Old Mice Demonstrate Organ Dysfunction as well as Prolonged Inflammation, Immunosuppression, and Weight Loss in a Modified Surgical Sepsis Model.

OBJECTIVES: Our goal was to "reverse translate" the human response to surgical sepsis into the mouse by modifying a widely adopted murine intra-abdominal sepsis model to engender a phenotype that conforms to current sepsis definitions and follows the most recent expert recommendations for animal preclinical sepsis research. Furthermore, we aimed to create a model that allows the study of aging on the long-term host response to sepsis. DESIGN: Experimental study. SETTING: Research laboratory. SUBJECTS: Young (3-5 mo) and old (18-22 mo) C57BL/6j mice. INTERVENTIONS: Mice received no intervention or were subjected to polymicrobial sepsis with cecal ligation and puncture followed by fluid resuscitation, analgesia, and antibiotics. Subsets of mice received daily chronic stress after cecal ligation and puncture for 14 days. Additionally, modifications were made to ensure that "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" recommendations were followed. MEASUREMENTS AND MAIN RESULTS: Old mice exhibited increased mortality following both cecal ligation and puncture and cecal ligation and puncture + daily chronic stress when compared with young mice. Old mice developed marked hepatic and/or renal dysfunction, supported by elevations in plasma aspartate aminotransferase, blood urea nitrogen, and creatinine, 8 and 24 hours following cecal ligation and puncture. Similar to human sepsis, old mice demonstrated low-grade systemic inflammation 14 days after cecal ligation and puncture + daily chronic stress and evidence of immunosuppression, as determined by increased serum concentrations of multiple pro- and anti-inflammatory cytokines and chemokines when compared with young septic mice. In addition, old mice demonstrated expansion of myeloid-derived suppressor cell populations and sustained weight loss following cecal ligation and puncture + daily chronic stress, again similar to the human condition. CONCLUSIONS: The results indicate that this murine cecal ligation and puncture + daily chronic stress model of surgical sepsis in old mice adhered to current Minimum Quality Threshold in Pre-Clinical Sepsis Studies guidelines and met Sepsis-3 criteria. In addition, it effectively created a state of persistent inflammation, immunosuppression, and weight loss, thought to be a key aspect of chronic sepsis pathobiology and increasingly more prevalent after human sepsis.

Stromal Overgrowth in a Brenner Tumor or Ovarian Fibroma With Minor Sex Cord Elements?

Computed tomography obtained as part of a urinary tract assessment in a 68-year-old woman incidentally detected a solid adnexal mass. Bilateral salpingo-oophorectomy revealed a unilateral, 4-cm, white to tan-yellow colored, focally calcified, left ovarian mass. Microscopically, the tumor was composed of bland fibroblasts, abundant collagen, and areas of calcification with a minor component composed of nests of epithelial cells with nuclear clefts focally evident, some of which contained central lumens with eosinophilic secretions. The major considerations were fibromatous overgrowth in a Brenner tumor or ovarian fibroma with minor sex cord elements. Immunostains for cytokeratin 7 showed diffuse positivity in the epithelial nests, whereas cytokeratin 20 and inhibin were negative, further supporting the diagnosis of a Brenner tumor.

A C-terminal region of Yersinia pestis YscD binds the outer membrane secretin YscC.

YscD is an essential component of the plasmid pCD1-encoded type III secretion system (T3SS) of Yersinia pestis. YscD has a single transmembrane (TM) domain that connects a small N-terminal cytoplasmic region (residues 1 to 121) to a larger periplasmic region (residues 143 to 419). Deletion analyses established that both the N-terminal cytoplasmic region and the C-terminal periplasmic region are required for YscD function. Smaller targeted deletions demonstrated that a predicted cytoplasmic forkhead-associated (FHA) domain is also required to assemble a functional T3SS; in contrast, a predicted periplasmic phospholipid binding (BON) domain and a putative periplasmic "ring-building motif" domain of YscD could be deleted with no significant effect on the T3S process. Although deletion of the putative "ring-building motif" domain did not disrupt T3S activity per se, the calcium-dependent regulation of the T3S apparatus was affected. The extreme C-terminal region of YscD (residues 354 to 419) was essential for secretion activity and had a strong dominant-negative effect on the T3S process when exported to the periplasm of the wild-type parent strain. Coimmunoprecipitation studies demonstrated that this region of YscD mediates the interaction of YscD with the outer membrane YscC secretin complex. Finally, replacement of the YscD TM domain with a TM domain of dissimilar sequence had no effect on the T3S process, indicating that the TM domain has no sequence-specific function in the assembly or function of the T3SS.

Molecular alterations in Hürthle cell neoplasms of thyroid: A fine needle aspiration cytology study with cytology-histology correlation.

BACKGROUND: Hürthle cell features are frequently observed on the fine-needle aspiration (FNA) cytology of thyroid nodules and often pose a diagnostic challenge because of a significant overlap between cytomorphologic features seen in benign and malignant lesions. Molecular alterations (MAs) associated with these lesions are not well described. The objective of the current study was to evaluate the molecular profile of Hürthle cell lesions classified as Hürthle cell neoplasm (HCN) on cytologic evaluation. METHODS: The authors retrospectively reviewed their electronic database for cytologic diagnoses of HCN from January 1, 2017 to March 31, 2020. RESULTS: In total, 279 cases from 275 patients who had a diagnosis of HCN were included in the study. Molecular testing results were available in 85 cases (51 with MAs and 34 without MAs) and, of those, 42 had histologic follow-up available. Eight of 10 malignant cases had MAs, whereas the remaining 2 cases were negative for MAs. The most frequently encountered predominant genetic alterations or classifier findings were chromosome copy number alterations (n = 15), followed by NRAS (n = 8), KRAS (n = 7), suspicious (n = 6), EIF1AX (n = 4), TSHR (n = 3), gene overexpression (n = 3), positive microRNA classifier (n = 2), and 1 each of BRAF K601E, TERT, and HRAS mutations. One hundred thirty-seven cases had histologic follow-up available; of those, 28 were classified as malignant, and 109 were classified as benign (neoplastic and nonneoplastic). The overall risk of malignancy associated with HCN was 20%, and the risk of HCN with MAs was 25%. CONCLUSIONS: The cytologic diagnosis of HCN includes various MAs without any obvious trend, and most malignant cases (80%) have some type of MA.

Educational Case: Ectopic Pregnancy.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Educational Case: Smooth Muscle Tumors of the Uterus.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Myxoid Myofibroblastoma of the Breast With Atypical Cells.

The differential diagnosis of myxoid lesions in the breast is broad and includes both benign and malignant entities. Assessment is particularly challenging on core biopsy specimens. Myofibroblastoma, initially thought to be more common in the adult male breast, is being recognized with increasing frequency in the female breast. The wider anatomic distribution of mammary-type myofibroblastoma has also become known, and many new morphological variants have been described. Though focal myxoid stroma may be noted in myofibroblastomas and occasional myofibroblastomas may contain atypical cells, there have been only 3 reports in the literature of myofibroblastomas with exclusive or predominantly myxoid stroma, and 2 of these contained atypical cells. We report another case of mammary myxoid myofibroblastoma with atypical cells in a 40-year-old woman and discuss the differential diagnoses of myxoid lesions in the breast.

An unusual case of chylothorax.

Pleural effusions occur in up to 70% of cases of malignant pleural mesothelioma (MPM). However, MPM rarely presents as a chylous effusion making it a diagnostic challenge. There are only six reported cases to date. Most cases of chylothoraces due to malignancy are due to lymphoma or bronchogenic carcinoma. We report an interesting case of MPM in a 75-year-old man who presented with recurrent chylothorax. He reported a four-month history of dyspnea and chest discomfort. Chest x-ray revealed a pleural effusion. Pleural fluid analysis was consistent with a chylothorax. Pleural fluid cytology was negative for malignancy. Computed tomography of the chest showed pleural calcifications, mediastinal adenopathy and left lung infiltrate. A fine needle aspirate of the lymph node and transbronchial biopsy specimen (TBBX) of the left lung infiltrate showed extensive reactive appearing mesothelial cells but none that appeared malignant. A video assisted thoracoscopic surgery was suggested but the patient declined. He returned 3 months later with recurrent pleural effusion and worsening airspace disease. Thoracentesis revealed a chylothorax again. Repeat analysis of TBBX and lymph node specimens showed extensive reactive appearing mesothelial cells. Due to concern for MPM, ancillary testing was obtained - loss of BRCA1 associated protein (BAP-1) and CDKN2A/p16 gene deletion. BAP1 staining was lost in the mesothelial cells supporting MPM. This case highlights a rare cause of MPM presenting as a chylous effusion. In a patient with an unknown etiology of chylothorax, MPM must remain in the differential.

Changing Pathology of the Thoracic Aorta From Acute to Chronic Dissection: Literature Review and Insights.

We review current knowledge regarding the natural transition of aortic dissection from acute to chronic stages. As this is not well understood, we also bring to bear new data from our institution. Type A dissection rarely transitions naturally into the chronic state; consequently, information is limited. Type B dissections are routinely treated medically and indeed undergo substantial changes during their temporal course. General patterns include: 1) the aorta dilates and, absent surgical intervention, aortic enlargement may cause mortality; 2) continued false lumen patency, particularly with an only partially thrombosed false lumen, increases aortic growth, whereas calcium-channel blockers affect aortic dilation favorably; 3) aortic dilation manifests a temporal dynamic, with early rapid growth and deceleration during transition; 4) the intimal flap dynamically changes over time via thickening, straightening, and loss of mobility; and 5) temporal remodeling, on the cellular level, initially shows a high grade of wall destruction; subsequently, significant fibrosis ensues.

Calcium-regulated type III secretion of Yop proteins by an Escherichia coli hha mutant carrying a Yersinia pestis pCD1 virulence plasmid.

A series of four large deletions that removed a total of ca. 36 kb of DNA from the ca. 70-kb Yersinia pestis pCD1 virulence plasmid were constructed using lambda Red-mediated recombination. Escherichia coli hha deletion mutants carrying the virulence plasmid with the deletions expressed a functional calcium-regulated type III secretion system. The E. coli hha/pCD1 system should facilitate molecular studies of the type III secretion process.