Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage ...mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.
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► Intestinal stem cells (ISCs) and progenitors express the IL-22 receptor ► Intestinal IL-22 increases after radiation injury but is decreased in GVHD ► Recipient innate lymphoid cells make IL-22 post-BMT, but they are eliminated by GVHD ► Recipient IL-22 deficiency increases crypt apoptosis, loss of ISC, and GVHD mortality
Context and Objective:
Pheochromocytomas and paragangliomas (PGLs) are neuroendocrine tumors of sympathetic or parasympathetic paraganglia. Nearly 40% of PGLs are caused by germline mutations. The ...present study investigated the effect of genetic alterations on metabolic networks in PGLs.
Design:
Homogenates of 32 sporadic PGLs and 48 PGLs from patients with mutations in SDHB, SDHD, SDHAF-2, VHL, RET, and NF-1 were subjected to proton (1H) nuclear magnetic resonance (NMR) spectroscopy at 500 MHz for untargeted and HPLC tandem mass spectrometry for targeted metabolite profiling.
Results:
1H NMR spectroscopy identified 28 metabolites in PGLs of which 12 showed genotype-specific differences. Part of these results published earlier reported low complex II activity (P < .0001) and low ATP/ADP/AMP content (P < .001) in SDH-related PGLs compared with sporadics and PGLs of other genotypes. Extending these results, low levels of N-acetylaspartic acid (NAA; P < .05) in SDH tumors and creatine (P < .05) in VHL tumors were observed compared with sporadics and other genotypes. Positive correlation was observed between NAA and ATP/ADP/AMP content (P < .001) and NAA and complex II activity (P < .0001) of PGLs. Targeted purine analysis in PGLs showed low adenine in cluster 1 compared with cluster 2 tumors (SDH P < .0001; VHL P < .05) whereas lower levels (P < .05) of guanosine and hypoxanthine were observed in RET tumors compared with SDH tumors. Principal component analysis (PCA) of metabolites could distinguish PGLs of different genotypes.
Conclusions:
The present study gives a comprehensive picture of alterations in energy metabolism in SDH- and VHL-related PGLs and establishes the interrelationship of energy metabolism and amino acid and purine metabolism in PGLs.
Aluminium, an environmentally abundant non-redox trivalent cation has long been implicated in the pathogenesis of Alzheimer's disease (AD). However, the definite mechanism of aluminium toxicity in AD ...is not known. Evidence suggests that trace metal homeostasis plays a crucial role in the normal functioning of the brain, and any disturbance in it can exacerbate events associated with AD. The present paper reviews the scientific literature linking aluminium with AD. The focus is on aluminium levels in brain, region-specific and subcellular distribution, its relation to neurofibrillary tangles, amyloid beta, and other metals. A detailed mechanism of the role of aluminium in oxidative stress and cell death is highlighted. The importance of complex speciation chemistry of aluminium in relation to biology has been emphasized. The debatable role of aluminium in AD and the cross-talk between aluminium and genetic susceptibility are also discussed. Finally, it is concluded based on extensive literature that the neurotoxic effects of aluminium are beyond any doubt, and aluminium as a factor in AD cannot be discarded. However, whether aluminium is a sole factor in AD and whether it is a factor in all AD cases still needs to be understood.
Abstract
X-ray binaries provide exceptional laboratories for understanding the physics of matter under the most extreme conditions. Until recently, there were few, if any, observational constraints ...on the circumbinary environments of X-ray binaries at ∼100–5000 au scales. It remains unclear how the accretion onto the compact objects or the explosions giving rise to the compact objects interact with their immediate surroundings. Here, we present the first high-contrast adaptive optics images of X-ray binaries. These observations target all X-ray binaries within ∼3 kpc accessible with the Keck/NIRC2 vortex coronagraph. This paper focuses on one of the first key results from this campaign; our images reveal the presence of 21 sources potentially associated with the
γ
Cassiopeiae analog high-mass X-ray binary RX J1744.7−2713. By conducting different analyses—a preliminary proper motion analysis, a color–magnitude diagram, and a probability of chance alignment calculation—we found that three of these 21 sources have a high probability of being bound to the system. If confirmed, they would be in wide orbits (∼450 to 2500 au). While follow-up astrometric observations will be needed in ∼5–10 yr to confirm further the bound nature of these detections, these discoveries emphasize that such observations may provide a major breakthrough in the field. In fact, they would be useful not only for our understanding of stellar multiplicity, but also for our understanding of how planets, brown dwarfs, and stars can form even in the most extreme environments.
Medical students' motivation and study strategies are crucial in determining academic performance. This study aimed to assess the motivation and learning strategies of medical students as well as ...their association with performance in anatomy examinations. The Motivated Strategies for Learning Questionnaire, two focus group discussions, and students' current anatomy cumulative grade point average (cGPA) were used. Generally, the medical students strongly felt that anatomy is fundamental to the practice of medicine and surgery. This result was consistent with high task value scores of 5.99 ± 1.25. They were also driven by extrinsic goal orientation (5.59 ± 1.42) and intrinsic goal orientation (5.08 ± 1.26). Most medical students typically relied on elaboration (5.35 ± 1.25) ahead of other cognitive strategies namely rehearsal (5.30 ± 1.11), organization (5.15 ± 1.34), and lowest‐rated critical thinking (4.77 ± 1.19). The students also relied on resource management strategies, effort regulation (5.15 ± 1.20) and time and study environment regulation (5.03 ± 1.03) more than the moderately scored peer learning (4.95 ± 1.50) and help‐seeking (4.95 ± 1.09). In the focus group discussions, students reported that they often narrate or explain to each other what they would have read and understood from anatomy lectures, tutorials, and textbooks. They also bemoaned the lack of institutional support for stress burdens. The motivation and learning strategies subscales were not correlated with anatomy cGPA. Males were driven by extrinsic goals and experienced significantly higher levels of test anxiety than females (P < 0.05). Knowing the motivation and learning strategies students employ early in the medical curriculum can be leveraged to promote self‐directed learning and academic achievement.
Malignant schwannoma, also called malignant peripheral nerve sheath tumor (MPNST), is a rare and aggressive tumor arising from the nerve sheath. We describe a rare case of endotracheal malignant ...peripheral nerve sheath tumor occurring in a middle-aged male who presented with asthma-like symptoms for 6 months with progressively increasing dyspnea. A computed tomogram (CT) scan of the thorax revealed near complete luminal obstruction of the trachea by a mass lesion at the level of the second and third tracheal rings. Microlaryngotracheoscopy revealed a fleshy pedunculated growth arising from the left side of the second and third tracheal rings and obliterating almost the entire tracheal lumen. Intraluminal complete excision of the mass was done. Later, he underwent excision of the 2nd and 3rd rings after the histopathology revealed MPNST. Patient after 28 months of follow-up is free of disease.
Background
Oral cavity squamous cell carcinoma (OCSCC) is the most common head and neck malignancy. Although the survival rate of patients with advanced‐stage disease remains approximately 20% to ...60%, when detected at an early stage, the survival rate approaches 80%, posing a pressing need for a well validated profiling method to assess patients who have a high risk of developing OCSCC. Tumor DNA detection in saliva may provide a robust biomarker platform that overcomes the limitations of current diagnostic tests. However, there is no routine saliva‐based screening method for patients with OCSCC.
Methods
The authors designed a custom next‐generation sequencing panel with unique molecular identifiers that covers coding regions of 7 frequently mutated genes in OCSCC and applied it on DNA extracted from 121 treatment‐naive OCSCC tumors and matched preoperative saliva specimens.
Results
By using stringent variant‐calling criteria, mutations were detected in 106 tumors, consistent with a predicted detection rate ≥88%. Moreover, mutations identified in primary malignancies were also detected in 93% of saliva samples. To ensure that variants are not errors resulting in false‐positive calls, a multistep analytical validation of this approach was performed: 1) re‐sequencing of 46 saliva samples confirmed 88% of somatic variants; 2) no functionally relevant mutations were detected in saliva samples from 11 healthy individuals without a history of tobacco or alcohol; and 3) using a panel of 7 synthetic loci across 8 sequencing runs, it was confirmed that the platform developed is reproducible and provides sensitivity on par with droplet digital polymerase chain reaction.
Conclusions
The current data highlight the feasibility of somatic mutation identification in driver genes in saliva collected at the time of OCSCC diagnosis.
A custom next‐generation sequencing test with unique molecular identifiers was designed that covers the coding regions of 7 frequently mutated genes in oral cavity squamous cell carcinoma (OCSCC). The minimal gene set predicted the incidence of at least 1 somatic aberration in 88% of patients with OCSCC, and the results demonstrate that this quick, sensitive, and noninvasive method can be used for the detection of low‐frequency, tumor‐associated mutations in saliva specimens collected from patients with OCSCC.
The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome ...13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17 similar to 92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P=0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17 similar to 92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17 similar to 92 cluster. Overexpression of miR-17 similar to 92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17 similar to 92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17 similar to 92 cluster may therefore provide a novel therapeutic approach for patients with MCL.
Prior research has shown substantial shifts in procedure shares between specialty groups providing lumbar punctures. Our aim was to analyze national trends in lumbar punctures among the Medicare ...population from 2010 to 2018.
Medicare Part B Physician/Supplier Procedure Summary Master Files from 2010 to 2018 were analyzed for all Current Procedural Terminology, Version 4 codes related to lumbar punctures (62270 and 62272). Lumbar puncture procedure volume and utilization rates were assessed and stratified by place of service and specialty background of the providers.
From 2010 to 2018, the overall number of lumbar puncture procedures essentially has not changed (92,579 versus 92,533). Radiologists hold the largest and an increasing procedure share of diagnostic and overall lumbar punctures (overall share, 45.7% in 2010
= 42,296 versus 52.3% in 2018
= 48,414). Advanced practice providers have increased their procedure share (3.7% in 2010
= 3388 versus 8.4% in 2018
= 7785, + 129.8% procedure volume). Emergency medicine physicians and neurologists have a decreasing procedure share (21.8% versus 15.3% and 12.5% versus 8.8%, respectively). The inpatient hospital setting remains the largest place of service for lumbar punctures, recording a 5.3% increase in procedure share. The emergency department lumbar puncture volume has declined, with a 7.4% decrease in the overall procedure share. Similarly, the hospital outpatient department procedure volume has increased (+4%), while the private office volume has decreased (-1.7%).
During the past decade, lumbar puncture procedures among the Medicare population have remained stable, with a shift in procedure volume from the emergency department and private offices to the hospital setting, which has mainly affected radiologists and advanced practice providers.
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