Sirolimus is the USAN-assigned generic name for the natural product rapamycin. Sirolimus is produced by a strain of
Streptomyces hygroscopicus, isolated from a soil sample collected from Rapa Nui ...commonly known as Easter Island. Although sirolimus was isolated as an antifungal agent with potent anticandida activity, subsequent studies revealed impressive antitumor and immunosuppressive activities. Sirolimus demonstrates activity against several murine tumors, such as B16 43 melanocarcinoma, Colon 26 tumor, EM ependymoblastoma, and mammary and colon 38 solid tumors. Sirolimus is a potent inhibitor of antigen-induced proliferation of T cells, B cells, and antibody production. Demonstration of the potent immunosuppressive activity of sirolimus in animal models of organ transplantation led to clinical trials and subsequent approval by regulatory authorities for prophylaxis of renal graft rejection. Interest in sirolimus as an immunosuppressive therapy in organ transplantation derives from its unique mechanism of action, its unique side-effect profile, and its ability to synergize with other immunosuppressive agents. The molecular mechanism underlying the antifungal, antiproliferative, and immunosuppressive activities of sirolimus is the same. Sirolimus forms an immunosuppressive complex with intracellular protein, FKBP12. This complex blocks the activation of the cell-cycle–specific kinase, TOR. The downstream events that follow the inactivation of TOR result in the blockage of cell-cycle progression at the juncture of G1 and S phase.
Introduction: Allergic bronchopulmonary aspergillosis (ABPA) is a complex pulmonary disorder characterized by recurrent episodes of wheezing, fleeting pulmonary opacities and bronchiectasis. It is ...the most prevalent of the Aspergillus disorders with an estimated five million cases worldwide. Despite six decades of research, the pathogenesis, diagnosis and treatment of this condition remains controversial. The International Society for Human and Animal Mycology has formed a working group to resolve the controversies around this entity. In the year 2013, this group had proposed new criteria for diagnosis and staging, and suggested a treatment protocol for the management of this disorder. Since then, several pieces of new evidence have been published in the investigation and therapeutics of this condition.
Areas covered: A non-systematic review of the available literature was performed. We summarize the current evidence in the evaluation and treatment of this enigmatic disorder. We suggest modifications to the existing criteria and propose a new scoring system for the diagnosis of ABPA.
Expert commentary: All patients with asthma and cystic fibrosis should routinely be screened for ABPA using A. fumigatus-specific IgE levels. Glucocorticoids should be used as the first-line of therapy in ABPA, and itraconazole reserved in those with recurrent exacerbations and glucocorticoid-dependent disease.
Background: von Willebrand factor (VWF) and fibrinogen are major storage proteins of platelet α‐granules. VWF is synthesized by the megakaryocyte, the cell from which platelets bud, and fibrinogen is ...delivered to α‐granules by endocytosis.Aim: Considering biosynthetic origins, VWF and fibrinogen might be differentially packaged within platelets. We applied immunofluorescence microscopy to provide whole platelet, global information on the distributions of VWF and fibrinogen.Results: The distribution of VWF and fibrinogen were characterized in both the resting state and handling activated human platelets. Full cell volume image stacks were collected by spinning‐disk confocal microscopy, corrected for a small pixel shift between green and red channels, deconvolved, and visualized in a three‐dimensional space. In sum, we found that there was little overlap in the distribution of VWF and fibrinogen in resting state platelets. In an important control, the distributions of green and red secondary antibodies overlapped completely when different color secondary antibodies directed against the same first antibody were used. Moreover, the same result was observed using different first antibodies and switching second antibody color to switch the color of VWF and fibrinogen staining. No accumulation of fibrinogen in late endosomes or lysosomes was detected by co‐staining with LAMP2, a late endosome/lysosome membrane protein. Significantly, we found that in handling activated platelets there was differential retention of fibrinogen‐positive granules relative to VWF positive granules.Conclusion: Our results indicate that VWF and fibrinogen are differentially packaged in human platelets. Moreover, the results suggest that differential packaging could support differential release of α‐granule proteins.
Summary
Few studies have evaluated the utility of Aspergillus fumigatus‐specific IgG in allergic bronchopulmonary aspergillosis (ABPA). Herein, we evaluate the role of specific IgG in diagnosis and ...monitoring treatment response in ABPA. Forty‐eight control subjects with A. fumigatus‐associated asthma underwent A. fumigatus‐specific IgG measurements at baseline, while specific IgG was assayed in 102 treatment‐naïve subjects of ABPA at baseline, after eight weeks of glucocorticoid therapy, and during exacerbations. For determining the cut‐off of A. fumigatus‐specific IgG, we randomly classified two‐thirds of the study subjects (cases and controls) as the derivation cohort, while the remaining one‐thirds were labelled as the validation cohort. The best cut‐off value of A. fumigatus‐specific IgG in the derivation cohort was 26.9 mgA/L (sensitivity: 88%; specificity: 100%). Using this limit, the sensitivity and specificity of A. fumigatus‐specific IgG in diagnosis of ABPA was 89% and 100%, respectively, in the validation cohort. In contrast, the sensitivity of Aspergillus precipitins was only 27.4%. Following treatment, the A. fumigatus‐specific IgG increased in 38 (37.2%) subjects, while it decreased in three (23.1%) of the 13 subjects experiencing an exacerbation. The A. fumigatus‐specific IgG was found to be an extremely useful test in the diagnosis and differential diagnosis of ABPA but is unreliable in monitoring treatment response in this disorder.
A basilar artery intraluminal septation is an exceedingly rarely reported, presumed congenital abnormality. In our clinical practice, we have occasionally noticed an intraluminal band within the ...inferior aspect of the basilar artery on CTA. Furthermore, we have noticed, at times, the presence of a punctate calcification associated with this finding. We hypothesized that what previous studies have called "basilar septations" in fact represent miniature and thus aberrant basilar fenestrations.
We retrospectively reviewed CTA studies obtained between January 1, 2017, and August 31, 2019. Identified intraluminal basilar abnormalities were classified as either basilar septations or basilar fenestrations. Association with other posterior circulation abnormalities was documented.
A total of 3509 studies were examined. A basilar intraluminal abnormality was evident in 80 patients (2.3%). Of these 80 patients, 59 were classified as having a basilar fenestration (1.7%) and 21 were classified as having basilar septations (0.6%). Associated calcification was evident in 3 of the basilar fenestration cases and 13 of the basilar septation cases.
Basilar septations most likely represent and should be referred to as aberrant basilar fenestrations. They should be interpreted as benign congenital incidental findings and should not be misinterpreted as focal dissections or arterial webs. Important variations in the morphology of aberrant basilar fenestrations exist, including areas of thinning, varying thickness, and nodularity. Therefore, when associated with calcification or nodularity, aberrant basilar fenestrations should not be confused with focal intraluminal thrombi or calcified or noncalcified emboli.
Background
Whether chronic pulmonary aspergillosis (CPA) has different immunophenotypes remains unknown.
Objective
To identify different CPA immunophenotypes using cluster analysis.
Methods
We used a ...subject‐centred multivariate clustering approach without prior assumptions to identify CPA phenotypes. We retrospectively included the data of treatment‐naïve subjects with CPA and excluded subjects with asthma and allergic bronchopulmonary aspergillosis (ABPA). We performed a scalable two‐step cluster analysis using the log‐likelihood distance measures to identify CPA phenotypes based on the blood immunological profile (total IgE, eosinophil count and Aspergillus‐specific IgE and IgG).
Results
We included 351 CPA subjects and found two clusters. Cluster 2 (n = 118) had significantly higher serum total IgE, peripheral blood eosinophil count, and serum A. fumigatus‐specific IgE and IgG than cluster 1 (n = 233). Cluster 2 subjects had a lower FEV1:FVC ratio on spirometry and were more likely to have a fungal ball (88 74.6% vs. 145 (62.2%), p = .023) on the CT thorax than cluster 1. After treatment discontinuation, cluster 2 had a longer median (interquartile range) time to relapse than cluster 1 (11.5 7.3–27.4 vs. 4 1.1–8.9 months, p = .005).
Conclusion
We identified two distinct CPA phenotypes, type‐2 dominant and non‐type‐2, with different clinical and radiological findings and treatment outcomes. Future studies should confirm our findings and investigate different treatment strategies based on CPA phenotypes.
Recurrent drought associated with climate change is a major constraint to wheat (Triticum aestivum L.) productivity. This study aimed to (i) quantify the effects of ...addition/substitution/translocation of chromosome segments from wild relatives of wheat on the root, physiological and yield traits of hexaploid wheat under drought, and (ii) understand the mechanism(s) associated with drought tolerance or susceptibility in wheat-alien chromosome lines.
A set of 48 wheat-alien chromosome lines (addition/substitution/translocation lines) with Chinese Spring background were used. Seedling root traits were studied on solid agar medium. To understand the influence of drought on the root system of adult plants, these 48 lines were grown in 150-cm columns for 65 d under full irrigation or withholding water for 58 d. To quantify the effect of drought on physiological and yield traits, the 48 lines were grown in pots under full irrigation until anthesis; after that, half of the plants were drought stressed by withholding water for 16 d before recording physiological and yield-associated traits.
The alien chromosome lines exhibited altered root architecture and decreased photochemical efficiency and seed yield and its components under drought. The wheat-alien chromosome lines T5DS·5S#3L (TA5088) with a chromosome segment from Aegilops speltoides (5S) and T5DL
5 V#3S (TA5638) with a chromosome segment from Dasypyrum villosum (5 V) were identified as drought tolerant, and the drought tolerance mechanism was associated with a deep, thin and profuse root system.
The two germplasm lines (TA5088 and TA5638) could be used in wheat breeding programs to improve drought tolerance in wheat and understand the underlying molecular genetic mechanisms of root architecture and drought tolerance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
The role of total and specific IgE in monitoring treatment responses in allergic bronchopulmonary aspergillosis (ABPA) remains poorly studied. Here in, we evaluate the utility of total and ...Aspergillus fumigatus specific IgE in the follow‐up of ABPA. Eighty‐one consecutive treatment‐naïve patients of ABPA (acute stage) with pulmonary infiltrates and bronchiectasis underwent measurement of total and A. fumigatus specific IgE at baseline, after 8 weeks of glucocorticoid therapy, and during exacerbations. There was clinical and radiological improvement after treatment with median decline of total IgE by 51.9%. The total IgE declined by at least 35%, 25% and 20% in 69 (85.2%), 76 (93.6%) and 78 (96.3%) patients, respectively. On the other hand, the A. fumigatus specific IgE increased in 42 (51.9%) subjects, and the mean increase was 1.4%, after 8 weeks. Among 13 patients with exacerbation, 12 (92.3%) had a rise of total IgE by >50%. The A. fumigatus specific IgE increased in only five (38.5%) subjects during exacerbation. Thus, the total IgE is a useful test in monitoring treatment responses in ABPA while A. fumigatus specific IgE has limited utility.
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