Gross and Histologic Placental Abnormalities Associated With Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To elucidate particular placental pathology findings that are associated with hypoxic ischemic encephalopathy (HIE) and determine which patterns are associated with adverse fetal/neonatal outcomes. STUDY DESIGN: Multi-institutional retrospective case-control study of newborns with HIE (2002-2022) and controls. Four perinatal pathologists performed gross and histologic evaluation of placentas of cases and controls. RESULTS: A total of 265 placentas of neonates with HIE and 122 controls were examined. Infants with HIE were more likely to have anatomic umbilical cord abnormalities (19.7% vs 7.4%, P = .003), fetal inflammatory response in the setting of amniotic fluid infection (27.7% vs 13.9%, P = .004), and fetal vascular malperfusion (30.6% vs 9.0%, P = <.001) versus controls. Fetal vascular malperfusion with maternal vascular malperfusion was more common in those who died of disease (P = .01). CONCLUSION: Placental pathology examination of neonates with HIE may improve our understanding of this disorder and its adverse outcomes.

A tip-predominant distribution of villous intraepithelial lymphocytes is not specific to celiac disease in children with Marsh I lesions.

OBJECTIVES: To assess if the distribution of villous intraepithelial lymphocytes (IELs) in a pediatric cohort with Marsh I histopathology is specific to celiac disease (CeD). METHODS: Multicenter, retrospective case-control study between January 2001 and December 2019 in children (<18 years) with and without CeD with intraepithelial lymphocytosis and normal villous architecture. Pathology specimens were reviewed by 2 study pathologists who were blinded to the final diagnosis. Morphologic features (villous height to crypt depth ratio [Vh:Cd]) and IELs in the villous tip, top, or bottom half of the villus were quantified. RESULTS: Of the 97 children with Marsh I histopathology identified during the study period, 63 were excluded due to an insufficient number of well-oriented villous-crypt complexes or a Vh:Cd less than 2. Villous IELs were measured in 34 cases (14 CeD, 20 non-CeD controls). There was no difference between the non-CeD and CeD groups in the mean IELs at the villous tip (14.0 ± 7.1 vs 11.7 ± 6.0, P = .31), top (46.4 ± 18.4 vs 38.3 ± 10.8, P = .11), or bottom (29.8 ± 16.8 vs 28.5 ± 12.8, P = .80) half of each villus, respectively. CONCLUSIONS: The distribution of IELs in Marsh I lesions is not specific for CeD.

COVID-19 vaccine deliberation in individuals directly impacted by incarceration.

Delays in vaccinating communities of color to COVID-19 have signaled a need to investigate structural barriers to vaccine uptake, with mass incarceration demanding greater characterization as a potential factor. In a nationally representative survey from February-March 2021 (N = 1,157), exposure to the criminal legal system, defined as having been incarcerated in prison or jail or having had a family member or close friend incarcerated, was associated with higher odds for COVID-19 vaccine deliberation. Individuals with criminal legal system exposure reported lower confidence in physician recommendation as a reason to get vaccinated. They were also more likely to decline vaccination out of fear it would cause COVID-19 infection, and that the vaccine might be promoted as a political tool. Our analysis suggests that populations impacted by the criminal legal system would benefit from targeted vaccine outreach by trusted community members who can address distrust during current and future pandemics.

Prostatic metaplasia and pilar differentiation in gender-affirming mastectomy specimens.

With the increasing practice of gender-affirming mastectomy as a therapeutic procedure in the setting of gender dysphoria, there has come a profusion of literature on the pathologic findings within these specimens. Findings reported in over 1500 patients have not included either prostatic metaplasia or pilar metaplasia of breast epithelium. We encountered both of these findings in the course of routine surgical pathology practice and therefore aimed to analyze these index cases together with a retrospective cohort to determine the prevalence, anatomic distribution, pathologic features, and associated clinical findings of prostatic metaplasia and pilar metaplasia in the setting of gender-affirming mastectomy. In addition to the 2 index cases, 20 additional archival gender-affirming mastectomy specimens were studied. Before mastectomies, all but 1 patient received testosterone cypionate, 6/22 patients received norethindrone, and 21/22 practiced breast binding. Prostatic metaplasia, characterized by glandular proliferation along the basal layer of epithelium in breast ducts, and in one case, within lobules, was seen in 18/22 specimens; 4/22 showed pilar metaplasia, consisting of hair shafts located within breast ducts, associated with squamoid metaplasia resembling hair matriceal differentiation. By immunohistochemistry, prostatic metaplasia was positive for PSA in 16/20 cases and positive for NKX3.1 in 15/20 cases. Forty-three reduction mammoplasty control cases showed no pilar metaplasia and no definite prostatic metaplasia, with no PSA and NKX3.1 staining observed. We demonstrate that prostatic metaplasia and pilar metaplasia are strikingly common findings in specimens from female-assigned-at-birth transgender patients undergoing gender-affirming mastectomy. Awareness of these novel entities in the breast is important, to distinguish them from other breast epithelial proliferations and to facilitate accrual of follow-up data for better understanding their natural history.

Pathology Trainee Redeployment and Education During the COVID-19 Pandemic: An Institutional Experience.

Pathology training programs throughout the United States have endured unprecedented challenges dealing with the ongoing coronavirus disease 2019 pandemic. At Houston Methodist Hospital, the Department of Pathology and Genomic Medicine planned and executed a trainee-oriented, stepwise emergency response. The focus was on optimizing workflows among areas of both clinical and anatomic pathology, maintaining an excellent educational experience, and minimizing trainee exposure to coronavirus disease 2019. During the first phase of the response, trainees were divided into 2 groups: one working on-site and the other working remotely. With the progression of the pandemic, all trainees were called back on-site and further redeployed within our department to meet the significantly increased workload demands of our clinical laboratory services. Adjustments to trainee educational activities included, among others, the organization of a daily coronavirus disease 2019 virtual seminar series. This series served to facilitate communication between faculty, laboratory managers, and trainees. Moreover, it became a forum for trainees to provide updates on individual service workflows and volumes, ongoing projects and research, as well as literature reviews on coronavirus disease 2019-related topics. From our program's experience, redeploying pathology trainees within our department during the coronavirus disease 2019 pandemic resulted in optimization of patient care while ensuring trainee safety, and importantly, helped to maintain continuous high-quality education through active involvement in unique learning opportunities.

TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing.

Intracellular nucleic acid sensors often undergo sophisticated modifications that are critical for the regulation of antimicrobial responses. Upon recognition of DNA, the cytosolic sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the second messenger cGAMP, which subsequently initiates downstream signaling to induce interferon-αß (IFNαß) production. Here we report that TRIM56 E3 ligase-induced monoubiquitination of cGAS is important for cytosolic DNA sensing and IFNαß production to induce anti-DNA viral immunity. TRIM56 induces the Lys335 monoubiquitination of cGAS, resulting in a marked increase of its dimerization, DNA-binding activity, and cGAMP production. Consequently, TRIM56-deficient cells are defective in cGAS-mediated IFNαß production upon herpes simplex virus-1 (HSV-1) infection. Furthermore, TRIM56-deficient mice show impaired IFNαß production and high susceptibility to lethal HSV-1 infection but not to influenza A virus infection. This adds TRIM56 as a crucial component of the cytosolic DNA sensing pathway that induces anti-DNA viral innate immunity.

Interaction between GABA and norepinephrine in interleukin-1beta-induced suppression of the luteinizing hormone surge.

Interleukin-1beta (IL-1beta), a cytokine that is closely associated with inflammation and immune stress, is known to interfere with reproductive functions. Earlier studies have demonstrated that IL-1beta inhibits the luteinizing hormone (LH) surge during the afternoon of proestrus in female rats. We have shown that this effect is most probably mediated through a reduction in norepinephrine (NE) levels in the medial preoptic area (MPA) of the hypothalamus. However, the mechanism by which IL-1beta decreases NE levels in the MPA is unclear. We hypothesized that the inhibitory neurotransmitter, GABA could play a role in decreasing NE levels in the MPA. To test this, ovariectomized, steroid-primed rats were injected (i.p.) with either PBS-BSA (control) or 5 microg of IL-1beta, alone or in combination with i.c.v. administration of GABA-A and GABA-B receptor antagonists, Bicuculline and CGP 35348 (CGP) respectively. Animals were subjected to push-pull perfusion of the MPA and perfusates collected at 30 min intervals were analyzed for both NE and GABA levels using HPLC-EC. Simultaneously, serial plasma samples were obtained through jugular catheters and were analyzed for LH levels using RIA. Compared to control rats, NE levels decreased significantly in the MPA in IL-1beta-treated rats (p<0.05). Concurrently, there was a significant increase in GABA levels in the MPA (p<0.05). The GABA-A receptor antagonist, bicuculline, was able to reverse the effect of IL-1beta on NE and LH, while the GABA-B receptor antagonist, CGP 35348 was without any effect. This leads us to conclude that the IL-1beta-induced suppression of the LH surge is most probably mediated through an increase in GABA levels in the MPA which causes a reduction in NE levels. This is probably one of the mechanisms by which IL-1beta inhibits reproductive functions.

IGF1 receptor expression protects against microenvironmental stress found in the solid tumor.

The insulin-like growth factor 1 receptor (IGF1R) is a tyrosine kinase, transmembrane receptor expressed in most body tissues and required for normal growth of cells. In cell culture, overexpression of the receptor has been shown to promote transformation and enhance cell survival in response to selected cytotoxic agents. As tumors develop, abnormalities in vascularization lead to a heterogeneous environment that includes areas of hypoxia, low pH and low glucose. Here we report that the overexpression of the IGF1R promotes increased survival in cells exposed to hypoxia, low pH and low glucose. Furthermore, cells lacking the receptor due to targeted disruption of the IGF1R gene do not survive as well as normal cells in such conditions. In addition, we find that cells can activate the IGF1R gene promoter in response to these conditions, and immunoblot analyses show increased receptor protein levels in cell exposed to hypoxia. Our results suggest a pathway of cancer cell adaptation to the tumor microenvironment in which conditions of the environment may induce expression of IGF1R, and this subsequent overexpression of the receptor may increase cell survival in such conditions.