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Charles Austin Beard : the return of the master historian of American imperialism
\"In the face of the ruinous costs of empire, about which Charles Austin Beard warned at the time of the Second World War, the life and work of this American prophet merit reexamination today\"-- Provided by publisher.
Book
MALDI Imaging Mass Spectrometry Profiling of N-Glycans in Formalin-Fixed Paraffin Embedded Clinical Tissue Blocks and Tissue Microarrays
A recently developed matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) method to spatially profile the location and distribution of multiple N-linked glycan species in frozen tissues has been extended and improved for the direct analysis of glycans in clinically derived formalin-fixed paraffin-embedded (FFPE) tissues. Formalin-fixed tissues from normal mouse kidney, human pancreatic and prostate cancers, and a human hepatocellular carcinoma tissue microarray were processed by antigen retrieval followed by on-tissue digestion with peptide N-glycosidase F. The released N-glycans were detected by MALDI-IMS analysis, and the structural composition of a subset of glycans could be verified directly by on-tissue collision-induced fragmentation. Other structural assignments were confirmed by off-tissue permethylation analysis combined with multiple database comparisons. Imaging of mouse kidney tissue sections demonstrates specific tissue distributions of major cellular N-linked glycoforms in the cortex and medulla. Differential tissue distribution of N-linked glycoforms was also observed in the other tissue types. The efficacy of using MALDI-IMS glycan profiling to distinguish tumor from non-tumor tissues in a tumor microarray format is also demonstrated. This MALDI-IMS workflow has the potential to be applied to any FFPE tissue block or tissue microarray to enable higher throughput analysis of the global changes in N-glycosylation associated with cancers.
Journal Article
Rhomboid Intercostal and Subserratus Plane Block: A Cadaveric and Clinical Evaluation
BACKGROUND AND OBJECTIVESFascial plane blocks are rapidly emerging to provide safe, feasible alternatives to epidural analgesia for thoracic and abdominal pain. We define a new option for chest wall and upper abdominal analgesia, termed the rhomboid intercostal and subserratus plane (RISS) block. The RISS tissue plane extends deep to the erector spinae muscle medially and deep to the serratus anterior muscle laterally. We describe a 2-part proof-of-concept study to validate the RISS block, including a cadaveric study to evaluate injectate spread and a retrospective case series to assess dermatomal coverage and analgesic efficacy.
METHODSFor the cadaveric portion of the study, bilateral ultrasound-guided RISS blocks were performed on 6 fresh cadavers with 30 mL of 0.5% methylcellulose with india ink. For the retrospective case series, we present 15 patients who underwent RISS block or RISS catheter insertion for heterogeneous indications including abdominal surgery, rib fractures, chest tube–associated pain, or postoperative incisional chest wall pain.
RESULTSIn the cadaveric specimens, we identified staining of the lateral branches of the intercostal nerves from T3 to T9 reaching the posterior primary rami deep to the erector spinae muscle medially. In the clinical case series, dermatomal coverage was observed in the anterior hemithorax with visual analog pain scores less than 5 in patients who underwent both single-shot and continuous catheter infusions.
CONCLUSIONSOur preliminary cadaveric and clinical data suggest that RISS block anesthetizes the lateral cutaneous branches of the thoracic intercostal nerves and can be used in multiple clinical settings for chest wall and upper abdominal analgesia.
Journal Article
Multiplexed imaging mass spectrometry of the extracellular matrix using serial enzyme digests from formalin-fixed paraffin-embedded tissue sections
We report a multiplexed imaging mass spectrometry method which spatially localizes and selectively accesses the extracellular matrix on formalin-fixed paraffin-embedded tissue sections. The extracellular matrix (ECM) consists of (1) fibrous proteins, post-translationally modified (PTM) via N- and O-linked glycosylation, as well as hydroxylation on prolines and lysines, and (2) glycosaminoglycan-decorated proteoglycans. Accessing all these components poses a unique analytical challenge. Conventional peptide analysis via trypsin inefficiently captures ECM peptides due to their low abundance, intra- and intermolecular cross-linking, and PTMs. In previous studies, we have developed matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) techniques to capture collagen peptides via collagenase type III digestion, both alone and after N-glycan removal via PNGaseF digest. However, in fibrotic tissues, the buildup of ECM components other than collagen-type proteins, including elastin and glycosaminoglycans, limits efficacy of any single enzyme to access the complex ECM. Here, we have developed a novel serial enzyme strategy to define the extracellular matrix, including PTMs, from a single tissue section for MALDI-IMS applications.
Journal Article
Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse
Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.
Journal Article
The impacts of antipsychotic medications on eating-related outcomes: A mixed methods systematic review
Almost all antipsychotics are associated with weight gain. Given the gravity of this side-effect and its consequences, it is imperative to understand the mechanisms involved. One mechanism that could contribute to this side effect is the impact of antipsychotics on eating-related outcomes.
We aimed to synthesise the available quantitative research on the effects of first- and second-generation antipsychotics on eating-related outcomes, and qualitative research exploring people's experiences with these medications in relation to appetite and eating behaviours (PROSPERO protocol CRD42022340211).
We searched Medline, PsycInfo, and Web of Science from inception to 9 May 2024. Quantitative data were synthesised without meta-analysis using vote counting based on direction of effect. Qualitative data were synthesised using thematic synthesis.
Searches identified 8,746 citations yielding 61 separate studies; 55 quantitative and 6 qualitative, published 1982-2024. Using GRADE, our assessment of the quantitative review findings ranged from low to very low-level certainty. Given the lack of direct evidence from high-quality placebo-controlled trials, it is pertinent to interpret the quantitative findings with caution. Using GRADE-CERQual, our assessment of the qualitative review findings ranged from low to very low-level certainty; these findings suggest that the relationship between antipsychotics and food intake is influenced by an interplay of individual, interpersonal and external factors, the most significant of which is food environment.
The internal validity of this review was affected by the serious limitations of the included quantitative studies and the paucity of qualitative evidence.
We used GRADE and GRADE-CERQual frameworks to enhance the transparency of our judgement of the certainty of the evidence. Lived experience perspectives were incorporated in different stages of the review to enhance its relevance and practical implications.
There is insufficient evidence from well-conducted studies to determine the effect of antipsychotics on eating-related outcomes.
Journal Article
The External Oblique Intercostal Block: Anatomic Evaluation and Case Series
Abstract
Study Objective
We report a modified block technique aimed at obtaining upper midline and lateral abdominal wall analgesia: the external oblique intercostal (EOI) block.
Design
A cadaveric study and retrospective cohort study assessing the potential analgesic effect of the EOI block.
Setting
Cadaver lab and operating room.
Patients
Two unembalmed cadavers and 22 patients.
Interventions
Bilateral ultrasound-guided EOI blocks on cadavers with 29 mL of bupivacaine 0.25% with 1 mL of India ink; single-injection or continuous EOI blocks in patients.
Measurements
Dye spread in cadavers and loss of cutaneous sensation in patients.
Main Results
In the cadaveric specimens, we identified consistent staining of both lateral and anterior branches of intercostal nerves from T7 to T10. We also found consistent dermatomal sensory blockade of T6–T10 at the anterior axillary line and T6–T9 at the midline in patients receiving the EOI block.
Conclusions
We demonstrate the potential mechanism of this technique with a cadaveric study that shows consistent staining of both lateral and anterior branches of intercostal nerves T7–T10. Patients who received this block exhibited consistent dermatomal sensory blockade of T6–T10 at the anterior axillary line and T6–T9 at the midline. This block can be used in multiple clinical settings for upper abdominal wall analgesia.
Journal Article