[Effects of caspase recruitment domain protein 9 gene knockout on airway inflammation in C57BL/6 mice with steroid resistant asthma].

Objective: To investigate the role of caspase recruitment domain protein 9 (CARD9) in airway injury and inflammation of steroid resistant asthma in C57BL/6 mice. Methods: C57BL/6 mice were divided into A group (control group), B group (model group) and C group (dexamethasone treatment group), with 6 mouse in each group using random number table. The mouse asthma model was established in B and C group by subcutaneous injection of ovalbumin (OVA)/complete Freund adjuvant (CFA) in the abdomen and OVA aerosol challenge, the pathological change and cell count in broncho alveolar lavage fluid (BALF) were detected in order to confirm the model as steroid resistant asthma, and the lung tissue inflammatory infiltration was scored. Western blot was used to detect the changes of CARD9 protein between the group A and B; then wild-type and CARD9 knockout mice were divided into D group (wild-type control group), E group (wild-type model group), F group (CARD9 knockout control group) and G group (CARD9 knockout model group), the following indicators were observed and compared after establishing steroid resistant asthma model separately: HE staining was used to observe the pathological changes of lung tissue, ELISA was used to detect the protein levels of interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-17(IL-17) in BALF, and RT-PCR was used to detect the mRNA levels of CXC motif chemokine ligand-10 (CXCL-10) and IL-17 in lung. Results: The inflammatory score (3.33±0.82 vs 0.67±0.52) and BALF total cell count [(10.13±4.83) ×105/ml vs (3.76±0.84) ×105/ml] in B group were higher than those in the A group with statistical significance (P<0.05). There was no significant difference between group C and group B in inflammatory infiltration score (2.83±0.75 vs 3.33±0.82) and BALF total cell count [(9.80±3.19) ×105/ml vs (10.13±4.83) ×105/ml] (P>0.05). Moreover the protein level of CARD9 was increased in the B group than A group (0.245±0.090 vs 0.047±0.014, P=0.004). Compared to E group and F group, more obviously inflammatory cells, neutrophils, eosinophils infiltration and tissue injury were observed in G group (P<0.05), so did the expression of IL-4 (P<0.05), IL-5 and IL-17. Meanwhile the mRNA expression levels of IL-17 and CXCL-10 also increased in lung tissue (P<0.05) of G group. Conclusion: CARD9 gene deletion may aggravate the steroid resistant of asthma by increasing neutrophil chemokines, such as IL-17 and CXCL-10, therefore increasing infiltration of neutrophils in C57BL/6 mice asthma model.

Infliximab versus ciclosporin in steroid resistant acute severe ulcerative colitis: a model-based cost-utility analysis of data from CONSTRUCT pragmatic trial.

BACKGROUND: There is limited evidence in the literature on the long-term effectiveness and cost-effectiveness of treatments for Acute Severe Ulcerative Colitis (ASUC). The study aimed to perform decision analytic model-based long-term cost-utility analysis (CUA) of infliximab versus ciclosporin for steroid-resistant ASUC investigated in CONSTRUCT pragmatic trial. METHODS: A decision tree (DT) model was developed using two-year health effect, resource use and costs data from CONSTRUCT trial to estimate relative cost-effectiveness of two competing drugs from the United Kingdom (UK) National Health Services (NHS) perspective. Using short-term trial data, a Markov model (MM) was then developed and evaluated over further 18 years. Both DT and MM were combined to investigate cost-effectiveness of infliximab versus ciclosporin for ASUC patients over 20-year time horizon, with a rigorous multiple deterministic and probabilistic sensitivity analyses to address uncertainty in results. RESULTS: The decision tree mirrored trial-based results. Beyond 2-year trial follow-up, Markov model predicted a decrease in colectomy rate, but it remained slightly higher for ciclosporin. NHS costs and quality adjusted life years (QALYs) over base-case 20 year time horizon were £26,793 and 9.816 for ciclosporin and £34,185 and 9.106 for infliximab, suggesting ciclosporin dominates infliximab. Ciclosporin had 95% probability of being cost-effective at a willingness-to-pay (WTP) threshold value up to £20,000. CONCLUSION: Using data from a pragmatic RCT, the cost-effectiveness models produced incremental net health benefit in favour of ciclosporin relative to infliximab. Results from long-term modelling indicated that ciclosporin remains dominant compared with infliximab for the treatment of NHS ASUC patients, however, these need to be interpreted cautiously. TRIAL REGISTRATION: CONSTRUCT Trial registration number ISRCTN22663589; EudraCT number: 2008- 001968-36 (Date 27/08/2008).

Successful treatment of acute myocardial injury of Duchenne muscular dystrophy with steroids: a case report.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked muscular disease which is caused by the absence of dystrophin. Troponin elevation with acute chest pain may indicate acute myocardial injury in these patients. We report a case of DMD that presented with ACP and troponin elevation, who was diagnosed with acute myocardial injury, and successfully treated with corticosteroids. CASE PRESENTATION: A 9-year-old with DMD was admitted to the emergency department with the complaint of acute chest pain. His electrocardiogram (ECG) revealed inferior ST elevation and serum troponin T was elevated. The transthoracic echocardiography (TTE) demonstrated inferolateral and anterolateral hypokinesia with depressed left ventricular function. An ECG-gated coronary computed tomography angiography ruled out acute coronary syndrome. Cardiac magnetic resonance imaging revealed mid-wall to sub-epicardial late gadolinium enhancement at the basal to the mid inferior lateral wall of the left ventricle and corresponding hyperintensity on T2-weighted imaging, consistent with acute myocarditis. A diagnosis of acute myocardial injury associated with DMD was made. He was treated with anticongestive therapy and 2 mg/kg/day of oral methylprednisolone. Chest pain resolved the next day, and ST-segment elevation returned to normal on the third day. Troponin T decreased in the sixth hour of oral methylprednisolone treatment. TTE on the fifth day revealed improved left ventricular function. CONCLUSION: Despite advances in contemporary cardiopulmonary therapies, cardiomyopathy remains the leading cause of death in patients with DMD. Acute chest pain attacks with elevated troponin in patients with DMD without coronary artery disease may indicate acute myocardial injury. Recognition and appropriate treatment of acute myocardial injury episodes in DMD patients may delay the development of cardiomyopathy.

CLIPPERS Syndrome After Vaccination. An Unusual ASIA Presentation.

The chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) were described a decade ago. There are a limited number of reports and these diseases are still underdiagnosed. We presented a 35 years-old patient with clinical manifestations of cerebellum affection and enhancement in the MRI, with the influenza vaccine as the only triggering factor. Infectious diseases, malignancy, and additional systemic involvement were ruled out; therefore, on suspicion of CLIPPERS syndrome, the patient received corticosteroid therapy with an adequate response. The knowledge of CLIPPERS syndrome as an unusual ASIA presentation and high response to the corticosteroids may lead to a timely diagnosis, appropriate treatment, and follow up with better outcomes for patients.

Assessment of the Androstenedione Assay on a Roche Analytical Platform and Comparison with Different Methods.

BACKGROUND: D4-androstenedione (D4ASD) is an intermediate hormone of androgen biosynthesis by the gonads and the adrenal glands. The interest in D4ASD concentration assessment resides in diagnostics of androgenic hyperproduction pathologies. Currently, many D4ASD quantification methods are available on the market including immunological methods that remain problematic due to the possible cross-reactivity with endogenous or exogenous steroids. METHODS: Recently Roche® launched a new fully automated instrument for the measurement of D4ASD concentration. In this paper, the criteria of analytical performance (repeatability and intermediate precision) of the D4ASD Roche® assay were assessed and compared with 2 different methods including a radioimmunoassay (RIA) as well as a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. RESULTS: Repeatability and intermediate precision of the D4ASD Roche® were acceptable according to the prede-fined RICOS standard (CV ≤ 7.9%) and the assay showed a good correlation with other assays considering the 95% CI obtained for the slope and the y-intercept. CONCLUSIONS: This method demonstrates acceptable criteria of analytical performance with an intermediate imprecision and a trueness within the fixed acceptance limits.

The pathogenesis hypothesis and research progress of CLIPPERS: A literature review.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is still a rare autoimmune disease in the world. In recent years, there are more and more reports about the clinical manifestations of CLIPPERS, but the specific etiology and pathogenesis are not clear. In this paper, by collating the literature reported in recent years, in the reported effective treatment cases, we found the current hypothesis about the pathogenesis of CLIPPERS. Three pathogenesis hypotheses: organ-specific autoimmunity; virus infection affects autoimmunity; and helper T lymphocyte 17 mediates autoimmunity. Although it is hypothetical, it is expected to further clarify the pathogenesis, evolution characteristics, and treatment of CLIPPERS, so as to provide a reference for further understanding of the disease. In the future, more observations and studies are needed to further verify the feasibility of the hypothesis. This article expands on atypical clinical manifestations and summarizes treatment options. Hope to provide a reference for clinical diagnosis and treatment of CLIPPERS.

Sordera súbita idiopática: factores pronóstico y resultados del tratamiento de rescate con dexametasona intratimpánica / Idiopathic sudden sensorineural hearing loss: prognostic factors and outcomes of salvage treatment with intratympanic dexamethasone

Introducción y objetivos: La sordera súbita idiopática se define habitualmente, como una pérdida auditiva superior o igual a 30 dB HL, en 3 o más frecuencias consecutivas, con un tiempo de instauración inferior a 72 horas, de causa desconocida. Siendo actualmente motivo de discusión el efecto de la terapia esteroidea en este síndrome, evaluaremos la eficacia del corticoide intratimpánico (CIT) como tratamiento de rescate. Como objetivo secundario, estudiaremos la influencia de determinados factores considerados de riesgo o pronóstico. Pacientes y métodos: Se comparan los resultados de dos grupos de población con edad y pérdida auditiva similar. El primero, de 99 pacientes, recibió exclusivamente tratamiento sistémico con corticoides. En el segundo de 70, con una sordera súbita idiopática refractaria al tratamiento general, instilamos corticoide intratimpánico. Comparamos las diferencias de umbral medio auditivo en el momento del diagnóstico y a los 3 meses, además del grado general de recuperación. Resultados: La aplicación intratimpánica de 3 dosis de dexametasona (8mg/ml) en la sordera súbita idiopática refractaria, no ha producido, en nuestra población, un cambio significativo respecto al tratamiento sistémico. Analizamos también la influencia de los factores pronósticos seleccionados. Discusión: Desconocemos la eficacia del tratamiento con corticoides en la sordera súbita idiopática. El tipo de lesión y las características del paciente podrían ser decisivos en el pronóstico final y en el resultado terapéutico. Conclusiones: El tratamiento de rescate con CIT, no ha aportado mejoría auditiva significativa en la población estudiada. Los factores con peor pronóstico son: la presencia de síntomas vestibulares, la hipoacusia de grado profundo, la caída audiométrica hacia tonos agudos, el inicio del tratamiento después de 2 semanas y fundamentalmente, la falta de mejoría de al menos 10 dB el 4º día de tratamiento. (AU)

Introduction and objectives: Idiopathic Sudden Sensorineural Hearing Loss (ISSNHL) is commonly defined as greater than 30 dB of hearing loss in at least 3 audiometric frequencies occurring over 3 days or less, of unknown cause. Since the effect of steroid therapy in this syndrome is currently under discussion, we will evaluate the efficacy of intratympanic corticosteroid (ITC) as rescue treatment. As a secondary objective, we will study the influence of certain factors considered risk or prognostic. Patients and methods: The results of two population groups with similar age and hearing loss are compared. The first of 99 patients received exclusively systemic treatment with corticosteroids. In the second group of 70, with ISSNHL refractory to general treatment, we instilled intratympanic corticosteroids. We compared the differences in mean hearing threshold at diagnosis and at 3 months, as well as the general degree of recovery. Results: Intratympanic application of 3 doses of dexamethasone (8mg/ml) in refractory ISSNHL did not produce, in our population, a significant change with respect to systemic treatment. We also analyzed the influence of selected prognostic factors. Discussion: We do not know the efficacy of corticosteroid treatment in idiopathic sudden deafness. The type of lesion and patient characteristics could be decisive in the final prognosis and therapeutic outcome. Conclusions: Rescue treatment with ITC has not provided significant hearing improvement in the population studied. The factors with the worst prognosis are the presence of vestibular symptoms, profound hearing loss, high-frequency hearing loss in audiometry, the beginning of treatment after 2 weeks and fundamentally, the lack of improvement of at least 10 dB on the 4th day of treatment. (AU)

Preoperative intra-articular steroid injections within 3 months increase the risk of periprosthetic joint infection in total knee arthroplasty: a systematic review and meta-analysis.

OBJECTIVE: Albeit with no disease-modifying effects, intra-articular steroid injections (IASIs) are still widely used to relieve symptoms of knee osteoarthritis. Previous literature has reported conflicting results regarding the safety of IASI in terms of periprosthetic joint infection (PJI) in total knee arthroplasty (TKA). This study tried to determine whether preoperative IASIs increased the risk of PJI, with different time intervals between the injections and surgery. METHODS: A computerized search of MEDLINE, EMBASE, and Cochrane Library was conducted for studies published before October 2022, which investigated the PJI rates of patients who received IASIs before TKA and patients who did not. The primary outcome was the association between preoperative IASI and PJI in TKA. The time point from which IASIs could be applied without risking PJI was also assessed. RESULTS: Fourteen studies, with 113,032 patients in the IASI group and 256,987 patients in the control group, were included. The pooled odds ratio of PJI was 1.13 (95% confidence interval [CI] 1.00-1.27, p = 0.05), indicating no increased risk of PJI. With the time interval < 6 months, the pooled odds ratio was 1.19 (95% CI 0.99-1.43, p = 0.06). However, with the time interval < 3 months, the pooled odds ratio was 1.26 (95% CI 1.06-1.50, p < 0.01). CONCLUSION: IASI is not a safe procedure for patients who are expected to undergo TKA. The time interval between the injections and surgery was an important factor in assessing the safety of IASI. Preoperative injections that were applied within 3 months increased the risk of PJI in TKA.

A prospective, randomized, non-blinded, non-inferiority pilot study to assess the effect of low-dose anti-thymocyte globulin with low-dose tacrolimus and early steroid withdrawal on clinical outcomes in non-sensitized living-donor kidney recipients.

BACKGROUND: The optimal dose of anti-thymocyte globulin (ATG) as an induction regimen in Asian living-donor kidney recipients is unclear. METHODS: This is a pilot study in which 36 consecutive patients undergoing living-donor kidney transplantation were randomly assigned to receive either 4.5 mg/kg (n = 19) or 6.0 mg/kg (n = 17) of ATG; all patients had corticosteroid withdrawal within 7 days. The primary end point was a composite of biopsy-proven acute rejection, de novo donor-specific antibody formation, and graft failure. RESULTS: At 12 months post-transplant, biopsy-proven acute rejection was more common in the ATG4.5 group (21.1%) than in the ATG6.0 group (0%)(P = .048). Importantly, the rate of the composite end point was significantly higher in the ATG4.5 group (36.8% vs 0%)(P = .006). There were significant differences in neither the renal function nor adverse events between the two groups. One case of death-censored graft failure occurred in the ATG4.5 group and no mortality was observed overall. Compared with pre-transplantation, T cells, natural killer (NK) cells, and natural killer T (NKT) cells were significantly decreased in the first week post-transplantation except for B cells. Although T and NKT cells in both groups and NK cells in the ATG4.5 group had recovered to the pre-transplant levels, NK cells in the ATG6.0 group remained suppressed until six months post-transplant. CONCLUSIONS: Compared with ATG 6.0 mg/kg, ATG 4.5 mg/kg with early corticosteroid withdrawal and low dose maintenance regimen was associated with higher rates of acute rejection in non-sensitized Asian living-donor kidney recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02447822.

Intrahepatic infiltration of activated CD8+ T cells and mononuclear phagocyte is associated with idiosyncratic drug-induced liver injury.

Background: Idiosyncratic drug-induced liver injury (DILI) is caused by the interplay among drugs, their metabolites, and the host immune response. The characterization of infiltrated immune cells in the liver may improve the understanding of the pathogenesis of idiosyncratic DILI. This study investigated the phenotypes and clinical implications of liver-infiltrating immune cells in idiosyncratic DILI. Methods: From January 2017 to June 2021, 53 patients with idiosyncratic DILI who underwent liver biopsy were prospectively enrolled in this study. Immunohistochemical staining and flow cytometry analyses were performed on the biopsy specimens. Serum levels of CXC chemokine ligand 10 (CXCL10) and soluble CD163 were measured. A multivariate cox proportional hazards model was used to evaluate predictors of DILI resolution within 30 days. Results: The numbers of intrahepatic T cells and mononuclear phagocytes were positively correlated with serum levels of total bilirubin, alanine aminotransferase (ALT), and the model of end-stage liver disease score. The frequency of activated CD8+ T cells among liver-infiltrating CD8+ T cells in DILI livers was higher than that in healthy livers. Notably, the percentages of activated intrahepatic CD8+ T cells and mononuclear phagocytes in DILI livers showed a positive correlation with ALT. Additionally, serum CXCL10 level was positively correlated with intrahepatic T cell infiltration and ALT, and soluble CD163 level was positively correlated with intrahepatic mononuclear phagocyte infiltration and ALT. Thirty-six patients (70.6%) were treated with steroids. In multivariate analysis, total bilirubin and steroid use independently influenced DILI resolution within 30 days. Conclusions: Activated CD8+ T cells and mononuclear phagocyte are associated with liver injury caused by drugs. Therefore, we suggest that steroids are a potential treatment option for idiosyncratic DILI.

Ovarian steroid cell tumor (not otherwise specified) with subsequent spontaneous pregnancy after tumor removal: a case report and literature review.

Steroid cell tumors not otherwise specified are rare sex cord-stromal tumors of the ovary that may produce various steroids and are associated with hirsutism and virilization. We report a rare case of ovarian steroid cell tumor with subsequent spontaneous pregnancy after tumor removal. A 31-year-old woman presented with secondary amenorrhea, hirsutism, and inability to conceive. Clinical and diagnostic evaluations revealed a left adnexal mass and elevated serum total testosterone and 17α-hydroxyprogesterone levels. She underwent a left salpingo-oophorectomy, and histopathological examination confirmed the diagnosis of a steroid cell tumor not otherwise specified. Her serum total testosterone and 17α-hydroxyprogesterone normalized one month after surgery. Her menses resumed spontaneously one month after the operation. She spontaneously conceived 12 months after the surgery. The patient had an uncomplicated pregnancy and delivered a healthy male infant. In addition, we reviewed the literature on steroid cell tumors not otherwise specified with subsequent spontaneous pregnancies after surgery and data regarding pregnancy outcomes.

Executive summary of the position statement of the Spanish Societies SEQCML/SEEN/SEEP. Recommendations for the measurement of sex steroids in clinical practice.

Accurate measurement of sex steroids, particularly testosterone and estradiol, is relevant for the diagnosis and treatment of a wide range of conditions. Unfortunately, current chemiluminescent immunoassays have analytical limitations with important clinical consequences. This document reviews the current state of clinical assays for estradiol and testosterone measurements and their potential impact in different clinical situations. It also includes a series of recommendations and necessary steps to introduce steroid analysis by mass spectrometry into national health systems, a methodology recommended for more than a decade by international societies.

[A young woman with auto-immune pancreatitis]. / Acute pancreatitis bij een jonge patiënt.

BACKGROUND: Acute pancreatitis is a frequently diagnosed disease. The majority is caused by cholelithiasis or alcohol. There are also two forms of auto-immune pancreatitis (AIP). Type 2 AIP presents on a younger age compared with IgG4 related pancreatitis. Clinical presentation as an acute pancreatitis, a mass in the pancreas or with jaundice. There is an association with inflammatory bowel disease. CASE DESCRIPTION: A young patient with Crohn's disease developed abdominal pain compatible with acute pancreatitis. After exclusion of other etiologies a diagnosis of type 2 auto-immune pancreatitis was made with MRI/MRCP and typical histology. She was clinically successfully treated with steroids and follow up scan clearly showed improvement. Steroids were slowly withdrawn. CONCLUSION: Also young patients and patients with a normal IgG4 can have an AIP. Diagnosis is based on clinical, radiological and histological criteria. Type 2 AIP is treated with steroids without the need for maintenance therapy.

An integrated approach of network pharmacology, molecular docking, and experimental verification uncovers kaempferol as the effective modulator of HSD17B1 for treatment of endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological malignancies globally, and the development of innovative, effective drugs against EC remains a key issue. Phytoestrogen kaempferol exhibits anti-cancer effects, but the action mechanisms are still unclear. METHOD: MTT assays, colony-forming assays, flow cytometry, scratch healing, and transwell assays were used to evaluate the proliferation, apoptosis, cell cycle, migration, and invasion of both ER-subtype EC cells. Xenograft experiments were used to assess the effects of kaempferol inhibition on tumor growth. Next-generation RNA sequencing was used to compare the gene expression levels in vehicle-treated versus kaempferol-treated Ishikawa and HEC-1-A cells. A network pharmacology and molecular docking technique were applied to identify the anti-cancer mechanism of kaempferol, including the building of target-pathway network. GO analysis and KEGG pathway enrichment analysis were used to identify cancer-related targets. Finally, the study validated the mRNA and protein expression using real-time quantitative PCR, western blotting, and immunohistochemical analysis. RESULTS: Kaempferol was found to suppress the proliferation, promote apoptosis, and limit the tumor-forming, scratch healing, invasion, and migration capacities of EC cells. Kaempferol inhibited tumor growth and promotes apoptosis in a human endometrial cancer xenograft mouse model. No significant toxicity of kaempferol was found in human monocytes and normal cell lines at non-cytotoxic concentrations. No adverse effects or significant changes in body weight or organ coefficients were observed in 3-7 weeks' kaempferol-treated animals. The RNA sequencing, network pharmacology, and molecular docking approaches identified the overall survival-related differentially expressed gene HSD17B1. Interestingly, kaempferol upregulated HSD17B1 expression and sensitivity in ER-negative EC cells. Kaempferol differentially regulated PPARG expression in EC cells of different ER subtypes, independent of its effect on ESR1. HSD17B1 and HSD17B1-associated genes, such as ESR1, ESRRA, PPARG, AKT1, and AKR1C1\2\3, were involved in several estrogen metabolism pathways, such as steroid binding, 17-beta-hydroxysteroid dehydrogenase (NADP+) activity, steroid hormone biosynthesis, and regulation of hormone levels. The molecular basis of the effects of kaempferol treatment was evaluated. CONCLUSIONS: Kaempferol is a novel therapeutic candidate for EC via HSD17B1-related estrogen metabolism pathways. These results provide new insights into the efficiency of the medical translation of phytoestrogens.

Cyclosporine as an alternative immunosuppressant for steroid-resistant drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a multiorgan reaction associated with a broad range of commonly used medications. Most cases of DRESS syndrome resolve with cessation of the inciting agent; however, use of systemic immunosuppression, most commonly with oral corticosteroids, is also recommended in cases with visceral organ involvement.We report a case of steroid-resistant relapsing-remitting DRESS syndrome secondary to sulfasalazine. Our patient experienced significant flare of symptoms of DRESS syndrome with multiple attempts to wean prednisolone. Initiation of cyclosporine as an alternative immunosuppressive agent to long-term corticosteroids has resulted in a 6-month remission in both dermatological and hepatic sequelae of DRESS syndrome.

Metabolic perturbations in pregnant rats exposed to low-dose perfluorooctanesulfonic acid: An integrated multi-omics analysis.

Emerging epidemiological evidence has linked per- and polyfluoroalkyl substances (PFAS) exposure could be linked to the disturbance of gestational glucolipid metabolism, but the toxicological mechanism is unclear, especially when the exposure is at a low level. This study examined the glucolipid metabolic changes in pregnant rats treated with relatively low dose perfluorooctanesulfonic acid (PFOS) through oral gavage during pregnancy [gestational day (GD): 1-18]. We explored the molecular mechanisms underlying the metabolic perturbation. Oral glucose tolerance test (OGTT) and biochemical tests were performed to assess the glucose homeostasis and serum lipid profiles in pregnant Sprague-Dawley (SD) rats randomly assigned to starch, 0.03 and 0.3 mg/kg·bw·d groups. Transcriptome sequencing combined with non-targeted metabolomic assays were further performed to identify differentially altered genes and metabolites in the liver of maternal rats, and to determine their correlation with the maternal metabolic phenotypes. Results of transcriptome showed that differentially expressed genes at 0.03 and 0.3 mg/kg·bw·d PFOS exposure were related to several metabolic pathways, such as peroxisome proliferator-activated receptors (PPARs) signaling, ovarian steroid synthesis, arachidonic acid metabolism, insulin resistance, cholesterol metabolism, unsaturated fatty acid synthesis, bile acid secretion. The untargeted metabolomics identified 164 and 158 differential metabolites in 0.03 and 0.3 mg/kg·bw·d exposure groups, respectively under negative ion mode of Electrospray Ionization (ESI-), which could be enriched in metabolic pathways such as α-linolenic acid metabolism, glycolysis/gluconeogenesis, glycerolipid metabolism, glucagon signaling pathway, glycine, serine and threonine metabolism. Co-enrichment analysis indicated that PFOS exposure may disturb the metabolism pathways of glycerolipid, glycolysis/gluconeogenesis, linoleic acid, steroid biosynthesis, glycine, serine and threonine. The key involved genes included down-regulated Ppp1r3c and Abcd2, and up-regulated Ogdhland Ppp1r3g, and the key metabolites such as increased glycerol 3-phosphate and lactosylceramide were further identified. Both of them were significantly associated with maternal fasting blood glucose (FBG) level. Our findings may provide mechanistic clues for clarifying metabolic toxicity of PFOS in human, especially for susceptible population such as pregnant women.

AIDS-Related Kaposi Sarcoma Associated with Steroid-Unresponsive Periorbital Lymphedema that Responded to Chemotherapy.

BACKGROUND As an AIDS-defining illness, the neoplasm Kaposi sarcoma (KS) classically presents as cutaneous lesions that are often associated with periorbital edema. This association with KS is important because it frequently leads to the misuse of steroids in HIV-infected patients. This report presents 2 cases of AIDS-related Kaposi sarcoma (AIDS-KS) associated with severe steroid-unresponsive periorbital lymphedema that responded to chemotherapy. CASE REPORT Case 1: A 30-year-old African-American man with KS-related periorbital edema suffered progression after receiving multiple corticosteroids for a presumed hypersensitivity reaction. After multiple hospitalizations, the patient's KS had disseminated, and he eventually opted for hospice. Case 2: A 29-year-old White male with recurrent facial edema had been repeatedly treated with corticosteroids for impending anaphylaxis reactions. He had multiple admissions with similar presentations, and it was found that his KS had progressed. After receiving chemotherapy, his facial edema has not recurred. CONCLUSIONS The failure to recognize periorbital edema as tumor-associated edema has direct consequences for the management of AIDS-KS. In addition to a delay in administering chemotherapy, the mischaracterization of periorbital edema as a hypersensitivity/allergic reaction often prompts the use of corticosteroids, potentially exacerbating the underlying AIDS-KS. Despite the current evidence, clinicians continue to order steroids in advanced AIDS-KS patients presenting with periorbital edema. Although that management is started with the best intentions and done with concerns for airway compromise, this anchoring bias could lead to devastating consequences and a rather poor prognosis.