We hypothesized that de novo donor‐specific antibody (DSA) causes complement‐dependent endothelial cell injury in kidney transplants, as assessed by expression of endothelial cell–associated ...transcripts (ENDATs), that may be attenuated through complement inhibition. In total, 15 participants (five control, 10 treatment) with DSA and deteriorating renal function were enrolled. The treatment group received 6 mo of eculizumab followed by 6 mo of observation, whereas controls were observed. The primary end point was percentage change in estimated GFR (eGFR) trajectory over the treatment period. The treatment group had an improved eGFR trajectory versus control, based on our predetermined two‐sided 0.10 significance level (p = 0.09). Within‐subject analysis of treated participants at 6‐mo intervals did not show significant change (p = 0.60). Modeling C1q status showed that C1q‐positive patients had significantly higher mean eGFR than patients with negative C1q (p = 0.04). Biopsies revealed elevated renal ENDATs in most participants, but ENDATs were not reduced with complement inhibition. Our data suggest that eculizumab treatment may stabilize kidney function in patients with chronic persistent DSA based on our pilot a priori significance threshold. ENDAT expression predicative of acute humoral injury is not reduced with complement inhibition in this chronic setting. Further studies will be necessary to determine which patients may benefit from eculizumab.
Preliminary evidence suggests an association between terminal complement inhibition and stabilization of renal function in kidney transplant recipients who have deteriorating glomerular filtration caused by chronic, persistent donor‐specific antibody.
The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. However, although monoclonal antibodies targeting the cytotoxic T‐lymphocyte ...antigen‐4 and programmed death‐1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatological immune‐related adverse events (irAEs), ranging from mild to life‐threatening. Several publications have addressed the clinical and histopathological classification of these skin‐directed irAEs, their impact on anti‐tumour immunity and survival, and the critical role of supportive oncological dermatology in their management. In this paper, we review the current understanding of the mechanistic drivers of immune‐related skin toxicities with a focus on inflammatory, immunobullous and melanocyte/pigment‐related reactions. We detail the specific immune‐based mechanisms that may underlie different cutaneous reactions. We also discuss potential mechanisms as they relate to extracutaneous irAEs and the lessons learned from these, the potential overlap with cutaneous irAEs, techniques to study differences in immune‐related vs. de novo skin reactions, and how treatment of these AEs impacts cancer treatment, patient quality of life and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood‐based biomarkers that could help ultimately predict onset and/or severity of these irAEs, and to implement rational mechanistic‐based treatment strategies that are targeted to the irAEs while potentially avoiding reducing the anti‐tumour effect of ICIs.
Immune checkpoint inhibitor therapies have revolutionized the field of cancer therapy, but are associated with cutaneous immune‐related adverse events (irAEs), ranging from mild to life‐threatening. We review the mechanisms involved in the pathogenesis of cutaneous irAEs, with an emphasis on inflammatory/immunobullous reactions and pigment changes. We also discuss experimental methods to study the immunopathogenesis of cutaneous irAEs, and lessons learned from the study of extracutaneous irAEs.
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The evolution of a Type IIn supernova (SN IIn) is governed by the interaction between the SN ejecta and a hydrogen-rich circumstellar medium. The SNe IIn thus allow us to probe the late-time ...mass-loss history of their progenitor stars. We present a sample of SNe IIn from the untargeted, magnitude-limited surveys of the Palomar Transient Factory (PTF) and its successor, the intermediate PTF (iPTF). To date, statistics on SN IIn optical light-curve properties have generally been based on small (≲10 SNe) samples from targeted SN surveys. The SNe IIn found and followed by the PTF/iPTF were used to select a sample of 42 events with useful constraints on the rise times as well as with available post-peak photometry. The sample SNe were discovered in 2009−2016 and have at least one low-resolution classification spectrum, as well as photometry from the P48 and P60 telescopes at Palomar Observatory. We study the light-curve properties of these SNe IIn using spline fits (for the peak and the declining portion) and template matching (for the rising portion). We study the peak-magnitude distribution, rise times, decline rates, colour evolution, host galaxies, and K-corrections of the SNe in our sample. We find that the typical rise times are divided into fast and slow risers at 20 ± 6 d and 50 ± 11 d, respectively. The decline rates are possibly divided into two clusters (with slopes 0.013 ± 0.006 mag d
−1
and 0.040 ± 0.010 mag d
−1
), but this division has weak statistical significance. We find no significant correlation between the peak luminosity of SNe IIn and their rise times, but the more luminous SNe IIn are generally found to be more long-lasting. Slowly rising SNe IIn are generally found to decline slowly. The SNe in our sample were hosted by galaxies of absolute magnitude −22 ≲
M
g
≲ −13 mag. The K-corrections at light-curve peak of the SNe IIn in our sample are found to be within 0.2 mag for the observer’s frame
r
-band, for SNe at redshifts
z
< 0.25. By applying K-corrections and also including ostensibly “superluminous” SNe IIn, we find that the peak magnitudes are
M
r
peak
= −19.18 ± 1.32 mag. We conclude that the occurrence of conspicuous light-curve bumps in SNe IIn, such as in iPTF13z, are limited to 1.4
+14.6
−1.0
% of the SNe IIn. We also investigate a possible sub-type of SNe IIn with a fast rise to a ≳50 d plateau followed by a slow, linear decline.
For the first time in the literature, experimental determination of entire sets of exact interdiffusion coefficients in quaternary and quinary alloy systems is reported. Using the method of ...body-diagonal diffusion couple, a set of nine quaternary interdiffusion coefficients were evaluated in Fe–Ni–Co–Cr and a set of sixteen quinary interdiffusion coefficients were determined in a Fe–Ni–Co–Cr–Mn system, both at approximately equimolar compositions. Regions of uphill interdiffusion and zero flux planes were observed for nickel and cobalt in quinary couples, indicating the existence of strong diffusional interactions in Fe–Ni–Co–Cr–Mn alloys. The strong diffusional interactions were also manifested in the large magnitudes of cross coefficients in both the systems. The existence of strong diffusional interactions in high-entropy alloys (HEAs) as observed through experimentally determined interdiffusion coefficients in this study establishes beyond doubt the fact that cross interdiffusion coefficients cannot be ignored in HEAs.
Abstract It is well known that physical inactivity leads to loss of muscle mass, but it also causes bone loss. Mechanistically, osteoclastogenesis and bone resorption have recently been shown to be ...regulated by vibration. However, the underlying mechanism behind the inhibition of osteoclast formation is yet unknown. Therefore, we investigated whether mechanical vibration of osteoclast precursor cells affects osteoclast formation by the involvement of fusion-related molecules such as dendritic cell-specific transmembrane protein (DC-STAMP) and P2X7 receptor (P2X7R). RAW264.7 (a murine osteoclastic-like cell line) cells were treated with 20 ng/ml receptor activator of NF-κB ligand (RANKL). For 3 consecutive days, the cells were subjected to 1 h of mechanical vibration with 20 μm displacement at a frequency of 4 Hz and compared to the control cells that were treated under the same condition but without the vibration. After 5 days of culture, osteoclast formation was determined. Gene expression of DC-STAMP and P2X7R by RAW264.7 cells was determined after 1 h of mechanical vibration, while protein production of the DC-STAMP was determined after 6 h of postincubation after vibration. As a result, mechanical vibration of RAW264.7 cells inhibited the formation of osteoclasts. Vibration down-regulated DC-STAMP gene expression by 1.6-fold in the presence of RANKL and by 1.4-fold in the absence of RANKL. Additionally, DC-STAMP protein production was also down-regulated by 1.4-fold in the presence of RANKL and by 1.2-fold in the absence of RANKL in RAW264.7 cells in response to mechanical vibration. However, vibration did not affect P2X7R gene expression. Mouse anti-DC-STAMP antibody inhibited osteoclast formation in the absence of vibration. Our results suggest that mechanical vibration of osteoclast precursor cells reduces DC-STAMP expression in osteoclast precursor cells leading to the inhibition of osteoclast formation.
Aerosolized vaccine can be used as a needle-free method of immunization against measles, a disease that remains a major cause of illness and death. Data on the immunogenicity of aerosolized vaccine ...against measles in children are inconsistent.
We conducted an open-label noninferiority trial involving children 9.0 to 11.9 months of age in India who were eligible to receive a first dose of measles vaccine. Children were randomly assigned to receive a single dose of vaccine by means of either aerosol inhalation or a subcutaneous injection. The primary end points were seropositivity for antibodies against measles and adverse events 91 days after vaccination. The noninferiority margin was 5 percentage points.
A total of 1001 children were assigned to receive aerosolized vaccine, and 1003 children were assigned to receive subcutaneous vaccine; 1956 of all the children (97.6%) were followed to day 91, but outcome data were missing for 331 children because of thawed specimens. In the per-protocol population, data on 1560 of 2004 children (77.8%) could be evaluated. At day 91, a total of 662 of 775 children (85.4%; 95% confidence interval CI, 82.5 to 88.0) in the aerosol group, as compared with 743 of 785 children (94.6%; 95% CI, 92.7 to 96.1) in the subcutaneous group, were seropositive, a difference of -9.2 percentage points (95% CI, -12.2 to -6.3). Findings were similar in the full-analysis set (673 of 788 children in the aerosol group 85.4% and 754 of 796 children in the subcutaneous group 94.7% were seropositive at day 91, a difference of -9.3 percentage points 95% CI, -12.3 to -6.4) and after multiple imputation of missing results. No serious adverse events were attributable to measles vaccination. Adverse-event profiles were similar in the two groups.
Aerosolized vaccine against measles was immunogenic, but, at the prespecified margin, the aerosolized vaccine was inferior to the subcutaneous vaccine with respect to the rate of seropositivity. (Funded by the Bill and Melinda Gates Foundation; Measles Aerosol Vaccine Project Clinical Trials Registry-India number, CTRI/2009/091/000673.).
Integrative organ crosstalk regulates key aspects of energy homeostasis, and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that crosstalk ...between the liver and pancreatic islets modulates β cell growth in response to insulin resistance, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, as well as in vitro islet culture approaches, we demonstrate that humoral, nonneural, non-cell-autonomous factor(s) induces β cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β cell growth factor(s) in insulin-resistant states.
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► Circulating nonneuronal factors drive β cell replication in LIRKO mice ► LIRKO serum increases mouse and human islet β cell replication in vitro ► LIRKO serum induces selective β cell replication in vivo ► Hepatocyte-derived factors stimulate mouse and human β cell replication in vitro
Diabetes is a chronic disease resulting from the loss of functional insulin-producing β cell mass. One of the major challenges to effective therapies for diabetes is the identification of factors that promote regeneration of β cells. Kulkarni and colleagues report the liver as a source of a nonneural, nonautonomous systemic factor(s) that promotes selective β cell proliferation. The ability of this putative circulating factor to enhance proliferation of both mouse and human β cells highlights a conserved feature in the regulation of glucose homeostasis.
Rectal duplication Kulkarni, B; Oak, S N; Karmarkar, S J ...
Journal of postgraduate medicine (Bombay),
1995 Apr-Jun, Letnik:
41, Številka:
2
Journal Article
Recenzirano
Duplications of the alimentary tract are of a great rarity, particularly so in the rectum. Because of its rarity, the difficulty of making a correct diagnosis and of selection of proper approach for ...treatment, this entity bears a special significance. The present case report deals with a female newborn who presented with imperforate anus and a rectovestibular fistula and a mass prolapsing at the introitus. Complete excision of the mass was carried out through the perineal approach and the child then underwent, a PSARP for the correction of the rectal anomaly. Histology confirmed the mass to be a rectal duplication.
A series of Cu1−xCoxFe2O4 (x = 0, 0.25, 0.5, 0.75, 1.0) ferrospinels prepared by low temperature coprecipitation method and glycine nitrate combustion method has been studied in gas phase methylation ...of phenol. Phenol methylation gives mainly o-cresol and 2,6-xylenol as major products and among various compositions, x = 0.50 shows good catalytic performance irrespective of the preparation method. The difference in properties of the fresh and spent catalysts was thoroughly characterized by adopting various physico-chemical characterization techniques with special emphasize on magnetic measurements. Various conclusions derived from magnetic study are in good agreement with our previous study of XRD and Mossbauer on same catalyst system. Redistribution of cations occurred during the reaction is evidenced from the increase of saturation magnetization in the spent. Spent x = 0.0 shows high Tc close to the value of Fe3O4 indicating that the material has ended with a solid solution of Fe3O4 and CuFe2O4 along with other reduced phases.
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