farm, aimed to optimise the vaccination regime by measuring the in vitro neutralising virus antibody responses of 51 calves before and after vaccination with a one or two dose vaccination regime starting at 2-7 months old. The presence of maternal antibodies was associated with poor post-vaccination antibody responses after a single dose of vaccine in calves less than 6 months old. However, a second dose of vaccine given three weeks later, improved the antibody responses in all ages of calves. This confirms the view that in regularly vaccinated farms, some combination of delay and revaccination is needed to achieve effective immunization of calves. Sera from cows and pre-vaccinated calves neutralised homologous serotype A vaccine virus more strongly than a heterologous serotype A field virus, but this pattern was reversed in some calves after vaccination. The strength of heterologous responses in calves 49 days after first vaccination correlated to the amount of transferred maternal antibody, suggesting that pre-existing antibodies could have modulated the specificity of these active antibody responses. If confirmed, such an effect by pre-existing antibodies could have wider implications for broadening the coverage of FMD vaccine responses.
B cell homeostasis has been shown to critically depend on BAFF, the B cell activation factor from the tumor necrosis factor (TNF) family. Although BAFF is already known to bind two receptors, BCMA ...and TACI, we have identified a third receptor for BAFF that we have termed BAFF-R. BAFF-R binding appears to be highly specific for BAFF, suggesting a unique role for this ligand-receptor interaction. Consistent with this, the BAFF-R locus is disrupted in A/WySnJ mice, which display a B cell phenotype qualitatively similar to that of the BAFF-deficient mice. Thus, BAFF-R appears to be the principal receptor for BAFF-mediated mature B cell survival.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The purpose of this study was to determine the relative sensitivity and specificity of 10-2 visual fields (10-2 VFs), multifocal electroretinography (mfERG), and spectral domain optical coherence ...tomography (SD-OCT) in detecting hydroxychloroquine retinopathy.
A total of 121 patients taking hydroxychloroquine (n=119) or chloroquine (n=2) with 10-2 VF, mfERG, and SD-OCT tests were retrospectively reviewed. Rates of test abnormality were determined.
Retinopathy was present in 14 and absent in 107. Eleven of 14 (78.6%) patients with retinopathy were overdosed. Twelve (85.7%) had cumulative dosing greater than 1,000 g. The sensitivities of 10-2 VF, mfERG, and SD-OCT in detecting retinopathy were 85.7%, 92.9%, and 78.6%, respectively. The specificities of 10-2 VF, mfERG, and SD-OCT in detecting retinopathy were 92.5%, 86.9%, and 98.1%, respectively. Positive predictive values of 10-2 VF, mfERG, and SD-OCT in detecting retinopathy were less than 30% for all estimates of hydroxychloroquine retinopathy prevalence. Negative predictive values were >99% for all tests.
Based on published estimates of hydroxychloroquine retinopathy prevalence, all three tests are most reliable when negative, allowing confident exclusion of retinopathy in patients taking ≤6.5 mg/kg/day. Each test is less useful in allowing a confident diagnosis of retinopathy when positive, especially in patients taking ≤6.5 mg/kg/day.
Nutrients limiting phytoplankton growth in the ocean are a critical control on ocean productivity and can underpin predicted responses to climate change. The extensive western subtropical North ...Pacific is assumed to be under strong nitrogen limitation, but this is not well supported by experimental evidence. Here, we report the results of 14 factorial nitrogen–phosphorus–iron addition experiments through the Philippine Sea, which demonstrate a gradient from nitrogen limitation in the north to nitrogen–iron co‐limitation in the south. While nitrogen limited sites responded weakly to nutrient supply, co‐limited sites bloomed with up to ~60‐fold increases in chlorophyll a biomass that was dominated by initially undetectable diatoms. The transition in limiting nutrients and phytoplankton growth capacity was driven by a gradient in deep water nutrient supply, which was undetectable in surface concentration fields. We hypothesize that this large‐scale phytoplankton response gradient is both climate sensitive and potentially important for regulating the distribution of predatory fish.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Multiple myeloma is a life-threatening hematological malignancy, which is rarely curable by conventional therapies. Immunotherapy, using tumor antigen-specific, cytotoxic T-lymphocytes, may represent ...an alternative or additional treatment for multiple myeloma. In this study, we used hybrid cell lines, generated by fusion of an EBV B-lymphoblastoid cell line (B-LCL) and myeloma cells, to stimulate
peripheral blood lymphocytes (PBLs) from patients with multiple myeloma. We investigated induction of antigen-specific, cytotoxic T-lymphocytes to the well-defined tumor associated antigens (TAAs) hTERT, MUC1, MAGE-C1 and CS1, which have been shown to be expressed in a high proportion of cases of multiple myeloma. HLA-A2-peptide pentamer staining, interferon-γ and perforin ELISpot assays, as well as cytotoxicity assays were used. Following several rounds of
stimulation, the hybrid cell lines induced antigen-specific, cytotoxic T-lymphocytes to four candidate TAAs in PBLs from HLA-A2
multiple myeloma patients, using known HLA-A2 restricted peptide epitopes of the TAAs. In contrast, the HLA-A2
myeloma cell line U266 failed to induce antigen-specific, cytotoxic T-lymphocytes
. Our data indicate that B-LCL/myeloma hybrid cell lines induce antigen-specific, cytotoxic T-lymphocytes in PBLs isolated from multiple myeloma patients
and may represent a novel strategy for use in adoptive immunotherapy of multiple myeloma.
Objective To determine whether programmed cell death 4 (PDCD-4) is altered in autologous leiomyoma and myometrial tissues and what microRNA-21's (miR-21) role is in PDCD-4 expression, apoptosis, and ...translation. Design Laboratory research. Setting Academic medical center. Patient(s) Myometrial and leiomyoma tissues from patients with symptomatic leiomyomata. Intervention(s) Tissue analysis and miR-21 knockdown in cultured immortalized myometrial (UtM) and leiomyoma (UtLM) cells. Main Outcome Measure(s) MiR-21 and PDCD-4 mRNA and protein expression. Result(s) Leiomyoma tissues robustly expressed the full-length 51 kd isoform of PDCD-4, but normal myometrial tissue had negligible expression. Consistent with autologous tissues, UtLM cells expressed elevated miR-21 and a similar pattern of PDCD-4 compared with UtM cells. Knockdown of miR-21 increased PDCD-4 levels in UtM cells and UtLM cells, indicating that it can regulate PDCD-4 expression. Loss of miR-21 also increased cleavage of caspase-3 (apoptosis marker) and increased phosphorylation of elongation factor-2 (marker of reduced translation) in both cell lines. Conclusion(s) Elevated leiomyoma miR-21 levels are predicted to decrease PDCD-4 levels, thus leiomyomas differ from other tumors where loss of PDCD-4 is associated with tumor progression. Our studies indicate regulation of PDCD-4 expression is not a primary miR-21 function in leiomyomas, but instead miR-21 is able to impact cellular apoptosis and translation, through unknown targets, in a manner consistent with its involvement in the pathophysiology of uterine fibroids.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A fuel cell operating with aqueous sodium borohydride and hydrogen peroxide streams, with one, two and four cells (electrode area 64, 128 and 256
cm
2) connected in a bipolar mode in a filterpress ...flow cell is reported. The oxidation of borohydride ion was carried out on Au/C particles supported on a carbon felt electrode while the reduction of hydrogen peroxide was carried out on carbon supported Pt on a carbon paper substrate. Comparable cell potentials and power densities to direct borohydride fuel cells reported in the literature were obtained. The challenges to further development includes: increasing the low current density and avoid decomposition of borohydride and peroxide ions. The maximum power obtained at 20
°C for one, two and four cell stacks was 2.2, 3.2 and 9.6
W (34.4, 25 and 37.5
mW
cm
−2, respectively) with cell voltages of 1.06, 0.81 and 3.2
V at current densities of 32, 16 and 12
mA
cm
−2, respectively.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Nitrogen fixation is critical for the biological productivity of the ocean, but clear mechanistic controls on this process remain elusive. Here, we investigate the abundance, activity, and drivers of ...nitrogen-fixing diazotrophs across the tropical western North Pacific. We find a basin-scale coherence of diazotroph abundances and N
fixation rates with the supply ratio of iron:nitrogen to the upper ocean. Across a threshold of increasing supply ratios, the abundance of
genes and N
fixation rates increased, phosphate concentrations decreased, and bioassay experiments demonstrated evidence for N
fixation switching from iron to phosphate limitation. In the northern South China Sea, supply ratios were hypothesized to fall around this critical threshold and bioassay experiments suggested colimitation by both iron and phosphate. Our results provide evidence for iron:nitrogen supply ratios being the most important factor in regulating the distribution of N
fixation across the tropical ocean.
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