GRN, NOTCH3, FN1, and PINK1 expression in eutopic endometrium - potential biomarkers in the detection of endometriosis - a pilot study.

PURPOSE: Endometriosis (EM) is a common gynecological disease affecting 10-15% of women of reproductive age. However, molecular mechanisms and pathogenesis are still not completely understood. Furthermore, due to the absence of a reliable clinical biomarker, the only viable method for the often-delayed definitive diagnosis is laparoscopic surgery. Our objective was to analyze molecular differences of selected endometrial proteins and genes of women suffering from different stages of EM compared with healthy women to evaluate potential clinical biomarkers. METHODS: We analyzed eutopic endometrial tissue samples from women undergoing a laparoscopic surgery (n = 58). mRNA gene expression of progranulin (GRN), neurogenic locus notch homolog protein (NOTCH3), fibronectin (FN1), and PTEN-induced kinase 1 (PINK1) was analyzed using qRT-PCR. Protein expression was determined using ELISA and immunohistochemistry. RESULTS: Significant differences in gene expression between the different stages of the disease were noted for GRN, NOTCH3, FN1, and PINK1 (p < 0.05). The endometrium of women with minimal EM (ASRM I) showed the highest mRNA expression. Protein levels of GRN and FN1 on the other hand were significantly decreased in the endometrium of women with EM compared with those of healthy controls. Furthermore, for GRN and FN1, we could detect a correlation of protein expression with the severity of the disease. CONCLUSION: Our findings suggest a potential use of GRN and FN1 as clinical biomarkers to detect endometriosis. In addition, GRN, NOTCH3, FN1, and PINK1 could potentially be useful to differentiate between the underlying stages of the disease. However, a validation with a larger study population is needed.

Endometrial expression of receptivity markers subject to ovulation induction agents.

PURPOSE: Implantation rates differ according to ovulation induction agents in ART. This study investigates the different local endometrial effects of LH- versus hCG-induced ovulation. METHODS: Endometrial stromal cells from healthy patients were cultured with hCG or LH in different concentrations, supplemented with 250 ng/mL hCG and progesterone after 2 and 5 days. In addition after decidualization induction, cells were treated with hCG (50 or 250 ng/mL) or LH (10 or 50 ng/mL) for 3 days. Receptivity markers expression was evaluated by real-time quantitative PCR on day 3 and 6. RESULTS: On day 3, non-decidualized cells treated with LH showed an increased expression of IGFBP1, IL-8 and CXCL12 compared to hCG. The expression pattern changed on day 6, where cells treated with hCG showed higher expression of implantation markers compared to LH-treated cells. Furthermore, on day 3, decidualized cells treated with hCG250 showed an increased IL8 and CXCL12 expression compared to LH10. CONCLUSIONS: LH seems to modulate the local endometrial expression of receptivity markers earlier compared to hCG; however, the effect is not sustained over time in cells without prior decidualization. Though, in decidualized cells, pattern changed and an earlier positive effect of hCG was shown on IL-8 and CXCL12.

Comparison of semiologies between tilt-induced psychogenic nonsyncopal collapse and psychogenic nonepileptic seizures.

We sought to characterize the clinical features of tilt-induced psychogenic nonsyncopal collapse (PNSC) from a cohort of young patients and to compare the semiologies between PNSC and EEG-confirmed psychogenic nonepileptic seizures (PNES). A PNSC diagnosis was made if a clinical event occurred during tilt-table testing that the patient regarded as fainting, but neither hypotension nor EEG changes were present. A diagnosis of PNSC was made in 17.6% of all patients referred during the 15-month study period. Cohorts with psychogenic nonsyncopal collapse (n=40) and PNES (n=40) did not differ in age (15.5±2.2 versus 14.6±2.7, p=.11) or female gender (80% versus 72.5%, p=.43). Psychogenic nonsyncopal collapse events were briefer than PNES events (median: 45 versus 201.5s, p<.001). Negative motor signs (head drop, body limpness) predominated in PNSC (85% versus 20%, p<.001), while the positive motor signs of convulsion occurred more often with PNES (90% versus 30%, p<.001). Behavioral arrest (25% versus 32.5%, p=.46) and eye closure (85% versus 72.5%, p=.21) did not differ between PNSC and PNES. Patients with PNSC were more likely to be tearful before (30% versus 7.5%, p=.02) and after (62.5% versus 7.5%, p<.001) an event. In conclusion, although overlap exists, the features of PNSC generally appear similar to neurally mediated syncope, while the features of PNES generally appear similar to epileptic seizures. Psychogenic nonsyncopal collapse and PNES likely represent similar disorders that differ primarily by clinical semiologies and referral patterns.

The response to ACTH is determined early in the treatment of infantile spasms.

Although adrenocorticotropic hormone is the most commonly used treatment for infantile spasms in the United States, the optimal regimen for this indication is not known. The purpose of this study was to elucidate the optimal adrenocorticotropic hormone treatment duration. We conducted a retrospective chart review of response to adrenocorticotropic hormone among all patients with infantile spasms managed at our institution from January 2009 to September 2013. Treatment response was defined as clinical remission for greater than or equal to 28 days starting at any point within the adrenocorticotropic hormone course and remission of hypsarrhythmia (or definite EEG improvement if hypsarrhythmia was absent at baseline). For responders, the diagnostic and post-treatment EEG tracings were reviewed. Electroclinical remission was achieved in 21 of 39 patients (54%) receiving adrenocorticotropic hormone, including 11/25 (44%) receiving a long course (typically 12 weeks) and 10/14 (71%) receiving a short course (typically four weeks). The mean time to clinical remission was 5.8 days (median: 5 days; range: 1-20 days). Only one patient responded beyond two weeks of treatment. This study provides Class IV evidence that among patients with infantile spasms, the response to adrenocorticotropic hormone is most often determined early in the treatment course. Given the importance of rapid remission, clinicians should consider adding or changing treatment if infantile spasms do not resolve within two weeks of adrenocorticotropic hormone initiation. Further study is needed to determine the optimal adrenocorticotropic hormone regimen for infantile spasms.

Iron pyrite thin films synthesized from an Fe(acac)3 ink.

Iron pyrite (cubic FeS2) is a promising candidate absorber material for earth-abundant thin-film solar cells. Here, we report on phase-pure, large-grain, and uniform polycrystalline pyrite films that are fabricated by solution-phase deposition of an iron(III) acetylacetonate molecular ink followed by sequential annealing in air, H2S, and sulfur gas at temperatures up to 550 °C. Phase and elemental compositions of the films are characterized by conventional and synchrotron X-ray diffraction, Raman spectroscopy, Auger electron spectroscopy, secondary ion mass spectrometry, and X-ray photoelectron spectroscopy (XPS). These solution-deposited films have more oxygen and alkalis, less carbon and hydrogen, and smaller optical band gaps (E(g) = 0.87 ± 0.05 eV) than similar films made by chemical vapor deposition. XPS is used to assess the chemical composition of the film surface before and after exposure to air and immersion in water to remove surface contaminants. Optical measurements of films rich in marcasite (orthorhombic FeS2) show that marcasite has a band gap at least as large as pyrite and that the two polymorphs share similar absorptivity spectra, in excellent agreement with density functional theory models. Regardless of the marcasite and elemental impurity contents, all films show p-type, weakly activated transport with curved Arrhenius plots, a room-temperature resistivity of ~1 Ω cm, and a hole mobility that is too small to measure by Hall effect. This universal electrical behavior strongly suggests that a common defect or a hole-rich surface layer governs the electrical properties of most FeS2 thin films.

Pediatric Resident Confidence in Assessing Neurological Cases: A Nationwide Survey.

BACKGROUND: A relative shortage of pediatric neurologists in proportion to estimated neurological disorders often results in general pediatricians evaluating and treating children with complex neurological conditions. Dedicated rotations in pediatric neurology are not mandated during medical school or pediatric residency. We evaluated the perceptions of a large cohort of pediatric residents and program directors (PDs) regarding child neurology training. METHODS: Using an online tool, surveys were sent to pediatric residents and pediatric and pediatric neurology PDs. RESULTS: Response rates were 41% from pediatric residency programs, yielding 538 resident responses; 31% from pediatric PDs; and 62% from pediatric neurology PDs. Only 27% of the surveyed residents reported completing a neurology rotation during residency, 89% of whom expressed a subjective improvement in confidence with neurological assessments. Factors affecting comfort with eliciting a neurological history included exposure to a neurology rotation during residency, year of training, duration of neurology rotation in medical school, and inpatient exposure to neurological patients, whereas those associated with examination additionally included program size and postresidency plans. Overall, 80% of surveyed residents, 78% of pediatric PDs, and 96% of pediatric neurology PDs acknowledged the potential value of a mandatory pediatric neurology rotation during residency. CONCLUSION: We suggest that a mandatory pediatric neurology rotation will boost the confidence of current and future pediatric trainees in assessing common neurological conditions of childhood.

Patient and healthcare team recommended medication adherence strategies for hydroxychloroquine: results of a qualitative study informing intervention development.

OBJECTIVE: Patients identified as black and from disadvantaged backgrounds have a twofold higher hydroxychloroquine (HCQ) non-adherence, which contributes to worse lupus outcomes and disparities. Yet, most adherence interventions lack tailored strategies for racially and socioeconomically diverse patients who face unique challenges with HCQ. We aimed to examine a broadly representative group of patients with SLE and physician perspectives on HCQ adherence and adherence strategies to redesign an adherence intervention. METHODS: We conducted four virtual focus groups (90 min each) with 11 racially and socioeconomically diverse patients with SLE recruited from two health systems. Additionally, we hosted two focus group meetings with nine healthcare advisors. In focus groups, patients: (1) shared their perspectives on using HCQ; (2) shared concerns leading to non-adherence; (3) discussed strategies to overcome concerns; (4) prioritised strategies from the most to least valuable to inform an adherence intervention. In two separate focus groups, healthcare advisors gave feedback to optimise an adherence intervention. Using content analysis, we analysed transcripts to redesign our adherence intervention. RESULTS: Worry about side effects was the most common barrier phrase mentioned by patients. Key themes among patients' concerns about HCQ included: information gaps, logistical barriers, misbeliefs and medication burden. Finally, patients suggested adherence strategies and ranked those most valuable including co-pay assistance, personal reminders, etc. Patient and healthcare advisors informed designing a laminate version of an adherence intervention to link each barrier category with four to six patient-recommended adherence strategies. CONCLUSION: We developed a patient stakeholder-informed and healthcare stakeholder-informed tailored intervention that will target non-adherence at the individual patient level.

Changes in protein expression due to metformin treatment and hyperinsulinemia in a human endometrial cancer cell line.

The incidence of endometrial cancer (EC) has increased over the past years and mainly affects women above the age of 45 years. Metabolic diseases such as obesity and type II diabetes mellitus as well as associated conditions like polycystic ovary syndrome (PCOS), insulin resistance and hyperinsulinemia lead to elevated levels of circulating estrogens. Increased estrogen concentrations, in turn, further trigger the proliferation of endometrial cells and thus promote EC development and progression, especially in the absence of progesterone as seen in postmenopausal women. Elevated blood glucose levels in diabetic patients further contribute to the risk of EC development. Metformin is an insulin-sensitizing biguanide drug, commonly used in the treatment of type II diabetes mellitus, especially in obese patients. Besides its effects on glucose metabolism, metformin displayed anti-cancer effects in various cancer types, including EC. Direct anti-cancer effects of metformin target signaling pathways that are involved in cellular growth and proliferation, e.g. the AKT/PKB/mTOR pathway. Further proteins and pathways have been suggested as potential targets, but the underlying mechanism of action of metformin's anti-cancer activity is still not completely understood. In the present study, the effects of metformin on protein expression were investigated in the human EC cell line HEC-1A using an affinity proteomic approach. Cells were treated with 0.5 mmol/L metformin over a period of 7 days and changes in the expression pattern of 1,300 different proteins were compared to the expression in untreated control cells as well as insulin-treated cells. Insulin treatment (100 ng/mL) was incorporated into the study in order to implement a model for insulin resistance and associated hyperinsulinemia, conditions that are often observed in obese and diabetic patients. Furthermore, the culture medium was supplemented with 10 nmol/L ß-estradiol (E2) during treatments to mimic increased estrogen levels, a common risk factor for EC development. Based on the most prominent and significant changes in expression, a set of 80 proteins was selected and subjected to a more detailed analysis. The data revealed that metformin and insulin targeted similar pathways in the present study and mostly acted on proteins related to proliferation, migration and tumor immune response. These pathways may be affected in a tumor-promoting as well as a tumor-suppressing way by either metformin treatment or insulin supplementation. The consequences for the cells resulting from the detected expression changes were discussed in detail for several proteins. The presented data helps identify potential targets affected by metformin treatment in EC and allows for a better understanding of the mechanism of action of the biguanide drug's anti-cancer activity. However, further investigations are necessary to confirm the observations and conclusions drawn from the presented data after metformin administration, especially for proteins that were regulated in a favorable way, i.e. AKT3, CCND2, CD63, CD81, GFAP, IL5, IL17A, IRF4, PI3, and VTCN1. Further proteins might be of interest, where metformin counteracted unfavorable effects that have been induced by hyperinsulinemia.

Use of Continuous EEG Monitoring in Children Presenting With Encephalopathy Following Convulsive Status Epilepticus.

PURPOSE: The Critical Care Continuous EEG Task Force of the American Clinical Neurophysiology Society recommends continuous EEG (cEEG) monitoring in patients with persistent encephalopathy following convulsive status epilepticus. This recommendation is based on data, which correlates prolonged nonconvulsive seizures and nonconvulsive status epilepticus with worse neurologic outcomes. Compliance with these recommendations may be limited by barriers such as inadequate resource and staff availability. We surveyed members of the Child Neurology Society to determine the barriers that prevent them from appropriately using cEEG, and how they have successfully overcome such obstacles. METHODS: A survey was electronically distributed to Child Neurology Society members, which assessed demographics, current clinical practices, and cEEG utilization in critically ill children, with an emphasis on resource availability and strategies to overcome resource limitations. RESULTS: One hundred forty-six physicians from Child Neurology Society completed the survey. Fifty-three (39.8%) respondents use cEEG to detect nonconvulsive seizures/nonconvulsive status epilepticus in most (>90%) of their pediatric patients who present with persistent encephalopathy following convulsive status epilepticus. Forty-four respondents (34.4%) perceive barriers to performing cEEG monitoring, and 107 (84.9%) of the respondents are implementing changes to overcome barriers. The two most commonly reported barriers included inadequate availability of technicians and EEG machines. The most common changes included hiring new EEG technologists and purchasing new machines. Other barriers included identification of appropriate patients and availability of remote EEG monitoring capabilities. CONCLUSIONS: Barriers, such as resource limitations, prevent compliance with the American Clinical Neurophysiology Society cEEG monitoring recommendations. Recognizing common limitations and learning from each other about successful strategies to overcome these barriers may improve care.

High Amplitude Background Slow Waves in Normal Children Aged 3 to 18 Months: Implications for the Consideration of Hypsarhythmia.

PURPOSE: To assess for the presence of high amplitude EEG background slow waves in normal young children. METHODS: One hundred children with normal development ages 3 to 18 months had normal EEGs for spells and did not have seizures or epilepsy. Three electroencephalographers retrospectively reviewed 5 minutes of stable stage II sleep to measure background slow waves for peak-to-peak amplitudes. A standard 10-20 longitudinal bipolar montage was used. Interrater agreement was assessed by intraclass correlation coefficient. RESULTS: Interrater agreement between reviewers in the assessment of recurrent slow wave amplitudes was excellent (intraclass correlation coefficient = 0.97). Slow wave amplitudes were the highest in the posterior head regions for all patients. We found recurring slow waves of <200 µV, 200 to 299 µV, 300 to 399 µV, 400 to 499 µV, and >500 µV in 17%, 49%, 30%, 3% and 1%, respectively. CONCLUSIONS: Although hypsarhythmia typically includes high amplitude background slow waves of >200 or >300 µV, we found that 83% and 34% of normal children had recurring posterior background slow waves of >200 or >300 µV, respectively. These data may be useful in the EEG background assessment of young children, for determining the presence or absence of hypsarhythmia, and determining treatment response in children with epileptic spasms.

Subtle and Severe: Microaggressions Among Racially Diverse Sexual Minorities.

In recent years, understanding prejudice and discrimination toward minorities has developed to include the investigation of microaggressions. Microaggressions are brief and commonplace verbal, behavioral, or environmental indignities. They are intentional or unintentional and communicate hostile, derogatory, or negative slights toward racial and sexual minorities. The purpose of this phenomenological study is to chronicle the prevalence and type of microaggressions experienced among a sample of 18 highly educated and racially diverse sexual minorities, 24-65 years of age. The impact of microaggressions on physical and psychological health is central to our investigation. Thematic data analysis was used to analyze 14 interviews and one focus group, which resulted in the following themes of microaggressions: (a) discomfort/disapproval with LGBT experience, (b) assumption of universal experience, (c) traditional gender role stereotyping, (d) denial of personal privacy, (e) exoticization, (f) ascription of intelligence, (g) policing bodies, and (h) assumption of criminality. Research findings may have implications for the development of interventions that can serve clinicians in their therapeutic work with microaggressed sexual minorities across racial diversity.

Diagnosis of Electrical Status Epilepticus During Slow-Wave Sleep With 100 Seconds of Sleep.

PURPOSE: Strategies for diagnosing electrical status epilepticus during slow-wave sleep (ESES) vary among interpreting neurologists. Our aim was to evaluate if the spike-wave index (SWI) for the first 100 seconds of sleep is reflective of the SWI when compared with a conventional method. METHODS: We reviewed EEGs from 2005 to 2011 that were considered diagnostic of ESES based on unspecified methods. The SWI for the first nonrapid eye movement sleep cycle (long method) was calculated by two neurophysiologists. Two different neurophysiologists calculated SWI for the first 100 seconds of sleep (short method). For the purposes of this study, ESES was defined as an SWI of >85%. The two SWI scores were compared. RESULTS: Fourteen EEGs were reviewed. Despite being considered by the initial interpreter as diagnostic of ESES, only 4 of the studies had an SWI of >85% based on each of the methods. For a diagnosis of ESES, the sensitivity of the short method is 80% and the specificity is 89%. Wilcoxon signed rank test was used to compare the long and short methods. A P value of 0.70 indicates no significant difference between the methods. Additionally, the Spearman correlation coefficient is 0.553 (P = 0.04), indicating moderate correlation between the methods. CONCLUSIONS: The SWI for the first 100 seconds of nonrapid eye movement sleep is predictive of the SWI for the entire first sleep cycle with a good sensitivity and specificity in our cohort. This suggests an alternative method for diagnosing ESES, which is comparable to analysis of a full night of sleep.

Utility of Neurodiagnostic Studies in the Diagnosis of Autoimmune Encephalitis in Children.

BACKGROUND: Autoimmune encephalitis is currently a clinical diagnosis without widely accepted diagnostic criteria, often leading to a delay in diagnosis. The utility of magnetic resonance imaging (MRI) and electroencephalography (EEG) in this disease is unknown. The objective of this study was to identify disease-specific patterns of neurodiagnostic studies (MRI and EEG) for autoimmune encephalitis in children. METHODS: We completed a retrospective chart review of encephalopathic patients seen at a large pediatric hospital over a four year interval. Clinical presentation, autoantibody status, and MRI and EEG findings were identified and compared. Individuals with autoantibodies were considered "definite" cases, whereas those without antibodies or those with only thyroperoxidase antibodies were characterized as "suspected." RESULTS: Eighteen patients met the inclusion criteria and autoantibodies were identified in nine of these. The patients with definite autoimmune encephalitis had MRI abnormalities within limbic structures, most notably the anteromedial temporal lobes (56%). Only individuals with suspected disease had nontemporal lobe cortical lesions. Sixteen patients had an EEG and 13 (81%) of these were abnormal. The most common findings were abnormal background rhythm (63%), generalized slowing (50%), focal slowing (43%), and focal epileptiform discharges (31%). Sleep spindle abnormalities occurred in 38% of patients. There were no specific differences in the EEG findings between the definite and suspected cases. Focal EEG findings only correlated with a focal lesion on MRI in a single definite case. CONCLUSIONS: Pediatric patients with definite autoimmune encephalitis have a narrow spectrum of MRI abnormalities. Conversely, EEG abnormalities are mostly nonspecific. All patients in our cohort had abnormalities on one or both of these neurodiagnostic studies.

Infantile Spasms Respond Poorly to Topiramate.

INTRODUCTION: Infantile spasms are seizures typical of an age-related epileptic encephalopathy. Although evidence supporting topiramate for infantile spasms is lacking, many clinicians use it for this indication. The aim of this study was to determine the rate of infantile spasm remission with topiramate at our institution. A low rate of infantile spasm remission was hypothesized. METHODS: This was a single-center retrospective medical record review of patients treated with topiramate for infantile spasms between January 2009 and September 2013. Records were reviewed for accuracy of diagnosis and outcome. Clinical remission of infantile spasms was defined as resolution for at least 28 days at any time during treatment with topiramate. For patients with clinical remission, posttreatment electroencephalographs were reviewed to assess for electrographic remission. To assess for confounding variables affecting remission rate, demographics and outcomes were compared with patients treated with adrenocorticotropic hormone within the same period using the same criteria for remission. RESULTS: Three of 31 (9.7%) patients achieved clinical remission with topiramate, two of whom also experienced electrographic remission. The third patient had electrographic remission with previous adrenocorticotropic hormone treatment but infantile spasm remission only after receiving topiramate. All three of these patients experienced subsequent electroclinical relapse during topiramate therapy. Although there were no significant demographic differences between the topiramate and adrenocorticotropic hormone cohorts, more adrenocorticotropic hormone patients achieved clinical remission (9.7% versus 56%; P < 0.001). DISCUSSION: Remission of infantile spasms with topiramate was uncommon and no patient experienced persistent electroclinical remission. These findings suggest that infantile spasms respond poorly to topiramate.

Dehydration and performance on clinical concussion measures in collegiate wrestlers.

CONTEXT: The effects of dehydration induced by wrestling-related weight-cutting tactics on clinical concussion outcomes, such as neurocognitive function, balance performance, and symptoms, have not been adequately studied. OBJECTIVE: To evaluate the effects of dehydration on the outcome of clinical concussion measures in National Collegiate Athletic Association Division I collegiate wrestlers. DESIGN: Repeated-measures design. SETTING: Clinical research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-two Division I healthy collegiate male wrestlers (age = 20.0 ± 1.4 years; height = 175.0 ± 7.5 cm; baseline mass = 79.2 ± 12.6 kg). INTERVENTION(S): Participants completed preseason concussion baseline testing in early September. Weight and urine samples were also collected at this time. All participants reported to prewrestling practice and postwrestling practice for the same test battery and protocol in mid-October. They had begun practicing weight-cutting tactics a day before prepractice and postpractice testing. Differences between these measures permitted us to evaluate how dehydration and weight-cutting tactics affected concussion measures. MAIN OUTCOME MEASURES: Sport Concussion Assessment Tool 2 (SCAT2), Balance Error Scoring System, Graded Symptom Checklist, and Simple Reaction Time scores. The Simple Reaction Time was measured using the Automated Neuropsychological Assessment Metrics. RESULTS: The SCAT2 measurements were lower at prepractice (P = .002) and postpractice (P < .001) when compared with baseline. The BESS error scores were higher at postpractice when compared with baseline (P = .015). The GSC severity scores were higher at prepractice (P = .011) and postpractice (P < .001) than at baseline and at postpractice when than at prepractice (P = .003). The number of Graded Symptom Checklist symptoms reported was also higher at prepractice (P = .036) and postpractice (P < .001) when compared with baseline, and at postpractice when compared with prepractice (P = .003). CONCLUSIONS: Our results suggest that it is important for wrestlers to be evaluated in a euhydrated state to ensure that dehydration is not influencing the outcome of the clinical measures.

Nonviolent communication training and empathy in male parolees.

The purpose of this study was to determine the impact of a behavioral intervention, nonviolent communication (NVC), on the development of empathic coping and communication skills in a sample of male parolees enrolled in substance abuse treatment (SAT; N = 30). At the end of the 8-week intervention, results revealed a significant increase (p = .01) in participants' empathy levels. Findings also revealed the acceptability and utility of NVC training to men on parole. Results suggest that NVC training may (a) be a useful addition to substance abuse treatment programs for parolees, (b) be effective in addressing problematic coping and communication styles resulting from incarceration and criminal behavior, and (c) assist paroled individuals in building and sustaining positive social support networks.