Introduction.

This article offers an overview of the life and work of Gerald N. Grob. As part of a generation of scholars intent on overturning the old "Whig history" of medicine, Grob pioneered the use of institutional history as an analytical tool. His work on American psychiatry combined a formidable command of archival sources with a strong commitment to putting medical practice in social context. Grob's personal and political views put him at odds with other scholars of the asylum; he conducted some very public feuds with David Rothman and Andrew Scull. At the same time, he showed a more benevolent side to younger historians interested in psychiatry; he took particular pains to encourage women (including the authors of this introduction) to enter a historical specialty then dominated by men. To honor Grob's legacy as a scholar and a person, this special issue features articles written by several generations of scholars influenced and inspired by his work.

Depletion of MHC class II invariant chain peptide or γ-δ T-cells ameliorates experimental preeclampsia.

Excessive innate immune system activation and inflammation during pregnancy can lead to organ injury and dysfunction and preeclampsia (PE); however, the molecular mechanisms involved are unknown. We tested the hypothesis that Toll-like receptor (TLR) activation induces major histocompatibility complex (MHC) class II invariant chain peptide (CLIP) expression on immune cells, makes them pro-inflammatory, and are necessary to cause PE-like features in mice. Treatment with VG1177, a competitive antagonist peptide for CLIP in the groove of MHC class II, was able to both prevent and treat PE-like features in mice. We then determined that γ-δ T cells are critical for the development of PE-like features in mice since γ-δ T-cell knockout mice, like CLIP deficient mice, are resistant to developing PE-like features. Placentas from women with PE exhibit significantly increased levels of γ-δ T cells. These preclinical data demonstrate that CLIP expression and activated γ-δ T cells are responsible for the development of immunologic PE-like features and that temporarily antagonizing CLIP and/or γ-δ T cells may be a therapeutic strategy for PE.

Human placenta-derived stromal cells decrease inflammation, placental injury and blood pressure in hypertensive pregnant mice.

Pre-eclampsia, the development of hypertension and proteinuria or end-organ damage during pregnancy, is a leading cause of both maternal and fetal morbidity and mortality, and there are no effective clinical treatments for pre-eclampsia aside from delivery. The development of pre-eclampsia is characterized by maladaptation of the maternal immune system, excessive inflammation and endothelial dysfunction. We have reported that detection of extracellular RNA by the Toll-like receptors (TLRs) 3 and 7 is a key initiating signal that contributes to the development of pre-eclampsia. PLacental eXpanded (PLX-PAD) cells are human placenta-derived, mesenchymal-like, adherent stromal cells that have anti-inflammatory, proangiogenic, cytoprotective and regenerative properties, secondary to paracrine secretion of various molecules in response to environmental stimulation. We hypothesized that PLX-PAD cells would reduce the associated inflammation and tissue damage and lower blood pressure in mice with pre-eclampsia induced by TLR3 or TLR7 activation. Injection of PLX-PAD cells on gestational day 14 significantly decreased systolic blood pressure by day 17 in TLR3-induced and TLR7-induced hypertensive mice (TLR3 144-111 mmHg; TLR7 145-106 mmHg; both P<0.05), and also normalized their elevated urinary protein:creatinine ratios (TLR3 5.68-3.72; TLR7 5.57-3.84; both P<0.05). On gestational day 17, aortic endothelium-dependent relaxation responses improved significantly in TLR3-induced and TLR7-induced hypertensive mice that received PLX-PAD cells on gestational day 14 (TLR3 35-65%; TLR7 37-63%; both P<0.05). In addition, markers of systemic inflammation and placental injury, increased markedly in both groups of TLR-induced hypertensive mice, were reduced by PLX-PAD cells. Importantly, PLX-PAD cell therapy had no effects on these measures in pregnant control mice or on the fetuses. These data demonstrate that PLX-PAD cell therapy can safely reverse pre-eclampsia-like features during pregnancy and have a potential therapeutic role in pre-eclampsia treatment.

Clinical signs, pathology and dose-dependent survival of adult wood frogs, Rana sylvatica, inoculated orally with frog virus 3 Ranavirus sp., Iridoviridae.

Amphibian populations suffer massive mortalities from infection with frog virus 3 FV3, genus Ranavirus, family Iridoviridae, a pathogen also involved in mortalities of fish and reptiles. Experimental oral infection with FV3 in captive-raised adult wood frogs, Rana sylvatica Lithobates sylvaticus, was performed as the first step in establishing a native North American animal model of ranaviral disease to study pathogenesis and host response. Oral dosing was successful LD50 was 10(2.93 2.423.44) p.f.u. for frogs averaging 35mm in length. Onset of clinical signs occurred 614days post-infection p.i. median 11 days p.i. and time to death was 1014 days p.i. median 12 days p.i.. Each tenfold increase in virus dose increased the odds of dying by 23-fold and accelerated onset of clinical signs and death by approximately 15. Ranavirus DNA was demonstrated in skin and liver of all frogs that died or were euthanized because of severe clinical signs. Shedding of virus occurred in faeces 710 days p.i. 34.5days before death and skin sheds 10 days p.i. 01.5days before death of some frogs dead from infection. Most common lesions were dermal erosion and haemorrhages haematopoietic necrosis in bone marrow, kidney, spleen and liver and necrosis in renal glomeruli, tongue, gastrointestinal tract and urinary bladder mucosa. Presence of ranavirus in lesions was confirmed by immunohistochemistry. Intracytoplasmic inclusion bodies probably viral were present in the bone marrow and the epithelia of the oral cavity, gastrointestinal tract, renal tubules and urinary bladder. Our work describes a ranaviruswood frog model and provides estimates that can be incorporated into ranavirus disease ecology models.

Expression of mPGES1 and p16 in feline and human oral squamous cell carcinoma: A comparative oncology approach.

Comparative cancer studies help us determine if discoveries in one species apply to another. Feline and human oral squamous cell carcinoma (FOSCC and HOSCC) are invasive tumours in which inflammation and abnormal p16 expression are reported. Immunohistochemistry was used to determine the expression of p16 and microsomal prostaglandin E2 synthase 1 (mPGES1) in 42 HOSCC and 45 FOSCC samples with known expression of cyclooxygenase 2 (COX2) and cluster of differentiation 147 (CD147). High p16 expression was more common in HOSCC tumour cells compared to adjacent stroma and oral epithelium (p < .05), with a similar but statistically nonsignificant pattern in FOSCC. Interestingly, high mPGES1 expression in FOSCC was more common in the adjacent epithelium compared to the other compartments (p < .05). In HOSCC, mPGES1 was more similar between compartments but was numerically more common in the tumour compartment (p > .05). There were nominal (p > 0.05) differences in marker expression between high and low mPGES1 expressing tumours in both species, including high p16 observed more commonly in high mPGES1 tumours, and COX-2 positive tumours being more common in low mPGES1 tumours. High CD147 HOSCC tumours were more common in the high mPGES1 HOSCC group (p < .05). In the FOSCC cohort, where there was no statistical difference in CD147 expression between high and low mPGES1 tumours, there were numerically higher CD147 cases in the high mPGES1group. Different expression patterns in FOSCC and HOSCC could be related to different risk factors. For example, p16 is a marker of papillomavirus-driven HOSCC, but a causal relationship between papillomaviruses and FOSCC has yet to be definitively demonstrated. The significance of high P16 expression in the absence of papillomavirus infection deserves further study, and the relative contributions of COX2 and mPGES1 to tumour inflammation and progression should be explored. The findings reveal potential similarities in FOSCC and HOSCC biology, while also demonstrating differences that may relate to risk factors and pathogenesis that are unique to each species.

A "win-win" perspective on workplace accommodations: RETAIN Kentucky's self-advocacy guide to promote successful return to work and stay at work outcomes for workers with disabilities.

BACKGROUND: Research has long documented the low cost and effectiveness of most workplace accommodations to enable qualified people with disabilities to seek, secure, and maintain employment. OBJECTIVE AND METHOD: RETAIN Kentucky's return to work and stay at work intervention involves focused training for participants on requesting needed accommodations from their employers. RESULTS: In this article, we describe the win-win approach to reasonable accommodations, which serves as the basis for helping Kentuckians with disabilities identify and request on-the-job supports to aid in their efforts to remain in the workforce. CONCLUSIONS: Workers with disabilities are more likely to stay in the workforce and continue making valuable contributions to the national and global economies if they have effective accommodations and other employment supports available to them.

Providing quality employment services to people living with asthma in the vocational rehabilitation program: A model for meeting the needs of an emerging clientele.

BACKGROUND: With incidence and prevalence rates of asthma diagnoses steadily increasing in the United States and worldwide over the past 30 years, people with asthma are an emerging vocational rehabilitation (VR) consumer population. OBJECTIVE: This article describes the job acquisition and return to work considerations facing employees with asthma. METHODS: Following an overview of the etiology, incidence, prevalence, and career development implications of this chronic respiratory disease, the authors present career preparatory and return to work recommendations to meet the needs of Americans with asthma across the phases of the VR process. RESULTS: The importance of access to quality healthcare, lifestyle, and environmental modifications to promote respiratory health, employer consultation, workplace accommodations and universal design, and interface with medical and mental health professionals is emphasized throughout the article. CONCLUSION: Asthma is an emerging disability that disproportionally affects people of color and people who live in poverty. Rehabilitation professionals must be prepared to meet the needs of this growing and diverse clientele as people with asthma seek assistance from the VR program in acquiring, maintaining, and advancing in meaningful, satisfying employment.

Endothelial cell transforming growth factor-ß receptor activation causes tacrolimus-induced renal arteriolar hyalinosis.

Arteriolar hyalinosis is a common histological finding in renal transplant recipients treated with the calcineurin inhibitor tacrolimus; however, the pathophysiologic mechanisms remain unknown. In addition to increasing transforming growth factor (TGF)-ß levels, tacrolimus inhibits calcineurin by binding to FK506-binding protein 12 (FKBP12). FKBP12 alone also inhibits TGF-ß receptor activation. Here we tested whether tacrolimus binding to FKBP12 removes an inhibition of the TGF-ß receptor, allowing ligand binding, ultimately leading to receptor activation and arteriolar hyalinosis. We found that specific deletion of FKBP12 from endothelial cells was sufficient to activate endothelial TGF-ß receptors and induce renal arteriolar hyalinosis in these knockout mice, similar to that induced by tacrolimus. Tacrolimus-treated and knockout mice exhibited significantly increased levels of aortic TGF-ß receptor activation as evidenced by SMAD2/3 phosphorylation, along with increased collagen and fibronectin expression compared to controls. Treatment of isolated mouse aortas with tacrolimus increased TGF-ß receptor activation and collagen and fibronectin expression. These effects were independent of calcineurin, absent in endothelial denuded aortic rings, and could be prevented by the small molecule TGF-ß receptor inhibitor SB-505124. Thus, endothelial cell TGF-ß receptor activation is sufficient to cause vascular remodeling and renal arteriolar hyalinosis.

The geographic origin of Helicobacter pylori influences the association of the homB gene with gastric cancer.

We found that South Korean Helicobacter pylori isolates predominantly carry homB at locus B and that there is no association between the homB allele and the cagA allele or the development of gastric cancer within this population. Uniquely, several East Asian strains carried multiple copies of the hom genes.

Return to work considerations in the lingering COVID-19 Era: Long COVID, multiple chemical sensitivity, and universal design.

This article discusses how COVID-19 has impacted the American workforce, symptoms of Long COVID syndrome, Multiple Chemical Sensitivity, and ways to avoid triggering its symptoms when sanitizing the workplace and using Universal Design practices to increase accessibility and decrease transmission of COVID-19 among workers. Interface with healthcare providers, rehabilitation professionals, and employers is emphasized.

Helicobacter pylori homB, but not cagA, is associated with gastric cancer in Iran.

While several distinct virulence factors of Helicobacter pylori have been shown to be associated with different clinical outcomes, there is still much to learn about the role of different bacterial factors in gastric carcinogenesis. This study looked at the distribution of the cagA, homA, and homB genes in strains isolated from patients suffering from gastroduodenal diseases in Iran and assessed if there was any association between disease state and the presence of the aforementioned virulence factors. Genomic DNA from 138 H. pylori strains was isolated and genotyped via PCR. Strains were obtained from dyspeptic patients (35 from gastritis patients, 62 from peptic ulcer patients, and 41 from gastric cancer patients) at the Teaching Touba Clinic and Imam Hospital of the Mazandaran University of Medical Sciences in Sari, Iran. The overall prevalence rates of cagA, homA, and homB were 58%, 54%, and 43%, respectively. Stratification of patients showed a significant difference in the prevalence of H. pylori virulence genes across the disease states. The frequency of homB was statistically significantly higher in gastric cancer patients (78%) than in patients suffering from peptic ulcers (20%) or gastritis (43%) (P < 0.0001). The presence of homB was also associated with the presence of cagA (r = 0.243). These data suggest that in this population the presence of homB may be a predictor of more virulent strains of H. pylori and influence the severity of disease manifestation.

Polymorphisms in the intermediate region of VacA impact Helicobacter pylori-induced disease development.

Helicobacter pylori is the etiological agent of diseases such as gastritis, gastric and duodenal ulcers, and two types of gastric cancers. While some insight has been gained into the etiology of these diverse manifestations, by and large, the reason that some individuals develop more severe disease remains elusive. Recent studies have focused on the roles of H. pylori toxins CagA and VacA on the disease process and have suggested that both toxins are intimately involved. Moreover, CagA and VacA are polymorphic within different H. pylori strains, and particular polymorphisms seem to show a correlation with the development of particular disease states. Among VacA polymorphisms, the intermediate region has recently been proposed to play a major role in disease outcome. In this article, we describe a detailed sequence analysis of the polymorphic intermediate region of vacA from strains obtained from a large South Korean population. We show that polymorphisms found at amino acid position 196 are associated with more severe disease manifestations. Additionally, polymorphisms found at amino acid position 231 are linked to disease in strains that carry the non-EPIYA-ABD allele of CagA. Collectively, these data help explain the impact of the VacA intermediate region on disease and lead to the hypothesis that there are allele-driven interactions between VacA and CagA.

Knowledge of young African American adults about heart disease: a cross-sectional survey.

BACKGROUND: African Americans have higher rates of cardiovascular disease (CVD) mortality than other ethnic groups. Young adults are prime targets for intervention strategies to prevent and reduce disease risk. The study purpose was to determine the level of knowledge of lifestyle risk factors for CVD among young African American adults in Phoenix. The results will be used to guide the development of CVD outreach programs targeted to this population. The Health Belief Model was used as a conceptual framework. METHODS: A convenience sample of 172 African American men and women aged 18-26 years completed a questionnaire adapted from the American Heart Association national surveys. Descriptive statistics were compared by age, gender, education level, and health status variables including BMI, smoking status, and physical activity. RESULTS: Some aspects of heart-disease were well known among young adult African Americans. Knowledge of certain other important risk factors (menopause) and preventive behaviors (eating fewer animal products), however, was more variable and inconsistent among the respondents. Differences in knowledge of individual variables was greater by education level than by gender overall. Predictors of a summary CVD knowledge score included higher education, female gender, and high self-efficacy (adjusted R2 = 0.158, p < .001). Predictors of self-efficacy in changing CVD risk were higher education and perceived low risk of CVD (adjusted R2 = 0.064, p < .001), but these characteristics explained only 6% of the variance. CONCLUSIONS: Evaluation of baseline knowledge of CVD is essential before designing and implementing health promotion programs. Existing strengths and weaknesses in knowledge can guide tailoring of programs to be more effective. Further research would help to identify the range of other characteristics that determine knowledge and risk perception.

Epidemiological link between gastric disease and polymorphisms in VacA and CagA.

Gastritis, peptic ulcer disease, and gastric cancer are a few of the diverse disease manifestations that have been shown to be associated with infection by Helicobacter pylori. Why some individuals develop more severe forms of disease remains largely unknown. In this study, 225 South Korean strains were genotyped for vacA and then analyzed to determine if particular genotypes varied across disease state, sex, or cagA allele. Of these strains, 206 strains carried an s1/i1/m1 allele, 11 strains carried an s1/i1/m2 allele, and 8 strains carried an s1/i2/m2 allele. By using Fisher's exact test, a statistical association between variations in the cagA and vacA alleles was identified (P = 0.0007), and by using log linear modeling, this variation was shown to affect the severity of disease outcome (P = 0.027). Additionally, we present evidence that variation within the middle region of VacA contributes significantly to the distribution of vacA alleles across gender (P = 0.008) as well as the association with disease outcome (P = 0.011). In this South Korean population, the majority of H. pylori strains carry the vacA s1/i1/m1 allele and the CagA EPIYA-ABD allele. These facts may contribute to the high incidence of gastric maladies, including gastric cancer.

Educational Case: Lupus Nephritis as an Example of Immune Complex-Mediated Glomerulonephritis.

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: Antiglomerular Basement Membrane Disease as an Example of Antibody-Mediated Glomerulonephritis.

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.

Informing Policy Change: A Study of Rapid Repeat Pregnancy in Adolescents to Increase Access to Immediate Postpartum Contraception.

Background: Rapid repeat pregnancy (RRP) is common among adolescents and is associated with adverse maternal and infant outcomes. Despite evidence that use of long-acting forms of contraception before hospital discharge can help minimize RRP rates, barriers to placement existed within the state of Indiana. We sought to determine state-specific RRP and induced abortion rates for adolescents based on chosen postpartum contraception to inform policy change. Methods: We examined a retrospective cohort of 227 adolescents (ages 12-18 years) who gave birth in Indiana between 2010 and 2012. Demographics, postpartum contraception, and subsequent pregnancies or abortions after the sentinel delivery were obtained. Rates of RRP based on type of immediate postpartum contraception, etonogestrel (ENG) contraceptive implant, depo-medroxyprogesterone acetate (DMPA) injection, and short-acting methods were compared. Bivariate and logistic regression analyses were conducted. Results: RRP rates were 3.7% for those with ENG contraceptive implant, 22.6% for those with DMPA, and 39.1% for those who choose short-acting methods (p = 0.01). Adolescents who did not choose an ENG contraceptive implant were significantly more likely to have an RRP (adjusted odds ratio [aOR] = 11.8, 95% confidence interval: 2.74-110.3), compared with other contraceptive methods, even after adjusting for covariates such as age, prior pregnancies, and postpartum visit attendance. Conclusions: Immediate postpartum receipt of ENG implant was significantly associated with a lower likelihood of RRP in adolescents in Indiana. These data facilitated state policy change regarding insurance reimbursement to improve statewide access for all women, regardless of age, showing how local data can inform policy change.

Polymorphism in the CagA EPIYA motif impacts development of gastric cancer.

Helicobacter pylori causes diseases ranging from gastritis to peptic ulcer disease to gastric cancer. Geographically, areas with high incidences of H. pylori infection often overlap with areas with high incidences of gastric cancer, which remains one of the leading causes of cancer-related deaths worldwide. Strains of H. pylori that carry the virulence factor cytotoxin-associated gene A (cagA) are much more likely to be associated with the development of gastric cancer. Moreover, particular C-terminal polymorphisms in CagA vary by geography and have been suggested to influence disease development. We conducted a large-scale molecular epidemiologic analysis of South Korean strains and herein report a statistical link between the East Asian CagA EPIYA-ABD genotype and the development of gastric cancer. Characterization of a subset of the Korean isolates showed that all strains from cancer patients expressed and delivered phosphorylatable CagA to host cells, whereas the presence of the cagA gene did not strictly correlate to expression and delivery of CagA in all noncancer strains.

Educational Case: Dysproteinemic Nephropathies: Renal Amyloidosis as an Example.

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.

Cyclooxygenase and CD147 expression in oral squamous cell carcinoma patient samples and cell lines.

OBJECTIVES: In oral squamous cell carcinoma (OSCC), cyclooxygenases (COX-1 and COX-2) contribute to inflammation, and cluster of differentiation factor 147 (CD147) contributes to invasiveness, but their relationship has not been previously examined within a cohort of patients with OSCC or OSCC cell lines. STUDY DESIGN: COX-2 and CD147 expression was determined by using immunohistochemistry on 39 surgical biopsy specimens of OSCC. Expression in tumor cells, stroma, and adjacent oral epithelium was characterized by using a visual grading system. COX-1, COX-2, and CD147 expression was determined in vitro by using OSCC cell lines (SCC25, BHY, and HN) and reverse transcriptase-quantitative polymerase chain reaction. Secretion of prostagladin E2 (PGE2) from OSCC cell lines was determined by using PGE2 enzyme-linked immunosorbent assay. RESULTS: Biopsy specimens showed higher COX-2 expression in tumor cells compared with stroma and adjacent epithelium (P < .05). There was no difference in CD147 expression among the tumor cells, stroma, and adjacent epithelium. In OSCC cell lines, there was a trend for COX-2 and CD147 gene expression to be coordinated. Interestingly, PGE2 secretion was more closely related to COX-1 expression than to COX-2 expression. CONCLUSIONS: COX-1, COX-2, and CD147 appear to be independently regulated in OSCC, potentially representing 2 therapeutic targets for future investigation. COX-1 expression in OSCC deserves further study because it may be an important determinant of PGE2 secretion from OSCC cells.