A DPSIR Approach to Selected Cr(VI) Impacted Groundwater Bodies of Central Greece

Bulletin of Environmental Contamination and Toxicology - The holistic approach of Driver-Pressure-State-Impact-Response (DPSIR) methodology was applied to selected Cr(VI) impacted groundwater...     

Female sexual behavior is disrupted in a preclinical mouse model of PCOS via an attenuated hypothalamic nitric oxide pathway

Women with polycystic ovary syndrome (PCOS) frequently experience decreased sexual arousal, desire, and sexual satisfaction. While the hypothalamus is known to regulate sexual behavior, the specific neuronal pathways affected in patients with PCOS are not known. To dissect the underlying neural circuitry, we capitalized on a robust preclinical animal model that reliably recapitulates all cardinal PCOS features. We discovered that female mice prenatally treated with anti-Müllerian hormone (PAMH) display impaired sexual behavior and sexual partner preference over the reproductive age. Blunted female sexual behavior was associated with increased sexual rejection and independent of sex steroid hormone status. Structurally, sexual dysfunction was associated with a substantial loss of neuronal nitric oxide synthase (nNOS)-expressing neurons in the ventromedial nucleus of the hypothalamus (VMH) and other areas of hypothalamic nuclei involved in social behaviors. Using in vivo chemogenetic manipulation, we show that nNOS^VMH neurons are required for the display of normal sexual behavior in female mice and that pharmacological replenishment of nitric oxide restores normal sexual performance in PAMH mice. Our data provide a framework to investigate facets of hypothalamic nNOS neuron biology with implications for sexual disturbances in PCOS.

Polycystic ovary syndrome (PCOS) is a highly prevalent disease affecting 5 to 18% of women of reproductive age worldwide (1, 2). PCOS is diagnosed upon the presence of at least two out of three prime features: high circulating levels of androgens (hyperandrogenism), menstrual irregularities (oligo-anovulation), and polycystic-like ovarian morphology (2, 3). Beyond its implications leading to female infertility, the disease is associated with several metabolic disruptions, cardiovascular diseases, and psychosocial disorders (4). Among these neurological implications, it has become clear that approximately 30% or more of patients with PCOS experience sexual dysfunctions, with clinical studies reporting a high risk of low sexual arousal, desire, and satisfaction and impaired lubrication and orgasm (5–9). These symptoms allude to disturbances in brain circuits controlling sexual function in the context of PCOS.Neural circuits driving female sexual behaviors are conserved among vertebrate species operating under the influence of sex steroid hormone modulation, which is paramount for partner interaction, receptivity, and sexual performance (10, 11). Indeed, gonadal sex hormones are implicated in shaping circuit architecture in the hypothalamus during development and activating these neonatally programmed circuits over reproductive adult life in many species (12–16). The hypothalamus integrates sensorial stimuli and autonomic arousal from endogenous sex drive cues (e.g., estrous phase, energy status, hormone milieu, genital stimulation) to convey this information to other brain areas and peripheral nerves (10, 17). The ventromedial nucleus of the hypothalamus (VMH) is considered the hub of specialized neurons, with intrinsic properties driving different components of sexual behavior (18–21). The VMH harbors neurons expressing neuronal nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide (NO), a key gaseous neurotransmitter that stimulates female sexual behavior (22, 23) and communicates with other circuits within the social brain (24, 25). Despite current advances unraveling novel pathways in the female sexual brain with specific behavioral responses, there is a clear lack of knowledge on how disturbances in these circuits may participate in sexual dysfunctions affecting one-third of women with PCOS.Growing evidence indicates that androgen excess in utero induces a developmental reprogramming of the female fetal brain toward the manifestation of PCOS traits later in life (26–29). Some studies have suggested that the clinical signs of hyperandrogenism have detrimental sexual effects (5), indicating a negative correlation between androgen levels and sexual function in PCOS. In recent years, it has been proposed that prenatal anti-Müllerian hormone excess may trigger gestational hyperandrogenism via the inhibition of placental aromatase (29, 30) and that women with PCOS display higher circulating levels of androgens and AMH during pregnancy as compared to healthy women (29, 31). Prenatal AMH-treated mice (PAMH) reliably recapitulate all the mouse equivalents of the PCOS Rotterdam criteria (29, 32) and are thus a preclinical model to mimic the human PCOS condition. PAMH female mice also display pronounced neuroendocrine dysfunction leading to exacerbated luteinizing hormone (LH) secretion (29), as in women with PCOS (33), denoting the presence of prenatally reprogrammed defects within the gonadotropin-releasing hormone (GnRH) neuronal network. Thus, prenatal AMH excess–mediated disruptions in the female brain may be key to understanding the pathophysiology of PCOS.Here, we investigated whether prenatal AMH excess could underpin defects in sex circuits promoting sexual dysfunction in PCOS-like female mice. We uncovered a profound decrease of nNOS and progesterone receptor (PR) expression in the VMH. These anatomical changes were also associated with significant impairment of sexual receptivity in PCOS-like female mice. Nevertheless, normal sexual function in PAMH female mice was restored to control levels upon peripheral injection of NO donor. Performing a series of acute functional manipulations in freely moving female mice, we showed that chemogenetic silencing of nNOS^VMH neurons in control female mice recapitulates PCOS-like sexual dysfunctions. Taken together, we unveiled a brain pathway potentially underpinning the etiology of low sexual drive in PCOS while pointing to prospective therapeutic approaches to rescue normal sexual function in these women.     

Effect of Cyclosporine Therapy With Low Doses of Corticosteroids on Idiopathic Nephrotic Syndrome

Cyclosporine (CyA) has an immunosuppressive effect that might suggest a therapeutic role in idiopathic glomerular conditions. We focused on the optimization of CyA treatment control in patients with idiopathic nephrotic syndrome by using trough‐level CyA measurements (C0) and the 2‐h postdose levels (C2). Twenty‐two patients (14 male, 8 female) with idiopathic nephrotic syndrome and the mean age of 51 ± 18 months (mean [M] ± standard deviation [SD]) were enrolled in our study during a period of 10 months (range: 3–18 months). All of the patients received CyA (2–3 mg/kg) in combination with methylprednisolone. In the present study protocol CyA concentrations (C0, C2), renal function, lipid profile, and degree of proteinuria were determined. The mean proteinuria of our patients before treatment was 11 972 ± 7953 mg/24 H (±SD) and the mean creatinine level (Cr) was 0.99 ± 0.37 mg/dL (±SD). Proteinuria decreased significantly already from the first month of therapy with CyA to 3578 ± 2470 mg/24 H (M± SD), and during the whole study period this reduction was significant (0.56 ± 0.37 gr/24 H (M ± SD), P < 0.05). At the same time renal function preserved, 1.09 ± 0.48 mg/dL (M ± SD). The blood levels of C0 were 135.10 ± 97.36 ng/mL (M ± SD) and the blood levels of C2 were 725 ± 256 ng/mL (M ± SD) at the first month of therapy. At the same time renal function preserved, 1.09 ± 0.48 mg/dL (M ± SD). Total cholesterol levels reduced significantly during study period (276.89 ± 45.57 to 200.67 ± 40.27 mg/dL [M ± SD]). The mean number of antihypertensive medication remained the same. The whole therapeutic protocol did not provoke any kind of side effects and CyA was quite tolerated by our patients. Treatment of idiopathic nephrotic syndrome with low doses of CyA with methylprednisolone leads to remission of proteinuria without deterioration of renal function. Blood levels of C0 for monitoring and treatment of nephrotic syndrome agrees with recent literature, while our study focus on establishing the proper levels of C2 for the treatment of nephrotic syndrome. The efficacy of CyA is combined with safety and tolerance.     

Feasibility of nasal epithelial brushing for the study of airway epithelial functions in CF infants.

BACKGROUND: For a better understanding of the early stages of cystic fibrosis (CF), it is of major interest to study respiratory epithelial cells obtained as early as possible. Although bronchoalveolar lavage has been proposed for this purpose, nasal brushing, which is a much less invasive technique, has seldom been used in CF infants. The aim of the present study was to examine in a few infants the feasibility of a nasal brushing technique for studies of airway epithelial functions in very young CF infants. METHODS: In 5 CF (median age 12, range 1-18 months) and 10 control infants (median age 5, range 1-17 months), a nasal brushing was performed by means of a soft sterile cytology brush, after premedication with oral paracetamol (15 mg/kg body weight) and rectal midazolam (0.2 mg/kg body weight). Samples were used for microbiological, cytological and functional studies. RESULTS: The procedure was well tolerated. Number of cells collected was similar in CF and non-CF patients (CF: median 230x10(3), range 42x10(3)-900x10(3); non-CF: median 340x10(3), range 140x10(3)-900x10(3)). Median number of viable cells was 67% (range 31-84%). Freshly obtained samples were successfully used for studies of ciliary beating frequency and cAMP-dependent chloride efflux. In 7 out of 17 cell cultures, confluence was obtained (CF: 2 out of 7; non-CF: 5 out of 10). The feasibility of studying protein release and mRNA expression of IL-8, IL-6 and TNF-alpha, under basal conditions and after stimulation by Pseudomonas aeruginosa, was demonstrated. CONCLUSIONS: By means of a simple nasal brushing technique easily performed and well tolerated, it is feasible, in infants, to harvest respiratory cells in sufficient amounts to study the airway epithelium using a broad range of techniques including cell culture.     

Quality evaluation of the available Internet information regarding pain during orthodontic treatment

Objective:To investigate the quality of the data disseminated via the Internet regarding pain experienced by orthodontic patients.Materials and Methods:A systematic online search was performed for ‘orthodontic pain’ and ‘braces pain’ separately using five search engines. The first 25 results from each search term–engine combination were pooled for analysis. After excluding advertising sites, discussion groups, video feeds, and links to scientific articles, 25 Web pages were evaluated in terms of accuracy, readability, accessibility, usability, and reliability using recommended research methodology; reference textbook material, the Flesch Reading Ease Score; and the LIDA instrument. Author and information details were also recorded.Results:Overall, the results indicated a variable quality of the available informational material. Although the readability of the Web sites was generally acceptable, the individual LIDA categories were rated of medium or low quality, with average scores ranging from 16.9% to 86.2%. The orthodontic relevance of the Web sites was not accompanied by the highest assessment results, and vice versa.Conclusions:The quality of the orthodontic pain information cited by Web sources appears to be highly variable. Further structural development of health information technology along with public referral to reliable sources by specialists are recommended.     

Does Pregnancy-Associated Breast Cancer Imply a Worse Prognosis? A Matched Case-Case Study

Zusammenfassung

Hintergrund: Die Auswirkungen einer Schwangerschaft auf die Prognose des Mammakarzinoms werden in der Literatur kontrovers diskutiert. Wir haben eine gepaarte Fall-Fall-Studie konzipiert, in der schwangerschaftsasso-ziierte Mammakarzinom (SAM)-Fälle entsprechend ihres Stadiums, Alters und Jahr der Diagnosestellung mit Mammakarzinom-Patientinnen gepaart wurden. Patientinnen und Methoden: 39 aufeinanderfolgende SAM-Fälle wurden mit 39 prämenopausalen Fällen von Brust-krebs gepaart. Univariate und multivariate Überlebens-analysen mit Anpassung an Stadium, Grad, Östrogen-rezeptorstatus und Alter zum Zeitpunkt der Diagnose wurden durchgeführt. Ergebnisse: Hinsichtlich des Gesamtüberlebens deutete die univariate Analyse auf ein längeres Gesamtüberleben für nicht-SAM-Fälle vs. SAM-Fälle hin. Gleichzeitig war ein fortgeschritteneres Stadium ein Prädiktor für ein kürzeres Überleben. Die multivariate Analyse bestätigte die unabhängige ver-schlechternde Auswirkung einer Schwangerschaft. Inter-essanterweise ergab eine genestete Post-hoc-Analyse der SAM-Fälle Hinweise auf ein kürzeres Gesamtüberleben für das dritte Trimester. Die oben erwähnten Ergebnisse für das Gesamtüberleben konnten desweiteren bei der Untersuchung des rezidivfreien Überlebens reproduziert werden. Schlussfolgerung: Mit ihrem gepaarten Fall-Fall-Design deutet die vorliegende Studie darauf hin, dass Schwangerschaft ein schlechter Prognosefaktor beim Mammakarzinom ist.     

Education and age affect skill acquisition and retention in lay rescuers after a European Resuscitation Council CPR/AED course

Objectives

To examine whether education and age affect skill acquisition and retention in lay rescuers after a European Resuscitation Council (ERC) CPR/AED course.

Background

Because of the importance of bystander CPR/AED skills in the setting of cardiac arrest, acquisition and retention of resuscitation skills has gained a great amount of interest.

Methods

The ERC CPR/AED course format for written and practical evaluation was used. Eighty lay people were trained and evaluated at the end of the course, as well as at one, three, and six months.

Results

Retention of CPR/AED skills improved over time, recording the lowest practical scores at one month after initial training and the lowest written scores at initial training. In practical evaluation scores, when examined longitudinally, age presented a significant adverse effect and higher background education presented a non-significant positive effect. Moreover, regarding written evaluation scores, when examined longitudinally, education presented a significant positive effect while age did not significantly correlate with written scores.

Conclusions

Education and age affected retention of CPR/AED skills in lay rescuers. Also, our results suggest that the ERC CPR/AED course format may be poorly designed to discriminate between participants with different levels of practical and written resuscitation skills and merit a thorough investigation in future studies.