Health Disparities Curricula in General Surgery Residency Programs: A Critical Scoping Review.

INTRODUCTION: In 2021, the structural determinants of health (SDOH) were added to the Accreditation Council of Graduate Medical Education common program requirements for all accredited residency programs, including general surgery. In this study, we sought to explore the current scope of, and concepts used in, health disparities curricula for general surgery residents, specifically investigating how general surgery residents learn about health disparities and the SDOH. METHODS: We searched PubMed, EMBASE, Education Research Complete (EBSCOhost), and Web of Science Core Collection using keywords related to health disparities and the SDOH. Inclusion criteria consisted of all studies published after 2005 that discussed health disparities curricula for Accreditation Council of Graduate Medical Education-accredited general surgery residency programs. Five thousand three hundred seventeen articles were screened using a two-phase process. Data extraction and analysis was performed using critical review methods. RESULTS: Seventeen articles were identified. Within these articles, seven unique health disparities curricula were found. All seven of the identified curricula employed cultural frameworks as methods to mitigate health disparities. Three curricula, all published after 2011, included education on the SDOH. A wide variety of educational methods were utilized; in-person didactics was the most common. CONCLUSIONS: In the current literature, culture continues to play a large role in health disparities training for general surgery residents. Though further efforts are needed to understand the methods used in programs that have not published scholarly work, it is imperative to ensure that residents are provided with the sociopolitical perspective needed to understand the SDOH and serve all patients, including those affected by health disparities.

Effectiveness of Bupropion and Varenicline for Smokers With Baseline Depressive Symptoms.

INTRODUCTION: Smokers with concurrent depression are less likely to achieve abstinence, even with pharmacotherapy. The purpose of this secondary data analysis was to evaluate if the presence of any depressive symptoms at baseline alters the effectiveness of bupropion and varenicline for smoking cessation. AIMS AND METHODS: Eligible participants were enrolled via the internet and randomized 1:1 to receive a 12-week supply of either bupropion (n = 465) or varenicline (n = 499). Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-2). Follow-up surveys were conducted at weeks 4, 8, 12, 26, and 52 to assess self-reported quit. The primary outcome was 7-day point prevalence abstinence at 12 weeks follow-up (end-of-treatment). RESULTS: Participants who endorsed any depressive symptoms (PHQ-2 > 0; n = 280) were less likely to be quit at end-of-treatment compared to participants who did not endorse any symptoms (PHQ-2 = 0; n = 684) (OR = 0.56, 95% CI: 0.38 to 0.8, p = .003). Within the varenicline group, quit outcomes did not differ between those with and without depressive symptoms (21.3% vs. 26.9%, respectively). Within the bupropion group, however, those with symptoms had a significantly reduced quit rate compared to those without symptoms (7.0% vs. 17.3%, respectively). CONCLUSIONS: The presence of even one symptom of depression at the start of a quit attempt may adversely affect quit outcomes. Patients should be assessed for depressive symptoms when planning to quit smoking as it may inform the approach to treatment. However, future studies are needed to confirm these findings. IMPLICATIONS: Findings from the current study illustrate the importance of evaluating baseline sub-clinical depressive symptoms before a quit attempt using first-line pharmacotherapies. This secondary analysis of a large-scale randomized trial suggests that bupropion may be less effective for those with baseline depressive symptoms while varenicline may be equally effective for those with and without depressive symptoms.

Indolent T-Cell Lymphoproliferative Disease: A Rare Case of a Benign Lymphoma of the Gastrointestinal Tract With Extra-Gastrointestinal Involvement.

Indolent T-cell lymphoproliferative disease of the gastrointestinal (GI) tract is an exceedingly rare benign proliferation of clonal and mature-appearing lymphoid cells originating from the GI tract. We discuss the case of a 52-year-old woman with indolent T-cell lymphoproliferative disease of the GI tract manifesting as chronic diarrhea and profound weight loss. Interestingly, the patient also had extra-GI involvement of her disease process, which has not been previously reported. Our patient was managed with steroids with improvement in symptoms and weight gain. We provide a review of the literature to highlight the importance of early recognition and intervention of this disease entity.

Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study.

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31-1·57]), were male compared with female (1·38 [1·05-1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23-1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50-3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49-3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology.

Association Between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death Among Patients With Immune-Mediated Inflammatory Disease and COVID-19.

Importance: Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective: To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants: This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures: Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures: The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results: A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P < .001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P = .004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P = .33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. Conclusions and Relevance: In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs.

The Prevalence of Clinical Characteristics of Polycystic Ovary Syndrome among Indigenous Women: A Systematic Search and Review of the Literature.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged women; however, to date there has been no synthesis of the burden of PCOS specifically among indigenous women. We aimed to systematically identify and collate studies reporting prevalence and clinical features of PCOS among indigenous women worldwide. We performed a comprehensive search of six databases (Ovid MEDLINE, MEDLINE In Process & Other Non-Indexed Citations, EMBASE, EBM reviews, CINAHL, and SCOPUS) supplemented by gray literature searches and the screening of reference lists. A narrative synthesis was conducted. Fourteen studies met inclusion criteria; however, one was excluded as it assessed only children and adolescents younger than 15 years, with limited clinical relevance. Studies examined indigenous women from Australia, Sri Lanka, New Zealand, and the United States. Prevalence of PCOS was reported in only four studies and ranged from 3.05% for women in Sri Lanka to 26% for women in Australia. All included studies reported on at least one clinical feature of PCOS. Of the studies that reported on a comparison group from the same country, there was evidence of more severe features in indigenous women from New Zealand and the United States. The limited evidence available warrants further investigation of the burden of PCOS in indigenous women to build the knowledge base for effective and culturally relevant management of this condition.

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry.

OBJECTIVE: To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). METHODS: We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. RESULTS: Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. CONCLUSIONS: People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.

The leading edge: Emerging neuroprotective and neuroregenerative cell-based therapies for spinal cord injury.

Spinal cord injuries (SCIs) are associated with tremendous physical, social, and financial costs for millions of individuals and families worldwide. Rapid delivery of specialized medical and surgical care has reduced mortality; however, long-term functional recovery remains limited. Cell-based therapies represent an exciting neuroprotective and neuroregenerative strategy for SCI. This article summarizes the most promising preclinical and clinical cell approaches to date including transplantation of mesenchymal stem cells, neural stem cells, oligodendrocyte progenitor cells, Schwann cells, and olfactory ensheathing cells, as well as strategies to activate endogenous multipotent cell pools. Throughout, we emphasize the fundamental biology of cell-based therapies, critical features in the pathophysiology of spinal cord injury, and the strengths and limitations of each approach. We also highlight salient completed and ongoing clinical trials worldwide and the bidirectional translation of their findings. We then provide an overview of key adjunct strategies such as trophic factor support to optimize graft survival and differentiation, engineered biomaterials to provide a support scaffold, electrical fields to stimulate migration, and novel approaches to degrade the glial scar. We also discuss important considerations when initiating a clinical trial for a cell therapy such as the logistics of clinical-grade cell line scale-up, cell storage and transportation, and the delivery of cells into humans. We conclude with an outlook on the future of cell-based treatments for SCI and opportunities for interdisciplinary collaboration in the field.

Mesenteric panniculitis in a patient with new onset dermatomyositis.

Mesenteric panniculitis (MP), part of the spectrum of sclerosing mesenteritis, is an often asymptomatic disorder that is characterised by chronic inflammation of abdominal mesentery. We present a case of an 83-year-old woman who presented with proximal muscle weakness and erythematous, photosensitive rash of the face and upper torso and was subsequently diagnosed with dermatomyositis based on skin biopsy, electromyography and muscle biopsy. She had radiographic evidence of panniculitis on CT scan of the abdomen and pelvis for malignancy surveillance, which improved on serial CT scan 3 months after beginning treatment for her underlying dermatomyositis with prednisone and mycophenolate mofetil. Our case highlights that MP can be associated with underlying autoimmune disease. Connective tissue disease could be considered in the differential of MP when other etiologies such as surgery, trauma and malignancy are ruled out.

Creation of a score to predict risk of high conscious sedation requirements in patients undergoing endoscopy.

BACKGROUND AND AIMS: The administration of intravenous conscious sedation to patients undergoing GI endoscopy carries a risk of cardiopulmonary adverse events. Our study aim was to create a score that stratifies the risk of occurrence of either high-dose conscious sedation requirements or a failed procedure. METHODS: Patients receiving endoscopy via endoscopist-directed conscious sedation were included. The primary outcome was occurrence of sedation failure, which was defined as one of the following: (1) high-dose sedation, (2) the need for benzodiazepine/narcotic reversal agents, (3) nurse-documented poor patient tolerance to the procedure, or (4) aborted procedure. High-dose sedation was defined as >10 mg of midazolam and/or >200 µg of fentanyl or the meperidine equivalent. Patients with sedation failure (n = 488) were matched to controls (n = 976) without a sedation failure by endoscopist and endoscopy date. RESULTS: Significant associations with sedation failure were identified for age, sex, nonclonazepam benzodiazepine use, opioid use, and procedure type (EGD, colonoscopy, or both). Based on these 5 variables, we created the high conscious sedation requirements (HCSR) score, which predicted the risk of sedation failure with an area under the curve of 0.70. Compared with the patients with a risk score of 0, risk of a sedation failure was highest for patients with a score ≥3.5 (odds ratio, 17.31; P = 2 × 10-14). Estimated area under the curve of the HCSR score was 0.68 (95% confidence interval, 0.63-0.72) in a validation series of 250 cases and 250 controls. CONCLUSIONS: The HCSR risk score, based on 5 key patient and procedure characteristics, can function as a useful tool for physicians when discussing sedation options with patients before endoscopy.

Risk factors for infection and evaluation of Sepsis-3 in patients with trauma.

BACKGROUND: We aim to examine the risk factors associated with infection in trauma patients and the Sepsis-3 definition. METHODS: This was a retrospective cohort study of adult trauma patients admitted to a Level I trauma center between January 2014 and January 2016. RESULTS: A total of 1499 trauma patients met inclusion criteria and 15% (n = 232) had an infection. Only 19.8% (n = 46) of infected patients met criteria for Sepsis-3, with the majority (43%) of infected cases having a Sequential Organ Failure Assessment (SOFA) score greater on admission compared to the time of suspected infection. In-hospital death was 7% vs 9% (p = 0.65) between Sepsis-3 and infected patients, respectively. Risk factors associated with infection were female sex, admission SOFA score, Elixhauser score, and severe injury (P < 0.05). CONCLUSION: Patients with trauma often arrive with organ dysfunction, which adds complexity and inaccuracy to the operational definition of Sepsis-3 using changes in SOFA scores. Injury severity score, comorbidities, SOFA score, and sex are risk factors associated with developing an infection after trauma.

Reptile Embryology and Regeneration.

Reptiles (lizards, snakes, turtles, and crocodilians) are becoming increasingly popular as models for developmental investigations. In this review the leopard gecko, Eublepharis macularius, is presented as a reptilian model for embryonic and tissue regeneration studies. We provide details of husbandry and breeding and discuss aspects of embryonic nutrition, egg anatomy, and sex determination. We provide comprehensive protocols for transcardial perfusion, short-term anesthesia using the injectable anesthetic Alfaxan, and full-thickness cutaneous biopsy punches, used in geckos for the study of scar-free wound healing. We also provide modifications to three popular histological techniques (whole-mount histochemistry, immunohistochemistry, and double-label immunofluorescence) and provide details on bromodeoxyuridine (BrdU) labeling and immuno-detection.

Ask PCOS: Identifying Need to Inform Evidence-Based App Development for Polycystic Ovary Syndrome.

BACKGROUND: People are increasingly seeking health information and managing their health through electronic technologies. We aimed to determine if women with polycystic ovary syndrome (PCOS) identified a need for PCOS-related mobile health apps and to evaluate related apps currently available. DESIGN: A national survey of women and a review of apps available on the iOS and Android platforms. SETTING: Community recruitment in Australia in 2016 and review of mobile apps available in 2017. SAMPLE: The survey received 264 responses. Sixteen apps related to PCOS were evaluated. MAIN OUTCOME MEASURES: Survey: Women's likeliness to use mobile health apps, specifically a PCOS-related app and preferred features of apps. App review: Mapping of available apps and evaluation using the Mobile Application Rating Scale (MARS). RESULTS: Of 264 respondents, almost all women had a smartphone (98%), 72% had previously used an app to manage their health, and most (91%) would use a PCOS-specific app if available. The most important feature was the availability of current, evidence-based information. Current apps on PCOS lack provision of quality information. CONCLUSION: Women with PCOS would use a PCOS-specific app of good quality that responds to their needs and facilitates self-care; however, currently available apps are unlikely to meet their information needs.

Comorbidities and complications of polycystic ovary syndrome: An overview of systematic reviews.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting reproductive-aged women with adverse reproductive, metabolic and psychological outcomes. It has a complex pathophysiology and therefore requires a multidiscipline clinical approach. However, there remains limited research synthesizing the broad clinical implications of PCOS which would assist clinicians in the management of PCOS. OBJECTIVE: To summarize and appraise methodological quality of systematic reviews and meta-analyses evaluating complications and comorbidities associated with PCOS. METHODS: A literature search from MEDLINE, EMBASE, CINAHL PLUS and PROSPERO was performed until 15 September 2017. Article selection, data extraction and quality appraisal of included reviews using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool were performed in duplicate. A narrative synthesis of the findings was conducted. RESULTS: Twenty-three reviews were included. All reviews were of low (n = 2) to moderate quality (n = 21). PCOS was associated with adverse pregnancy outcomes (n = 2), impaired glucose tolerance (n = 6), insulin resistance (n = 6), increased risk of type 2 diabetes (n = 1), cardiovascular disease (n = 10), metabolic syndrome (n = 2), psychological stress (n = 7), endometrial cancer (n = 1) and vitamin D deficiency (n = 1). Obesity exacerbates many of these outcomes. CONCLUSIONS: There is a large body of reliable evidence for adverse metabolic outcomes and smaller, but consistent evidence for psychological issues in PCOS. We identified a shortage of systematic reviews regarding pregnancy outcomes of PCOS and significant gaps in knowledge of the association between PCOS and subclinical hyperthyroidism, vitamin D levels and cancers which future studies could aim to address.

Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice.

An immunotherapeutic strategy is discussed supporting anti-tumor activity toward malignancies overexpressing ganglioside D3. GD3 can be targeted by NKT cells when derived moieties are presented in the context of CD1d. NKT cells can support anti-tumor responses by secreting inflammatory cytokines and through cytotoxicity toward CD1d+GD3+ tumors. To overexpress GD3, we generated expression vector DNA and an adenoviral vector encoding the enzyme responsible for generating GD3 from its ubiquitous precursor GM3. We show that DNA encoding α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (SIAT8) introduced by gene gun vaccination in vivo leads to overexpression of GD3 and delays tumor growth. Delayed tumor growth is dependent on CD1d expression by host immune cells, as shown in experiments engaging CD1d knockout mice. A trend toward greater NKT cell populations among tumor-infiltrating lymphocytes is associated with SIAT8 vaccination. A single adenoviral vaccination introduces anti-tumor activity similarly to repeated vaccination with naked DNA. Here, greater NKT tumor infiltrates were accompanied by marked overexpression of IL-17 in the tumor, later switching to IL-4. Our results suggest that a single intramuscular adenoviral vaccination introduces overexpression of GD3 by antigen-presenting cells at the injection site, recruiting NKT cells that provide an inflammatory anti-tumor environment. We propose adenoviral SIAT8 (AdV-SIAT8) can slow the growth of GD3 expressing tumors in patients.

Scar-free cutaneous wound healing in the leopard gecko, Eublepharis macularius.

Cutaneous wounds heal with two possible outcomes: scarification or near-perfect integumentary restoration. Whereas scar formation has been intensively investigated, less is known about the tissue-level events characterising wounds that spontaneously heal scar-free, particularly in non-foetal amniotes. Here, a spatiotemporal investigation of scar-free cutaneous wound healing following full-thickness excisional biopsies to the tail and body of leopard geckos (Eublepharis macularius) is provided. All injuries healed without scarring. Cutaneous repair involves the development of a cell-rich aggregate within the wound bed, similar to scarring wounds. Unlike scar formation, scar-free healing involves a more rapid closure of the wound epithelium, and a delay in blood vessel development and collagen deposition within the wound bed. It was found that, while granulation tissue of scarring wounds is hypervascular, scar-free wound healing conspicuously does not involve a period of exuberant blood vessel formation. In addition, during scar-free wound healing the newly formed blood vessels are typically perivascular cell-supported. Immunohistochemistry revealed widespread expression of both the pro-angiogenic factor vascular endothelial growth factor A and the anti-angiogenic factor thrombospondin-1 within the healing wound. It was found that scar-free wound healing is an intrinsic property of leopard gecko integument, and involves a modulation of the cutaneous scar repair program. This proportional revascularisation is an important factor in scar-free wound healing.

Impact of early life ovariectomy on blood pressure and body composition in a female mouse model of systemic lupus erythematosus.

Because of the preponderance of women affected by the chronic autoimmune disease systemic lupus erythematosus (SLE), estrogen is thought to contribute to SLE disease progression. This is supported by evidence from experimental animal models of SLE showing that removal of estrogen in young female mice delays autoantibody production and renal injury and lengthens survival. Blood pressure and changes in body composition are important cardiovascular risk factors that can be regulated by estrogens. Because cardiovascular disease is the leading cause of death in patients with SLE, we used an established female mouse model of SLE (NZBWF1) to test whether early life removal of estrogen impacts the development of hypertension and changes in body composition commonly associated with SLE. Eight-week-old female SLE and control mice (NZW/LacJ) underwent either a sham operation or ovariectomy. Body weight, body composition (fat and lean masses), and renal injury (albuminuria) were monitored until mice reached 34 wk of age, at which time mean arterial pressure was assessed in conscious animals by a carotid catheter. Early life removal of the ovaries delayed the onset of autoantibody production and albuminuria while causing an increase in body weight and fat mass. Blood pressure in the adult was not altered by early life removal of the ovaries. These data suggest that estrogens may have a permissive role for the development of SLE while helping to maintain normal body weight and composition, which is associated with reduced cardiovascular risk.

Estrogen in cardiovascular disease during systemic lupus erythematosus.

PURPOSE: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. METHODS: PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. FINDINGS: The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against cardiovascular risk factors in adulthood. In addition, increasing evidence suggests that estrogen may have distinct temporal effects on cardiovascular risk factors during SLE. IMPLICATIONS: Data from experimental models of lupus suggest that estrogens may have an important permissive role for developing SLE early in life. However, their role in adulthood remains unclear, particularly for the effect on cardiovascular disease and its risk factors. Additional work is needed to understand the effect of estrogens in human SLE, and preclinical studies in experimental models of SLE may contribute important mechanistic insight to further advance the field.

17ß-Estradiol protects against the progression of hypertension during adulthood in a mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder with a high prevalence of hypertension and cardiovascular disease. Because SLE predominantly affects women, estrogen is commonly implicated as a contributor to SLE disease progression. Using an established mouse model of SLE (female NZBWF1), we tested whether estrogen has a causal role in the development of hypertension in adulthood. Thirty-week-old SLE and control mice (NZW/LacJ) underwent either a sham or ovariectomy (OVX) procedure. 17ß-Estradiol (E2; 5 µg/mouse, twice/week, subcutaneously) was administered to a subset of OVX mice. Mean arterial pressure (in mm Hg) was increased in SLE mice (134±4 versus 119±3 in controls). Contrary to our hypothesis, OVX exacerbated the hypertension in female SLE mice (153±3; P<0.05 versus SLE sham), and repletion of E2 prevented the OVX-induced increase in blood pressure (132±2). The prevalence of albuminuria was increased in SLE mice compared with controls (37% versus 0%). OVX increased the prevalence in SLE mice (70% versus 37% in SLE shams). Repletion of E2 completely prevented albuminuria in OVX SLE mice. Renal cortical tumor necrosis factor α was increased in SLE mice compared with controls and was further increased in OVX SLE. The OVX-induced increase in renal tumor necrosis factor α expression was prevented by repletion of E2. Treatment of OVX SLE mice with the tumor necrosis factor α inhibitor, etanercept, blunted the OVX-induced increase in blood pressure (140±2) and prevalence of albuminuria (22%). These data suggest that 17ß-estradiol protects against the progression of hypertension during adulthood in SLE, in part, by reducing tumor necrosis factor α.

Positioning ganglioside D3 as an immunotherapeutic target in lymphangioleiomyomatosis.

Tumors that develop in lymphangioleiomyomatosis (LAM) as a consequence of biallelic loss of TSC1 or TSC2 gene function express melanoma differentiation antigens. However, the percentage of LAM cells expressing these melanosomal antigens is limited. Here, we report the overexpression of ganglioside D3 (GD3) in LAM. GD3 is a tumor-associated antigen otherwise found in melanoma and neuroendocrine tumors; normal expression is largely restricted to neuronal cells in the brain. We also observed markedly reduced serum antibody titers to GD3, which may allow for a population of GD3-expressing LAM cells to expand within patients. This is supported by the demonstrated sensitivity of cultured LAM cells to complement mediated cytotoxicity via GD3 antibodies. GD3 can serve as a natural killer T (NKT) cell antigen when presented on CD1d molecules expressed on professional antigen-presenting cells. Although CD1d-expressing monocyte derivatives were present in situ, enhanced NKT-cell recruitment to LAM lung was not observed. Cultured LAM cells retained surface expression of GD3 over several passages and also expressed CD1d, implying that infiltrating NKT cells can be directly cytotoxic toward LAM lung lesions. Immunization with antibodies to GD3 may thus be therapeutic in LAM, and enhancement of existing NKT-cell infiltration may be effective to further improve antitumor responses. Overall, we hereby establish GD3 as a suitable target for immunotherapy of LAM.