Exogenous Exposure Research Articles

Progress of aspirin in endometrial neoplasms

Obesity and exogenous hormone exposure are the well-established endometrial cancer risk factors, which are associated with chronic inflammation. Some evidences have shown that inflammation is potentially related to the increased risk of endometrial neoplasms. Aspirin is one of the most studied non-steroidal anti-inflammatory drugs, which can benefit the endometrial cancer patients with obesity. Although aspirin-related bleeding has to be considered prior to therapy, in most cases, the benefits of low-dose aspirin therapy substantially will exceed the risk. Aspirin and other non-steroidal anti-inflammatory drugs are expected to become effective new methods for the treatment of the tumors. This paper reviews the progress of aspirin in endometrial neoplasms. Key words: Endometrial neoplasms; Aspirin; Non-steroidal anti-inflammatory drugs

Pseudomonas aeruginosa responds to exogenous polyunsaturated fatty acids (PUFAs) by modifying phospholipid composition, membrane permeability, and phenotypes associated with virulence

BackgroundPseudomonas aeruginosa, a common opportunistic pathogen, is known to cause infections in a variety of compromised human tissues. An emerging mechanism for microbial survival is the incorporation of exogenous fatty acids to alter the cell’s membrane phospholipid profile. With these findings, we show that exogenous fatty acid exposure leads to changes in bacterial membrane phospholipid structure, membrane permeability, virulence phenotypes and consequent stress responses that may influence survival and persistence of Pseudomonas aeruginosa.ResultsThin-layer chromatography and ultra performance liquid chromatography / ESI-mass spectrometry indicated alteration of bacterial phospholipid profiles following growth in the presence of polyunsaturated fatty acids (PUFAs) (ranging in carbon length and unsaturation). The exogenously supplied fatty acids were incorporated into the major bacterial phospholipids phosphatidylethanolamine and phosphatidylglycerol. The incorporation of fatty acids increased membrane permeability as judged by both accumulation and exclusion of ethidium bromide. Individual fatty acids were identified as modifying resistance to the cyclic peptide antibiotics polymyxin B and colistin, but not the beta-lactam imipenem. Biofilm formation was increased by several PUFAs and significant fluctuations in swimming motility were observed.ConclusionsOur results emphasize the relevance and complexity of exogenous fatty acids in the membrane physiology and pathobiology of a medically important pathogen. P. aeruginosa exhibits versatility with regard to utilization of and response to exogenous fatty acids, perhaps revealing potential strategies for prevention and control of infection.

Behind the bleed: analysis of the formation of subchorionic hematomas (SCH) in single euploid embryo transfer cycles by protocol

Subchorionic hematomas (SCH) are a known risk factor for poor obstetric outcomes such as spontaneous abortion and preterm delivery. We sought to determine if there is a difference in the prevalence of SCH formation in pregnancies after frozen embryo transfer (FET) between natural and programmed preparation. Retrospective cohort study of single euploid FET cycles resulting in clinical pregnancy performed between 1/2016 and 12/2017 at our center. All single euploid FET cycles utilizing Next Generation Sequencing were reviewed. Exclusion criteria included FET cycles with ploidy determined by aCGH, or cycles in which untested, mosaic, or multiple embryos were transferred. All transfer cycles that resulted in clinical pregnancy (defined as presence of gestational sac) were included. These cycles were analyzed by protocol; natural versus programmed. Patients undergoing programmed cycles took oral estradiol daily followed by either 50-75mg intramuscular progesterone (P4) in oil or vaginal P4 suppository. Patients undergoing natural cycles (or supplemented with letrozole for 5 days) were monitored until a dominant follicle reached >18mm and ovulation was confirmed followed by the initiation of vaginal P4 suppository. SCH were documented at the time of luteal ultrasound as a measurable clot behind the gestational sac. Primary outcome was the rate of SCH noted on luteal ultrasound. Statistical analyses included students T-test, chi-squared and Fischer’s Exact test where appropriate (mean +/- SD, p < 0.05). A total of 719 cycles were included; 86 natural and 633 programmed (Table 1). SCH formation was diagnosed in 12.9% (n = 93) of clinical pregnancies. The formation of SCH was significantly lower in natural cycles compared to programmed cycles (RR 0.4, 95% CI 0.17 - 0.98, p < 0.04). Relevant cycle parameters were similar between groups (Table 1); cycle day 28 estrogen was higher in programmed cycles reflecting exogenous estrogen exposure. When programmed cycles utilizing vaginal P4 only were excluded (n=36), the formation of SCH is still statistically lower in natural compared to programmed cycles (5.8% v 14.2%, RR 0.4 (0.17-0.97, p <0.03). SCH occurred less frequently in single euploid embryo transfers using a “natural” endometrial preparation. Further analyses of long term outcomes could help provide insight into estimates of obstetrical risk.Tabled 1SCH Formation in Clinical Pregnancies by FET Protocol: Patient and Cycle CharacteristicsNatural Cycles (n=86)Programmed Cycles (n=633)p - valueDeveloped SCH5.8% (5/86)14.0% (88/633)p < 0.04 RR 0.4 (0.17-0.98)Average CD SCH diagnosed44.8±3.547.7±7.3p < 0.40Age37.45±4.336.81±4.4p < 0.20CD 28 hCG202.3±147.4189.3±176.5p < 0.52CD 28 E2284.9±234.5477.4±395.2p < 0.0001CD 28 P426.4±11.326.7±17.9p < 0.89Transfer Difficulty Marked “Easy” by Provider91.9% (79/86)95.6% (605/633)p < 0.13 RR 1.84 (0.83-4.1)Endometrial Thickness (mm)8.8±1.510.4±2.4p < 0.54 Open table in a new tab

Identification of a Hexenal Reductase That Modulates the Composition of Green Leaf Volatiles.

Green leaf volatiles (GLVs), including six-carbon (C6) aldehydes, alcohols, and esters, are formed when plant tissues are damaged. GLVs play roles in direct plant defense at wound sites, indirect plant defense via the attraction of herbivore predators, and plant-plant communication. GLV components provoke distinctive responses in their target recipients; therefore, the control of GLV composition is important for plants to appropriately manage stress responses. The reduction of C6-aldehydes into C6-alcohols is a key step in the control of GLV composition and also is important to avoid a toxic buildup of C6-aldehydes. However, the molecular mechanisms behind C6-aldehyde reduction remain poorly understood. In this study, we purified an Arabidopsis (Arabidopsis thaliana) NADPH-dependent cinnamaldehyde and hexenal reductase encoded by At4g37980, named here CINNAMALDEHYDE AND HEXENAL REDUCTASE (CHR). CHR T-DNA knockout mutant plants displayed a normal growth phenotype; however, we observed significant suppression of C6-alcohol production following partial mechanical wounding or herbivore infestation. Our data also showed that the parasitic wasp Cotesia vestalis was more attracted to GLVs emitted from herbivore-infested wild-type plants compared with GLVs emitted from chr plants, which corresponded with reduced C6-alcohol levels in the mutant. Moreover, chr plants were more susceptible to exogenous high-dose exposure to (Z)-3-hexenal, as indicated by their markedly lowered photosystem II activity. Our study shows that reductases play significant roles in changing GLV composition and, thus, are important in avoiding toxicity from volatile carbonyls and in the attraction of herbivore predators.

Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes.

ABSTRACTThe mammalian stages of the parasite Trypanosoma cruzi, the causative agent of Chagas disease, exhibit a wide host species range and extensive within-host tissue distribution. These features, coupled with the ability of the parasites to persist for the lifetime of the host, suggest an inherent capacity to tolerate changing environments. To examine this potential, we studied proliferation and cell cycle dynamics of intracellular T. cruzi amastigotes experiencing transient metabolic perturbation or drug pressure in the context of an infected mammalian host cell. Parasite growth plasticity was evident and characterized by rapid and reversible suppression of amastigote proliferation in response to exogenous nutrient restriction or exposure to metabolic inhibitors that target glucose metabolism or mitochondrial respiration. In most instances, reduced parasite proliferation was accompanied by the accumulation of amastigote populations in the G1 phase of the cell cycle, in a manner that was rapidly and fully reversible upon release from the metabolic block. Acute amastigote cell cycle changes at the G1 stage were similarly observed following exposure to sublethal concentrations of the first-line therapy drug, benznidazole, and yet, unlike the results seen with inhibitors of metabolism, recovery from exposure occurred at rates inversely proportional to the concentration of benznidazole. Our results show that T. cruzi amastigote growth plasticity is an important aspect of parasite adaptation to stress, including drug pressure, and is an important consideration for growth-based drug screening.

PO-250 Investigating BRF2-dependent RNA polymerase III transcription deregulation in cancer

IntroductionSmall subsets of RNA Polymerase (Pol) III genes, including the selenocysteine tRNA gene, rely on the presence of the BRF2 transcription factor. Previously, we identified a redox-sensitive switch (Cysteine 361) which, when oxidised, can downregulate Pol III transcription at all BRF2-dependent promoters (Gouge et al. 2015).In cancer cells, BRF2 is frequently amplified and/or overexpressed. We hypothesised that activation of BRF2 is required for maintaining high levels of selenocysteine tRNA, as well as selenoproteins, during prolonged oxidative stress. Selenoproteins are required for redox homeostasis and ROS detoxification and we were able to demonstrate that cancer cells with high levels of expression of BRF2 are more resistant to oxidative stress-induced apoptosis (Gouge et al. 2015).We therefore set out to comprehensively understand the role of BRF2 activation in oncogenesis and its link to oxidative stress response pathways, which are often deregulated in cancer cells.Material and methodsHAP1 cells (fully haploid human CML-based cell line) were generated that carried a C361A mutation, which is a redox-insensitive mutant of the molecular pin. These were tested for their proliferative capacity and ability to withstand exogenous oxidative stress. Full length human BRF2 was overexpressed using lentiviral vectors in malignant and non-malignant cell lines; proliferative capacity and BRF2-dependent transcripts were monitored.Results and discussionsWe found that C361A HAP1 cells were more tolerant to exposure to exogenous oxidative stress using tBHP. However, the proliferative capacity of HAP1 3D spheroids without exogenous stress was not significantly altered by the presence of this mutation. We are investigating the effects of exogenous stress exposure in these cells to identify which BRF2-dependent transcripts are altered following exposure to tBHP.Overexpression of BRF2 in non-malignant cells is not sufficient to induce increased proliferative potential. Experiments to elucidate the effects of overexpression in malignant cell lines are still ongoing.ConclusionWe are continuing to investigate the effects of BRF2 amplification and overexpression on the transcriptional programme of cancer cells under oxidative stress conditions. Since selenocysteine-containing proteins have been implicated in cellular response to ferroptosis, we would like to investigate whether this is mediated by BRF2 overexpression and whether this can be exploited in a therapeutic setting.

The Type 3 Deiodinase: Epigenetic Control of Brain Thyroid Hormone Action and Neurological Function.

Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and receptors is critical to ensure specific levels of TH action in neural cells. The type 3 iodothyronine deiodinase (DIO3) inactivates THs and is highly present in the developing and adult brain, where it limits their availability and action. DIO3 deficiency in mice results in a host of neurodevelopmental and behavioral abnormalities, demonstrating the deleterious effects of TH excess, and revealing the critical role of DIO3 in the regulation of TH action in the brain. The fact the Dio3 is an imprinted gene and that its allelic expression pattern varies across brain regions and during development introduces an additional level of control to deliver specific levels of hormone action in the central nervous system (CNS). The sensitive epigenetic nature of the mechanisms controlling the genomic imprinting of Dio3 renders brain TH action particularly susceptible to disruption due to exogenous treatments and environmental exposures, with potential implications for the etiology of human neurodevelopmental disorders.

Environmental Sources of Bacteria Differentially Influence Host-Associated Microbial Dynamics.

Host-associated microbial dynamics are influenced by dietary and immune factors, but how exogenous microbial exposure shapes host-microbe dynamics remains poorly characterized. To investigate this phenomenon, we characterized the skin, rectum, and respiratory tract-associated microbiota in four aquarium-housed dolphins daily over a period of 6weeks, including administration of a probiotic during weeks 4 to 6. The environmental bacterial sources were also characterized, including the animals' human handlers, the aquarium air and water, and the dolphins' food supply. Continuous microbial exposure occurred between all sites, yet each environment maintained a characteristic microbiota, suggesting that the majority of exposure events do not result in colonization. Small changes in water physicochemistry had a significant but weak correlation with change in dolphin-associated bacterial richness but had no influence on phylogenetic diversity. Food and air microbiota were the richest and had the largest conditional influence on other microbiota in the absence of probiotics, but during probiotic administration, food alone had the largest influence on the stability of the dolphin microbiota. Our results suggest that respiratory tract and gastrointestinal epithelium interactions with air- and food-associated microbes had the biggest influence on host-microbiota dynamics, while other interactions, such as skin transmission, played only a minor role. Finally, direct oral stimulation with a foreign exogenous microbial source can have a profound effect on microbial stability. IMPORTANCE These results provide valuable insights into the ecological influence of exogenous microbial exposure, as well as laying the foundation for improving aquarium management practices. By comparing data for dolphins from aquaria that use natural versus artificial seawater, we demonstrate the potential influence of aquarium water disinfection procedures on dolphin microbial dynamics.

High C-X-C motif chemokine5 expression is associated with malignant phenotypes of prostate cancer cells via autocrine and paracrine pathways.

The present study aimed to examine the effects and mechanisms of exogenous C-X-C motif chemokine5(CXCL5) and lentiviral CXCL5 overexpression on the regulation of malignant behaviors of prostate cancer cells invitro and in a nude mouse xenograft model. The expression levels of CXCL5 and a number of tumor-related genes were assessed by using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), western blotting, ELISA, or immunohistochemistry in normal and cancerous prostate cells and tissues. Cell proliferation, colony formation, and Transwell assays were performed to determine the effects of exogenous, autocrine, and paracrine CXCL5 on prostate cancer cell proliferative and migratory capacity. The results indicated that CXCL5 expression was upregulated in PC‑3 and DU145 prostate cancer cells, in WPMY‑1 normal prostate stromal cells, and in RWPE‑1 prostate epithelial cells, as well as in prostate cancer tissue specimens. Exogenous CXCL5 exposure resulted in increase in prostate cancer cell proliferation, colony formation, and migration. In cells transfected with a CXCL5 overexpression vector, in cells cultured in conditioned medium from CXCL5-overexpressing WPMY cells, and in cells co-cultured with CXCL5‑OE WPMY cells prostate cancer cell malignant phenotypes were induced in an autocrine/paracrine fashion invitro; similar results were observed in nude mouse xenografts. CXCL5 overexpression also regulated expression of tumor-related genes, including BAX, N-Myc downstream-regulated gene3, extracellular signal-regulated kinase1/2, C-X-C chemokine receptor type 2, interleukin18, Bcl‑2, and caspase‑3. These data demonstrated that CXCL5 expression was upregulated in prostate cancer tissues and that exogenous CXCL5 protein exposure or CXCL5 overexpression promoted malignant phenotypes of prostate cancer cells invitro and invivo.

Ethylene modulates root cortical senescence in barley.

Root cortical senescence (RCS) is a poorly understood phenomenon with implications for adaptation to edaphic stress. It was hypothesized that RCS in barley (Hordeum vulgare L.) is (1) accelerated by exogenous ethylene exposure; (2) accompanied by differential expression of ethylene synthesis and signalling genes; and (3) associated with differential expression of programmed cell death (PCD) genes. Gene expression of root segments from four barley genotypes with and without RCS was evaluated using quantitative real-time PCR (qRT-PCR). The progression of RCS was manipulated with root zone ethylene and ethylene inhibitor applications. The results demonstrate that ethylene modulates RCS. Four genes related to ethylene synthesis and signalling were upregulated during RCS in optimal, low nitrogen and low phosphorus nutrient regimes. RCS was accelerated by root zone ethylene treatment, and this effect was reversed by an ethylene action inhibitor. Roots treated with exogenous ethylene had 35 and 46 % more cortical senescence compared with the control aeration treatment in seminal and nodal roots, respectively. RCS was correlated with expression of two genes related to programmed cell death (PCD). The development of RCS is similar to root cortical aerenchyma formation with respect to ethylene modulation of the PCD process.

Efficacy and safety of antenatal steroids.

Antenatal steroids (ANS) are among the most important and widely utilized interventions to improve outcomes for preterm infants. A significant body of evidence demonstrates improved outcomes in preterm infants (24-34 wk) delivered between 1 and 7 days after the administration of a single course of ANS. Moreover, ANS have the advantage of being widely available, low cost, and easily administered via maternal intramuscular injection. The use of ANS to mature the fetal lung is, however, not without contention. Their use in pregnancy is not FDA approved, and treatment doses and regimens remain largely unoptimized. Their mode of use varies considerably between countries, and there are lingering concerns regarding the safety of exposing the fetus to high doses of exogenous steroids. A significant proportion of women deliver outside the 1- to 7-day therapeutic window after ANS treatment, and this delay may be associated with an increased risk of adverse outcomes for both mother and baby. Today, animal-based studies are one means by which key questions of dosing and safety relating to ANS may be resolved, allowing for further refinement(s) of this important therapy. Complementary approaches using nonhuman primates, sheep, and rodents have provided invaluable advances to our understanding of how exogenous steroid exposure impacts fetal development. Focusing on these three major model groups, this review highlights the role of three key animal models (sheep, nonhuman primates, rodents) in the development of antenatal steroid therapy, and provides an up-to-date synthesis of current efforts to refine this therapy in an era of personalised medicine.

CD200fc enhances anti-tumoral immune response and inhibits visceral metastasis of breast carcinoma

CD200 is a widely expressed cell surface glycoprotein that inhibits excessive inflammation in autoimmunity, transplantation, and viral infections. We previously observed that visceral metastasis of highly aggressive and inflammatory 4THM breast carcinoma cells was markedly decreased in CD200 transgenic mice. The goal of this study was to determine whether exogenous exposure to CD200fc mimics the effects of endogenously over expressed CD200. Female BALB/c mice were injected with CD200fc two times a week for five times. Injection was started two days after orthotopic injection of 4THM cells. Tumor infiltrating Gr1+Cd11b+ cells were decreased while CD8+ cells were increased in CD200fc-treated animals. CD200fc injection significantly decreased lung and liver metastasis and the growth of primary tumors. CD200fc injection enhanced the tumor-induced IFN-g response while suppressing the IL-10 response. We observed excessive basal IL-6 secretion in MLC which was significantly decreased in CD200fc treated mice 12 days after injection of 4TM cells. These results are in accord with previous data from CD200 transgenic mice, and demonstrate for the first time that CD200 analogues might have therapeutic potential in the treatment of aggressive breast carcinoma which induces excessive systemic inflammation.

MRI background parenchymal enhancement, breast density and serum hormones in postmenopausal women.

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast‐enhanced magnetic resonance imaging (MRI). MRI‐density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of our study was to examine the relationship between BPE and MRI‐density and serum hormone concentrations in postmenopausal women. This was a study of cancer‐free postmenopausal women undergoing contrast‐enhanced breast MRI (N = 118). At the time of MRI all women completed a self‐administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI‐density. Compared to women with “minimal” BPE, those who had “marked” BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, p trend across all categories = 0.001; 150% increase, p trend = 0.001; and 158% increase, p trend = 0.001, respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI‐density and serum E1, E2 and bioavailable E2 were observed. Serum estrogen concentrations were significantly positively associated with BPE. Our study provides further evidence of the hormone‐sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast.

Genome-wide dissection and expression profiling of unique glyoxalase III genes in soybean reveal the differential pattern of transcriptional regulation

Reactive carbonyl species, such as methylglyoxal and glyoxal are very toxic in nature and can inactivate various cellular macromolecules such as DNA, RNA, and protein by forming advanced glycation end products. Conventional glyoxalase pathway with two enzymes- glyoxalase I and glyoxalase II, detoxify MG into D-lactate with the help of reduced glutathione. However, DJ-1/PfpI domain(s) containing DJ-1/ Hsp31 proteins do the same in a single step, and thus termed as “glyoxalase III”. A comprehensive genome-wide analysis of soybean identified eleven putative glyoxalase III proteins with DJ-1/PfpI domain encoded by seven genes. Most of these proteins are predicted to be mitochondria and chloroplast localized. In spite of similar function, a differential evolution pattern was observed between Hsp31 and DJ-1 proteins. Expression of GmDJ-1A, GmDJ-1B, and GmDJ-1D2 transcripts was found to be constitutive in different tissues and developmental stages. Transcript profiling revealed the strong substrate-specific upregulation of GmDJ-1 genes in response to exogenous methylglyoxal exposure. Out of seven genes, GmDJ-1D1 and GmDJ-1D2 showed maximum upregulation against salinity, dehydration, and oxidative stresses. Moreover, GmDJ-1D2 showed functional glyoxalase III enzyme activity by utilizing MG as a substrate. Overall, this study identifies some novel tissue-specific and abiotic stress-responsive GmDJ-1 genes that could be investigated further.

Carboxyhemoglobin: a primer for clinicians

One of carbon monoxide's several mechanisms of toxicity is binding with circulating hemoglobin to form carboxyhemoglobin, resulting in a functional anemia. While patients with carbon monoxide poisoning are often said to be "cherry-red," such discoloration is rarely seen. Carboxyhemoglobin levels cannot be measured with conventional pulse oximetry, can be approximated with pulse CO-oximetry, and are most accurately measured with a laboratory CO-oximeter. Carboxyhemoglobin levels are quite stable and can be accurately measured on a transported blood sample. For clinical purposes, arterial and venous carboxyhemoglobin levels can be considered to be equivalent. Carboxyhemoglobin levels are typically lower than 2% in non-smokers and lower than 5% in smokers. A level over 9% is almost always due to exogenous carbon monoxide exposure, even among smokers. Conversely, a low level does not exclude significant exposure under certain circumstances. As carboxyhemoglobin levels of poisoned patients do not correlate with symptoms or outcome, their greatest utility is a marker of exposure.

A Longitudinal Study of Estrogen-Responsive Tissues and Hormone Concentrations in Infants Fed Soy Formula.

Chemicals with hormonelike activity, such as estrogenic isoflavones, may perturb human development. Infants exclusively fed soy-based formula are highly exposed to isoflavones, but their physiologic responses remain uncharacterized. Estrogen-responsive postnatal development was compared in infants exclusively fed soy formula, cow-milk formula, and breast milk. We enrolled 410 infants born in Philadelphia-area hospitals between 2010 and 2014; 283 were exclusively fed soy formula (n = 102), cow-milk formula (n = 111), or breast milk (n = 70) throughout the study (birth to 28 or 36 weeks for boys and girls, respectively). We repeatedly measured maturation index (MI) in vaginal and urethral epithelial cells using standard cytological methods, uterine volume and breast-bud diameter using ultrasound, and serum estradiol and follicle-stimulating hormone levels. We estimated MI, organ-growth, and hormone trajectories by diet using mixed-effects regression splines. Maternal demographics did not differ between cow-milk-fed and soy-fed infants but did differ between formula-fed and breastfed infants. Vaginal-cell MI trended higher (P = 0.01) and uterine volume decreased more slowly (P = 0.01) in soy-fed girls compared with cow-milk-fed girls; however, their trajectories of breast-bud diameter and hormone concentrations did not differ. We observed no significant differences between boys fed cow-milk vs soy formula; estradiol was not detectable. Breastfed infants differed from soy-formula-fed infants in vaginal-cell MI, uterine volume, and girls' estradiol and boys' breast-bud diameter trajectories. Relative to girls fed cow-milk formula, those fed soy formula demonstrated tissue- and organ-level developmental trajectories consistent with response to exogenous estrogen exposure. Studies are needed to further evaluate the effects of soy on child development.

Environmental Exposures and Neuropsychiatric Disorders: What Role Does the Gut-Immune-Brain Axis Play?

Evidence is growing that environmental exposures-including xenobiotics as well as microbes-play a role in the pathogenesis of many neuropsychiatric disorders. Underlying mechanisms are likely to be complex, involving the developmentally sensitive interplay of genetic/epigenetic, detoxification, and immune factors. Here, we review evidence supporting a role for environmental factors and disrupted gut-immune-brain axis function in some neuropsychiatric conditions. Studies suggesting the involvement of an altered microbiome in triggering CNS-directed autoimmunity and neuropsychiatric disturbances are presented as an intriguing example of the varied mechanisms by which environmentally induced gut-immune-brain axis dysfunction may contribute to adverse brain outcomes. The gut-immune-brain axis is a burgeoning frontier for investigation of neuropsychiatric illness. Future translational research to define individual responses to exogenous exposures in terms of microbiome-dependent skew of the metabolome, immunity, and brain function may serve as a lens for illumination of pathways involved in the development of CNS disease and fuel discovery of novel interventions.

Exogenous reproductive hormone use in breast cancer survivors and previvors.

Considerable controversy exists regarding the safety of elective exogenous hormonal exposure among breast cancer survivors and women at high risk of developing the disease (referred to herein as 'previvors'). We performed a qualitative analysis focused on four areas of potential exogenous exposure to hormones among previvors and survivors: hormonal contraception; systemic hormone-replacement therapy (HRT); localized HRT; and hormonal manipulation for fertility preservation or enhancement. Herein, we discuss the available data and present clinical recommendations regarding the safety of hormonal exposure for both previvors and survivors. We found these data to be hampered by small cohort sizes, heterogeneous patient populations, and limited study designs, highlighting a great need to conduct further research with the aim of enabling better-informed patient management.

Delayed Allergic Cutaneous Hypersensitivity to Icodextrin

Rashes pose a unique challenge to general internists. Here we present a case of a 51-year-old female with end-stage renal disease (ESRD) on peritoneal dialysis who presented to a General Internal Medicine clinic with a vesiculobullous rash on palms and soles 6 months after using icodextrin dialysate, a widely used osmotic agent in peritoneal dialysis. The investigations were positive for an elevated eosinophil count, elevated IgE level and a skin biopsy consistent with an allergic reaction. Her symptoms and labs normalized after stopping icodextrin. There are some reports of allergic reactions to icodextrin which usually occur within a month of initiation of the agent and are self-limiting. Here we hope to report a case of a reaction that occurred 6 months after using icodextrin.&#x0D; Resume&#x0D; Les éruptions cutanées posent un défi particulier aux internistes généraux. Nous rapportons ici le cas d’une femme de 51 ans atteinte d’insuffisance rénale terminale (IRT), sous dialyse péritonéale, qui se présente à une clinique de médecine interne générale avec une éruption cutanée vésiculo-bulleuse sur les paumes et la plante des pieds. Depuis six mois, la patiente utilise un dialysat d’icodextrine, un agent osmotique largement utilisé en dialyse péritonéale. Les analyses ont révélé une numération élevée des éosinophiles, un taux élevé d’IgE et une biopsie cutanée a indiqué la présence d’une réaction allergique. Les symptômes et les résultats d’analyses se sont normalisés après l’arrêt de l’icodextrine. Des réactions d’allergie à l’icodextrine ont déjà été rapportées, mais celles-ci surgissent habituellement dans le mois suivant le début de l’usage de l’agent et se résorbent d’elles-mêmes. Nous désirons signaler un cas de réaction survenue six mois après le début de l’utilisation de l’icodextrine.&#x0D; &#x0D; &#x0D;

Premature Adrenarche.

Adrenarche is when a child's adrenal cortex starts to secrete adrenal androgen precursors. Dehydroepiandrosterone (DHEA) is the most abundant product of the adrenal cortex, and is a weak androgen agonist thought to be responsible for the clinical signs of pubarche by conversion to more potent androgens, testosterone, and dihydrotestosterone. DHEA's extra-adrenal sulfation product, dehydroepiandrosterone sulfate, is a stable marker for adrenal androgenic activity. Pubarche is the physical manifestation of androgenic hormone production, and includes the development of pubic and axillary hair, adult body odor, and acne. This stage is usually considered premature if it commences before age 8 years in girls or age 9 years in boys. Premature adrenarche is a diagnosis of exclusion, as true centrally mediated precocious puberty, congenital adrenal hyperplasia, exogenous androgen exposure, and androgen-secreting tumors must be ruled out. Premature adrenarche may be associated with a history of an infant who was small for gestational age at birth who then gained weight rapidly thereafter or became obese. In some instances, premature adrenarche may predict functional ovarian hyperandrogenism in adolescence. Management of premature adrenarche is largely aimed at observation, lifestyle adjustments for weight concerns, and monitoring for future possible persistent androgen excess and insulin resistance. [Pediatr Ann. 2018;47(1):e7-e11.].