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Δευτέρα 6 Νοεμβρίου 2017
Scholar : African Journal of Aquatic Science, Volume 42, Issue 3, October 2017 is now available online on Taylor & Francis Online
Scholar : These new articles for Journal of Clinical and Experimental Neuropsychology are available online
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Validation of the online prediction tool PREDICT v. 2.0 in the Dutch breast cancer population
Source:European Journal of Cancer, Volume 86
Author(s): M.C. van Maaren, C.D. van Steenbeek, P.D.P. Pharoah, A. Witteveen, G.S. Sonke, L.J.A. Strobbe, P.M.P. Poortmans, S. Siesling
BackgroundPREDICT version 2.0 is increasingly used to estimate prognosis in breast cancer. This study aimed to validate this tool in specific prognostic subgroups in the Netherlands.MethodsAll operated women with non-metastatic primary invasive breast cancer, diagnosed in 2005, were selected from the nationwide Netherlands Cancer Registry (NCR). Predicted and observed 5- and 10-year overall survival (OS) were compared for the overall cohort, separated by oestrogen receptor (ER) status, and predefined subgroups. A >5% difference was considered as clinically relevant. Discriminatory accuracy and goodness-of-fit were determined using the area under the receiver operating characteristic curve (AUC) and the Chi-squared-test.ResultsWe included 8834 patients. Discriminatory accuracy for 5-year OS was good (AUC 0.80). For ER-positive and ER-negative patients, AUCs were 0.79 and 0.75, respectively. Predicted 5-year OS differed from observed by −1.4% in the entire cohort, −0.7% in ER-positive and −4.9% in ER-negative patients. Five-year OS was accurately predicted in all subgroups.Discriminatory accuracy for 10-year OS was good (AUC 0.78). For ER-positive and ER-negative patients AUCs were 0.78 and 0.76, respectively. Predicted 10-year OS differed from observed by −1.0% in the entire cohort, −0.1% in ER-positive and −5.3 in ER-negative patients. Ten-year OS was overestimated (6.3%) in patients ≥75 years and underestimated (−13.%) in T3 tumours and patients treated with both endocrine therapy and chemotherapy (−6.6%).ConclusionsPREDICT predicts OS reliably in most Dutch breast cancer patients, although results for both 5-year and 10-year OS should be interpreted carefully in ER-negative patients. Furthermore, 10-year OS should be interpreted cautiously in patients ≥75 years, T3 tumours and in patients considering endocrine therapy and chemotherapy.
http://ift.tt/2yA6tfm
Phase II study of ipilimumab in adolescents with unresectable stage III or IV malignant melanoma
Source:European Journal of Cancer, Volume 86
Author(s): Birgit Geoerger, Christophe Bergeron, Lia Gore, Leonard Sender, Ira J. Dunkel, Cynthia Herzog, Lieve Brochez, Ofelia Cruz, Karsten Nysom, Elmer Berghorn, Burcin Simsek, Jun Shen, Alberto Pappo
BackgroundIpilimumab is approved for the treatment of advanced melanoma in adults; however, little information on the efficacy and safety of ipilimumab in younger patients is available.MethodsPatients aged 12 to <18 years with previously treated or untreated, unresectable stage III or IV malignant melanoma received ipilimumab 3 or 10 mg/kg every 3 weeks. Primary end-points were 1-year overall survival and safety.ResultsOver a period of 3.5 years, 12 patients received ipilimumab at either 3 mg/kg (n = 4) or 10 mg/kg (n = 8). The median number of ipilimumab doses was four for 3 mg/kg and three for 10 mg/kg. At 1 year, three of four patients on 3 mg/kg and five of eight patients on 10 mg/kg were alive. Two patients on 10 mg/kg had partial response, and one on 3 mg/kg had stable disease. One patient had durable partial response at 3 years without further treatment, at time of this report. There was one grade 3/4 immune-mediated adverse reaction with 3 mg/kg and five with 10 mg/kg. There were no treatment-related deaths. The study was stopped due to slow accrual.ConclusionsAt >1 year follow-up, ipilimumab demonstrated activity in melanoma patients aged 12 to <18 years, with a similar safety profile as that seen in adults. Our trial highlights the difficulties of enrolling younger patients with rare diseases in clinical trials for treatments that are approved in adults, suggesting adolescents with cancer types occurring predominantly in adults should be considered for inclusion in adult trials of promising new drugs.Clinical trial registration: NCT01696045.
http://ift.tt/2lWjObJ
The utility of anti-Müllerian hormone in the diagnosis and prediction of loss of ovarian function following chemotherapy for early breast cancer
Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): R.A. Anderson, J. Mansi, R.E. Coleman, D.J.A. Adamson, R.C.F. Leonard
AimChemotherapy results in permanent loss of ovarian function in some premenopausal women. Accurate identification in women with hormone-sensitive early breast cancer (eBC) would allow optimisation of subsequent endocrine treatment. We sought to assess whether analysis of anti-Müllerian hormone (AMH) using a sensitive automated assay could identify women who would not regain ovarian function after chemotherapy.MethodsData from women in the Ovarian Protection Trial in Premenopausal Breast Cancer Patients (OPTION) trial of goserelin (a gonadotrophin-releasing hormone (GnRH) analogue) for ovarian protection were analysed. Women were assessed for premature ovarian insufficiency (POI: amenorrhoea with elevated follicle-stimulating hormone (FSH)) at 24 months after diagnosis. The accuracy of AMH for the diagnosis of POI and its prediction from measurement at the end of chemotherapy was calculated.ResultsAMH below the level of detection showed good diagnostic accuracy for POI at 24 months (n = 73) with receiver operating characteristic (ROC) area under the curve of 0.86, sensitivity 1.0 and specificity 0.73 at the assay limit of detection. In women aged >40 at diagnosis who did not receive goserelin, AMH measured at end of chemotherapy also gave good prediction of POI at 24 months (area under the curve (AUC) 0.89 95% CI 0.75–1.0, n = 32), with sensitivity 0.91, specificity 0.82, diagnostic odds ratio (DOR) 42.8. FSH gave slightly lower AUC, and specificity was low at 0.55. Age but not tamoxifen impacted on AMH levels.ConclusionUsing this sensitive AMH assay, the finding of an undetectable AMH level in women aged >40 at the end of chemotherapy for eBC gave a good prediction that ovarian function would not return. This may allow alterations in post-chemotherapy endocrine management.
http://ift.tt/2yyW5Vc
Phase II, multicentre, randomised trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine as first-line chemotherapy in patients with HER2-negative metastatic breast cancer
Source:European Journal of Cancer, Volume 86
Author(s): Yeon Hee Park, Seock-Ah Im, Sung-Bae Kim, Joo Hyuk Sohn, Keun Seok Lee, Yee Soo Chae, Ki Hyeong Lee, Jee Hyun Kim, Young-Hyuck Im, Ji-Yeon Kim, Tae-Yong Kim, Kyung-Hun Lee, Jin-Hee Ahn, Gun Min Kim, In Hae Park, Soo Jung Lee, Hye Sook Han, Se Hyun Kim, Kyung Hae Jung
BackgroundPaclitaxel plus gemcitabine (PG) combination chemotherapy is a preferred chemotherapeutic regimen for patients with metastatic breast cancer (MBC). Eribulin mesylate is a halichondrin non-taxane inhibitor of microtubule dynamics. A recent pooled analysis with eribulin showed improved overall survival (OS) in various MBC patient subgroups pretreated with anthracycline and taxane. Furthermore, eribulin may have less neurotoxicity than paclitaxel.Patients and methodsThis study was a prospective randomised phase II, open-label, two-arm, multicentre study comparing eribulin plus gemcitabine (EG) with PG chemotherapy as a first-line treatment for patients with human epidermal growth factor receptor 2-negative MBC. We hypothesised that EG chemotherapy would not be inferior to PG chemotherapy. The primary end-point was progression-free survival (PFS), which was estimated to be 70% at 6 months for each arm. The secondary end-points were as follows: OS, neuropathic scale, toxicity and clinical benefit rate.ResultsA total of 118 patients (median age: 50, 24–66) were enrolled between March 2015 and March 2016 and were randomly assigned to PG (n = 59) or EG (n = 59) chemotherapy. The mean number of metastatic sites was 3 (range 1–8). The 6-month PFS rates for both arms were 72% for EG and 73% for PG (P = 0.457). There was no significant difference in OS between the two groups (not reached versus 21.2 months, P = 0.2234). The median number of chemotherapy cycles for both groups was 10 for EG and 8 for PG (range 2–32). Clinical benefit rates were 44% for EG and 49% for PG. Major toxicities were neutropenia and neurotoxicity. Grade II or above neurotoxicity was more common with PG than with EG (13.6% for EG versus 45.8% for PG, P < 0.0001).ConclusionEG chemotherapy had similar clinical benefits to PG chemotherapy in terms of PFS but less neurotoxicity.Trial registrationKCSG BR13-11; ClinicalTrials.gov, NCT02263495.
http://ift.tt/2AbaN0Y
Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial
Source:European Journal of Cancer, Volume 86
Author(s): N. Basset-Séguin, A. Hauschild, R. Kunstfeld, J. Grob, B. Dréno, L. Mortier, P.A. Ascierto, L. Licitra, C. Dutriaux, L. Thomas, N. Meyer, B. Guillot, R. Dummer, P. Arenberger, K. Fife, A. Raimundo, E. Dika, N. Dimier, A. Fittipaldo, I. Xynos, J. Hansson
BackgroundThe SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665), assessed safety and efficacy of vismodegib—a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)—in a patient population representative of clinical practice. Primary analysis data are presented.Patients and methodsPatients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal. Primary objective was safety. Efficacy variables were assessed as secondary end-points.ResultsEvaluable adult patients (N = 1215, 1119 locally advanced; 96 metastatic BCC) from 36 countries were treated; 147 patients (12%) remained on study at time of reporting. Median (range) treatment duration was 8.6 (0–44) months. Most patients (98%) had ≥1 treatment-emergent adverse event (TEAE). The incidence of the most common TEAEs was consistent with reports in previous analyses. No association between creatine phosphokinase (CPK) abnormalities and muscle spasm was observed. Serious TEAEs occurred in 289 patients (23.8%). Exposure ≥12 months did not lead to increased incidence or severity of new TEAEs. The majority of the most common TEAEs ongoing at time of treatment discontinuation resolved by 12 months afterwards, regardless of Gorlin syndrome status. Response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7–71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6–48.1) in patients with metastatic BCC.ConclusionsThe primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control.ClinicalTrials.govNCT01367665.
http://ift.tt/2hJMTms
Cognitive decline after major oncological surgery in the elderly
Source:European Journal of Cancer, Volume 86
Author(s): M. Plas, E. Rotteveel, G.J. Izaks, J.M. Spikman, H. van der Wal-Huisman, B. van Etten, A.R. Absalom, M.J.E. Mourits, G.H. de Bock, B.L. van Leeuwen
BackgroundElderly patients undergoing oncological surgery experience postoperative cognitive decline. The aims of this study were to examine the incidence of cognitive decline 3 months after surgery and identify potential patient-, disease- and surgery-related risk factors for postoperative cognitive decline in onco-geriatric patients.MethodsA consecutive series of elderly patients (≥65 years) undergoing surgery for the removal of a solid tumour were included (n = 307). Cognitive performance was assessed pre-operatively and 3 months postoperatively. Postoperative decline was defined as a decline in scores of cognitive tests of ≥25% on ≥2 of 5 tests.ResultsOf the patients who had completed the assessments, 117 (53%, 95% confidence interval [CI]: 47–60) had improved cognitive test scores, whereas 26 (12%, 95% CI: 7.6–16) showed cognitive decline at 3 months postoperatively. In patients aged >75 years, the incidence of overall cognitive decline 3 months postoperatively was 18% (95% CI: 9.3–27). In patients with lower pre-operative Mini–Mental State Examination (MMSE) score (≤26) the incidence was 37% (95% CI: 18–57), and in patients undergoing major surgery it was 18% (95% CI: 10.6–26). Of the cognitive domains, executive function was the most vulnerable to decline.ConclusionAbout half of the elderly patients show improvement in postoperative cognitive performance after oncological surgery, whereas 12% show cognitive decline. Advanced age, lower pre-operative MMSE score and major surgery are risk factors for cognitive decline at 3 months postoperatively and should be taken into account in the clinical decision-making progress. Research to develop interventions to preserve quality of life should focus on this high-risk subpopulation.
http://ift.tt/2Aegpaq
Very early response of circulating tumour–derived DNA in plasma predicts efficacy of nivolumab treatment in patients with non–small cell lung cancer
Source:European Journal of Cancer, Volume 86
Author(s): Yuki Iijima, Yosuke Hirotsu, Kenji Amemiya, Yoshihiko Ooka, Hitoshi Mochizuki, Toshio Oyama, Takahiro Nakagomi, Yoshinori Uchida, Yoichi Kobayashi, Toshiharu Tsutsui, Yumiko Kakizaki, Taichiro Goto, Yoshihiro Miyashita, Masao Omata
IntroductionImmunotherapy has become a treatment option for lung cancer. The utility of nivolumab as second-line treatment for non–small cell lung cancer has been proven, but predictive biomarkers influencing its efficacy remain unknown.MethodsThis study involved 14 patients who were treated with nivolumab from February 1 to September 30, 2016. The early response of the level of circulating tumour DNA (ctDNA) after starting nivolumab was evaluated to ascertain whether it could predict treatment outcome.ResultsOf the 14 patients, six were responders and eight were non-responders. DNA was analysed in both tumour tissue and plasma samples. Only somatic mutations confirmed by analysis of tumour tissue were defined as ctDNA. ctDNA was detected more often in the serial plasma samples of patients with high tumour volume (TV) (p = 0.02). ctDNA was detected in seven cases; basal and serial ctDNA analysis revealed that a decrease in allelic frequency (AF) of ctDNA showed high-level correspondence with a good durable response. When "2 weeks" was set as a clinically significant time point, changes in representative mutations of each case, defined as one of the highest baseline AF, showed 100% concordance with the response.ConclusionsIn patients with high TV, plasma analysis of ctDNA, as validated by tumour tissue, suggested that a durable good response to nivolumab could be predicted within 2 weeks.
http://ift.tt/2hJVWn9
Is initial excision of cutaneous melanoma by General Practitioners (GPs) dangerous? Comparing patient outcomes following excision of melanoma by GPs or in hospital using national datasets and meta-analysis
Source:European Journal of Cancer, Volume 86
Author(s): Peter Murchie, Edwin Amalraj Raja, David H. Brewster, Lisa Iversen, Amanda J. Lee
BackgroundMelanomas are initially excised in primary care, and rates vary internationally. Until now, there has been no strong evidence one way or the other that excising melanomas in primary care is safe or unsafe. European guidelines make no recommendations, and the United Kingdom (UK) melanoma guidelines require all suspicious skin lesions to be initially treated in secondary care based on an expert consensus, which lacks supporting evidence, that primary care excision represents substandard care. Despite this, studies have found that up to 20% of melanomas in the UK are excised by general practitioners (GPs). Patients receiving primary care melanoma excision may fear that their care is substandard and their long-term survival threatened, neither of which may be justified.MethodsScottish cancer registry data from 9367 people diagnosed with melanoma in Scotland between 2005 and 2013 were linked to pathology records, hospital data and death records. A Cox proportional hazards regression analysis, adjusting for key confounders, explored the association between morbidity and mortality and setting of primary melanoma excision (primary versus secondary care). A pooled estimate of the relative hazard of death of having a melanoma excised in primary versus secondary care including 7116 patients from a similar Irish study was also performed.ResultsThe adjusted hazard ratio (95% CI) of death from melanoma for those having primary care excision was 0.82 (0.61–1.10). Those receiving primary care excision had a median (IQR) of 8 (3–14) out-patient attendances compared to 10 (4–17) for the secondary care group with an adjusted relative risk (RR) (95% CI) of 0.98 (0.96–1.01). Both groups had a median of 1 (0–2) hospital admissions with an adjusted rate ratio of 1.05 (0.98–1.13). In the meta-analysis, with primary care as the reference, the pooled adjusted hazard ratio (HR, 95% CI) was 1.26 (1.07–1.50) indicating a significantly higher all-cause mortality among those with excision in secondary care.ConclusionsThe results of the Scottish and pooled analyses suggest that those receiving an initial excision for melanoma in primary care do not have poorer survival or increased morbidity compared to those being initially treated in secondary care. A randomised controlled trial to inform a greater role for GPs in the initial excision of melanoma is justified in the light of these results.
http://ift.tt/2Ad0lpN
Evaluation of estrogenic potency of a standardized hops extract on mammary gland biology and on MNU-induced mammary tumor growth in rats
Publication date: November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 174
Author(s): Annekathrin M. Keiler, Dana Macejova, Birgit M. Dietz, Judy L. Bolton, Guido F. Pauli, Shao-Nong Chen, Richard B. van Breemen, Dejan Nikolic, Florian Goerl, Michael H. Muders, Oliver Zierau, Günter Vollmer
Supplements with estrogenic activities are intensively investigated as potential alternatives for the treatment of menopausal symptoms. These investigations include studies on their safety regarding potential breast cancer risks. Therefore, the aim of this study was to assess whether or not a standardized hops (Humulus lupulus) extract, containing 0.42% of the estrogenic flavanone, 8-prenylnaringenin, would stimulate growth of methyl-nitrosourea (MNU) induced mammary cancer in ovariectomized (OVX) Sprague-Dawley (SD) rats or would impact on the proliferative activity within the normal mammary gland of Wistar rats. To induce tumorigenesis SD-rats received an intraperitoneal injection of 50mg/kg body weight of MNU on postnatal days PND 50 and 52. 28days later animals were OVX or were SHAM operated (positive control) and randomly allocated and maintained for 140days on either a phytoestrogen-free placebo diet (SHAM and negative control) or on the hops fortified diet. For the investigations in the normal mammary gland young adult Wistar rats were bilaterally OVX and randomly allocated to a control group fed to a phytoestrogen-free diet, or to a diet supplemented either with E2-benzoate or the hops extract. As a major result, the tumor incidence was 15% (3 tumors totally) in OVX controls, whereas it was 85% (39 tumors totally) in SHAM operated positive controls. No tumors were detectable in the hops group. In addition, no estrogenic activity of the hops extract was detectable in uterus and liver of these animals. In investigations on the normal mammary gland, no impact of hops extract on the expression of estrogen dependent proliferation markers or of progesterone receptor became apparent. In conclusion, the lack of growth stimulation of MNU-induced breast cancer in OVX SD-rats and the lack of stimulation proliferative events in the normal mammary gland of OVX Wistar rats by standardized hops extracts provides an important piece of evidence regarding the safety of these extracts in the management of menopausal symptoms.
http://ift.tt/2h8Us5e
Molecular pathways involved in the transport of nuclear receptors from the nucleus to cytoplasm
Publication date: Available online 26 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Angeles C. Tecalco-Cruz
Nuclear receptors (NRs) are transcription regulators that direct the expression of many genes linked to cellular processes, such as proliferation, differentiation, and apoptosis. Additionally, some cellular events are also modulated by signaling pathways induced by NRs outside of the nucleus. Hence, the subcellular transport of NRs is dynamic and is modulated by several signals, protein-protein interaction, and posttranslational modifications. Particularly, the exit of NRs from the nucleus to cytoplasm and/or other compartments is transcendental, as it is this export event, which determines their abundance in the cells' compartments, the activation or attenuation of nuclear or extranuclear pathways, and the magnitude and duration of their effects inside or outside of the nucleus. Consequently, an adequate control of the distribution of NRs is critical for homeostasis, because a deregulation in the nucleo-cytoplasmic transport of NRs could be involved in diseases including cancer as well as metabolic and vascular alterations. In this review, we investigated the pathways and molecular and biological aspects that have been described for the nuclear export of NRs so far and their functional relevance in some diseases. This information suggests that the transport of NRs out of the nucleus is a key mechanism for the identification of new therapeutic targets for alterations associated with the deregulation of the function of NRs.
http://ift.tt/2iz5h0S
Dose ranging effects of Vitamin D3 on the Geriatric Depression Score: A Clinical Trial
Publication date: Available online 2 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Vinod Yalamanchili, J. Christopher Gallagher
Depression is a common problem affecting millions, usually treated with selective serotonin uptake inhibitors. Interest in vitamin D as a co-therapy was stimulated by some association studies that correlated depression with low serum 25OHD levels. There are few longitudinal studies of vitamin D and depression and most are single doses of vitamin D. In this study we examined the effect of one-year treatment with several doses of vitamin D on the Geriatric depression score (GDS) in older Caucasian and African American women. The clinical trial was a study of seven daily oral doses of vitamin D (400-4800IU/d) in Black and White older women. The trial was a double blind, randomized and placebo controlled lasting 12-months. The main inclusion criterion was serum 25 hydroxyvitamin D (25OHD) ≤ 20ng/ml (50nmo/L). Calcium supplements were given to maintain calcium intake 1000mg in young people and 1200–1400mg/day in older women. Data on Geriatric depression (GDS) was collected using the validated long form at baseline and 12-months. The change in serum 25OHD was the primary outcome and GDS was one of the secondary outcomes. Adjustments were made for relevant covariates. Analysis of vitamin D effect was by dose low, medium and high compared to placebo or by quintiles. Serum 25OHD increased as a quadratic curve function to a mean of 46ng/ml (115nmol/l) in white women and 49ng/ml (122.5nmol/L) in black women on the highest dose of 4800 IU. In older women mean GDS scores changed from 3.8 (SD±4.2) at baseline to 3.6 (SD±4.1) at 12 months in whites and from 3.0 (SD±3.7) to 3.02 (SD±4.2) in Blacks. (p=0.790 in whites; p=0.958 in blacks). After 12-months there was no effect of dose on change in GDS score in women treated with different doses of vitamin D (p=0.507 in whites and p=0.340 in blacks). When both Caucasians and African Americans were divided into 3 dose groups, low (400-800 IU), medium (1600-3200 IU) and high (4000-4800 IU) doses, the change in score was 0.8 on low dose, −0.30 on medium dose and −0.31 on high dose compared to 0.11 on placebo (p=0.546). In summary, there was no improvement in GDS scores in Caucasians or African Americans on either increasing doses of vitamin D or quintiles of achieved response in serum 25OHD. The changes were small and not significant perhaps because of the relatively lower numbers of depressed women in the groups. Further studies should recruit larger numbers, 3 dose groups covering a serum25OHD range of 20–60ng/ml and more subjects with clinical depression in order to fully address the question of vitamin D effects on depression.
http://ift.tt/2h9t0ob
Calcitriol promotes proangiogenic molecules in keratinocytes in a diabetic foot ulcer model
Publication date: November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 174
Author(s): Valentin Trujillo, Paulina Marín-Luevano, Irma González-Curiel, Adrián Rodríguez-Carlos, Maira Ramírez-Reyes, Esther Layseca-Espinosa, José A. Enciso-Moreno, Lorenza Díaz, Bruno Rivas-Santiago
Foot ulceration is one of the most common and complex sequelae of diabetes mellitus, generally posing a therapeutic challenge due to poor healing responses and high rates of complications, including peripheral vascular disease, ischemia and infections. Calcitriol, the most active vitamin D metabolite, induces antimicrobial peptides production in keratinocytes from diabetic foot ulcers (DFU); however, little is known about its effects on angiogenic factors in this pathology. Herein we aimed at studying whether calcitriol induces angiogenic molecules in keratinocytes under normoxic and hypoxic conditions, and if these molecules are able to improve cell migration in vitro. Evaluation of DFU samples by immunohistochemistry showed increased VEGF and decreased angiogenin and HIF-1α expression compared to controls, suggesting an altered pattern of angiogenic factors in DFU. Interestingly, incubation of keratinocytes with calcitriol significantly upregulated VEGFA, HIF-1α and angiogenin gene expression, while the resulting cell culture media stimulated both endothelial cells and keratinocytes migration in an in vitro wound closure assay under a normoxic environment (p<0.05). Moreover, the culture media of calcitriol-treated keratinocytes stimulated cell migration in a similar extent as exogenous VEGF or EGF in endothelial and keratinocytes cells. These results suggest that the altered profile of angiogenic molecules in DFU might be improved by local or systemic treatment with calcitriol under normoxic conditions, which could probably be achieved with hyperbaric oxygen therapy. Given that calcitriol not only augments proangiogenic factors but also induces antimicrobial peptides expression, this hormone should be further investigated in clinical trials of DFU.
http://ift.tt/2iya42E
Editorial board
Publication date: November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 174
http://ift.tt/2h8C7Wc
Antitumoral effects of the alkynylphosphonate analogue of calcitriol EM1 on glioblastoma multiforme cells
Publication date: Available online 1 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): María Julia Ferronato, Eliana Noelia Alonso, Débora Gisele Salomón, María Eugenia Fermento, Norberto Ariel Gandini, Mario Alfredo Quevedo, Evangelina Mascaró, Cristian Vitale, Yagamare Fall, María Marta Facchinetti, Alejandro Carlos Curino
Glioblastoma multiforme (GBM) is the worst and most common brain tumor, characterized by high proliferation and invasion rates. The current standard treatment is mainly based on chemoradiotherapy and this approach has slightly improved patient survival. Thus, novel strategies aimed at prolonging the survival and ensuring a better quality of life are necessary. In the present work, we investigated the antitumoral effect of the novel analogue of calcitriol EM1 on GBM cells employing in vitro, in silico, and in vivo assays. In vitro, we demonstrated that EM1 treatment selectively decreases the viability of murine and human tumor cells without affecting that of normal human astrocytes. The analysis of the mechanisms showed that EM1 produces cell cycle arrest in the T98G cell line, which is accompanied by an increase in p21, p27, p57 protein levels and a decrease in cyclin D1, p-Akt-S473, p-ERK1/2 and c-Jun expression. Moreover, EM1 treatment also exerts in GBM cells anti-migratory effects and decreases their invasive capacity by a reduction in MMP-9 proteolytic activity. In silico, we demonstrated that EM1 is able to bind to the vitamin D receptor with greater affinity than calcitriol. Finally, we showed that EM1 treatment of nude mice administered at 50 ug/kg body weight during 21days neither induces hypercalcemia nor toxicity effects. In conclusion, all the results indicate the potential of EM1 analogue as a promising therapeutic alternative for GBM treatment.
Graphical abstract
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Antihypertensive responses of vasoactive androgens in an in vivo experimental model of preeclampsia.
Publication date: Available online 4 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Mercedes Perusquía, Andrea E. Hanson, Claudia M. Meza, Cris Kubli, Nieves Herrera, John N. Stallone
Dehydroepiandrosterone (DHEA), testosterone (TES) and its 5-reduced metabolites induce a nongenomic vasorelaxation in several vascular beds of mammals; similarly these hormones produce systemic hypotensive and antihypertensive responses in normotensive and hypertensive male rats. Thus, it was hypothesized that the antihypertensive response of androgens, whose levels are elevated during gestation, protect against gestational hypertension. An animal model of preeclampsia was induced in female Wistar rats using DOCA-salt-treated pregnant (PT) and normal pregnant (NP) rats. In vivo experiments in conscious rats revealed that bolus intravenous injections of DHEA, TES, 5α- or 5β-dihydrotestosterone (-DHT) log −1.0 to 2.0μmolk−1min−1, produced substantial transient reductions in arterial blood pressure (BP), without significant changes in heart rate (HR). Mean arterial blood pressure (MAP) was reduced significantly in both groups. PT rats were more sensitive to the antihypertensive responses of androgens than NP. DHEA and 5β-DHT were the most potent to reduce MAP: 66±07 and 69±2.0mmHg in PT but only 33±0.5 and 35±1.2mmHg in NP rats, respectively. In isolated aortas of PT and NP, the concentration-response curves to each androgen (0.1–100μM) indicated that KCl-induced pre-contraction is more sensitive to all androgens than phenylephrine (Phe) pre-contractions. Notably, 5β-DHT is the greatest vasorelaxant with KCl-induced contraction than with Phe contraction of both groups, suggesting a preferential blockade on L-VOCCs. TES exhibited minor vasorelaxing effect of aortas pre-contracted with KCl, compared to its precursor DHEA and its 5-reduced metabolites. These data show that these androgens exert acute vasorelaxing effects in vitro and remarkably, reduce the BP in vivo in PT and NP at term pregnancy. Moreover, a deficit in feto-placental androgen production during pregnancy may trigger the development of preeclampsia or gestational hypertension.
http://ift.tt/2iyjNpF
A high rate of novel CYP11B1 mutations in Saudi Arabia
Publication date: November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 174
Author(s): Ali S. Alzahrani, Meshael M. Alswailem, Avaniyapuram Kannan Murugan, Doha S. Alhomaidah, Cameron P. Capper, Richard J. Auchus, Ebtesam Qasem, Ohoud S. Alzahrani, Afaf Al-Sagheir, Bassam Bin-Abbas
Despite ethnic variation, 11 β-hydroxylase deficiency (11β-OHD) has generally been considered the second most common subtype of congenital adrenal hyperplasia (CAH). We report a high rate of novel mutations in this gene (CYP11B1) in patients from Saudi Arabia. We studied 16 patients with 11β-OHD from 8 unrelated families. DNA was isolated from peripheral blood. The 9 exons and exon-intron boundaries of CYP11B1 were PCR-amplified and directly sequenced. The novel mutations were functionally characterized using subcloning, in vitro mutagenesis, cell transfection and 11-deoxycortisol: cortisol conversion assays. Six mutations were found in these 8 unrelated families. Three of these mutations are completely novel and two have just been recently described as novel mutations from the same population. These include a single nucleotide insertion mutation in codon 18 (c.53_54insT) leading to frameshift and truncation in 4 siblings, a novel mutation (c.1343G>C, p.R448P) in 3 unrelated families, a novel mutation (c.1394A>T, p.H465L) in 2 siblings, a novel mutation (c.617G>T, p.G206V) in 1 patient, and a recently described non-sense novel mutation (c.780G>A, p.W260X) in another patient. Out of the 6 mutations described in this report, only one mutation (p.Q356X) was reported previously. In vitro functional testing of the 3 missense and nonsense novel mutations revealed complete loss of the 11 hydroxylase activity. We conclude that 11 β-OHD in Saudi Arabia has a unique genotype with a high rate of novel mutations. The novel p. R448P mutation is the most common mutation in this highly inbred population.
http://ift.tt/2h71Jmf
Estradiol Metabolites as Biomarkers of Endometrial Cancer Prognosis After Surgery
Publication date: Available online 29 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Yannick Audet-Delage, Jean Grégoire, Patrick Caron, Véronique Turcotte, Marie Plante, Pierre Ayotte, David Simonyan, Lyne Villeneuve, Chantal Guillemette
Endometrial cancer (EC) is the most common gynecologic malignancy prevailing after menopause. Defining steroid profiles may help predict the risk of recurrence after hysterectomy, which remains limited due to the lack of reliable markers. Adrenal precursors, androgens, parent estrogens and catechol estrogen metabolites were measured by mass spectrometry (MS) in preoperative serums and those collected one month after hysterectomy from 246 newly diagnosed postmenopausal EC cases. We also examined the associations between steroid hormones and EC status by including 110 healthy postmenopausal women. Steroid concentrations were analyzed in relation to clinicopathological features, recurrence and overall survival (OS). The mean follow-up time was 65.5 months and 26 patients experienced relapse after surgery for a recurrence incidence of 10.6% (6.4% Type I and 29.5% Type II). Recurrence and OS were related to a more aggressive disease but not linked to body mass index. Preoperative levels of estriol (E3) and estrone-sulfate (E1-S) were inversely associated with recurrence in a multivariate logistic regression analysis (Hazard ratios (HRs) of 0.31, P=0.039 and 3.01, P=0.024; respectively). All circulating steroids declined considerably after surgery almost reaching those of healthy women, except 4-methoxy-E2 (4MeO-E2) for which postoperative levels increased by 35% and were associated to a 68% decreased risk of recurrence (HR=0.32, P=0.015). Women diagnosed with both histological types of EC present significantly higher levels of steroids, in support of their mitogenic effects. The estrogen precursor E1-S, the anticancer metabolite 4MeO-E2, and E3 that exert mixed antagonist and agonist estrogenic activities and immunological effects, are potential independent prognostic factors.
http://ift.tt/2iyjriM
Uptake and metabolism of water-borne progesterone by the mussel, Mytilus spp. (Mollusca)
Publication date: Available online 26 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Tamar I. Schwarz, Ioanna Katsiadaki, Benjamin H. Maskrey, Alexander P. Scott
Previous studies have shown that mussels can pick up 17β-estradiol [E2] and testosterone [T] from water, metabolize them and conjugate them to fatty acids (esterification), leading to their accumulation in tissue. A key requirement for the esterification process is that a steroid must have a 'reactive' hydroxyl group to conjugate to a fatty acid (which in T, and probably E2, is the β-hydroxyl group on carbon 17). Progesterone (P) lacks any hydroxyl groups and theoretically cannot be esterified and hence should not accumulate in mussels in the same way as E2 or T. However, it is already known that mussels have an enzyme that can achieve 5α-reduction of the A ring of T and P and that there is also another reductase that can transform the 3-oxo group of the 5α-reduced A ring of T into a hydroxyl group. We hypothesized that, although intact P cannot be directly esterified, it might nevertheless be transformed into metabolites that can. To test this hypothesis, we investigated the rate and capacity of uptake, metabolism and potential depuration of tritiated P by the common mussel, Mytilus spp. We found that tritiated P was taken up from water at a similar rate to E2 and T (mean clearance rate 49mL−1 animal−1h−1) and that, as found with the other steroids, the rate of uptake could not be saturated by the addition of non-radioactive steroid (even at 7.6μgL−1). We found that up to 66% of the radioactivity that was taken up was present in the ester fraction, suggesting that hydroxylation of the P must indeed have occurred. We then definitively identified two metabolites in the ester fraction: 5α-pregnane-3β,20β-diol and 3β-hydroxy-5α-pregnan-20-one. These same two steroids were also present in the free steroid fraction. Intact P was not detected in either of the fractions. When undergoing depuration (under semi-static conditions), the radioactivity in the ester fraction remained at the same concentrations in the animals for at least 10 days. Our findings suggest that the lack of reactive hydroxyl groups on P does not preclude it from being taken up, metabolized and subsequently stored. Many questions remain, not least of which is why, when P seems to be so rapidly metabolized, two previous studies on mussels have reported concentrations of up to 30ngg−1 wet weight of P in their flesh.
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Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration
Publication date: November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 174
Author(s): Maria Meyer, Laura I. Garay, María Sol Kruse, Agustina Lara, Gisella Gargiulo-Monachelli, Michael Schumacher, Rachida Guennoun, Hector Coirini, Alejandro F. De Nicola, Maria Claudia Gonzalez Deniselle
Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons. The Wobbler (WR) mouse is a preclinical model sharing neuropathological similarities with human ALS. We have shown that progesterone (PROG) prevents the progression of motoneuron degeneration. We now studied if allopregnanolone (ALLO), a reduced metabolite of PROG endowed with gabaergic activity, also prevents WR neuropathology. Sixty-day old WRs remained untreated or received two steroid treatment regimens in order to evaluate the response of several parameters during early or prolonged steroid administration. ALLO was administered s.c. daily for 5days (4mg/kg) or every other day for 32days (3, 3mg/kg), while another group of WRs received a 20mg PROG pellet s.c. for 18 or 60days. ALLO administration to WRs increased ALLO serum levels without changing PROG and 5 alpha dihydroprogesterone (5α-DHP), whereas PROG treatment increased PROG, 5α-DHP and ALLO. Untreated WRs showed higher basal levels of serum 5α-DHP than controls. In the cervical spinal cord we studied markers of oxidative stress or associated to trophic responses. These included nitric oxide synthase (NOS) activity, motoneuron vacuolation, MnSOD immunoreactivity (IR), brain derived neurotrophic factor (BDNF) and TrkB mRNAs, p75 neurotrophin receptor (p75NTR) and, cell survival or death signals such as pAKT and the stress activated kinase JNK. Untreated WRs showed a reduction of MnSOD-IR and BDNF/TrkB mRNAs, associated to high p75NTR in motoneurons, neuronal and glial NOS hyperactivity and neuronal vacuolation. Also, low pAKT, mainly in young WRs, and a high pJNK in the old stage characterized WŔs spinal cord. Except for MnSOD and BDNF, these alterations were prevented by an acute ALLO treatment, while short-term PROG elevated MnSOD. Moreover, after chronic administration both steroids enhanced MnSOD-IR and BDNF mRNA, while attenuated pJNK and NOS in glial cells. Long-term PROG also increased pAKT and reduced neuronal NOS, parameters not modulated by chronic ALLO. Clinically, both steroids improved muscle performance. Thus, ALLO was able to reduce neuropathology in this model. Since high oxidative stress activates p75NTR and pJNK in neurodegeneration, steroid reduction of these molecules may provide adequate neuroprotection. These data yield the first evidence that ALLO, a gabaergic neuroactive steroid, brings neuroprotection in a model of motoneuron degeneration.
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Aromatase and neuroinflammation in rat focal brain ischemia
Publication date: November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 174
Author(s): Yu H. Zhong, Jasbeer Dhawan, Joel A. Kovoor, John Sullivan, Wei X. Zhang, Dennis Choi, Anat Biegon
Accumulating evidence suggests that expression of aromatase, the enzyme responsible for the conversion of androgens to estrogens, is transiently upregulated in rat stroke models. It was further suggested that increased aromatase expression is linked to neuroinflammation and that it is neuroprotective in females. Our goal was to investigate aromatase upregulation in male rats subjected to experimental stroke in relationship to neuroinflammation, infarct and response to treatment with different putative neuroprotective agents. Intact male rats were subjected to transient (90min) middle cerebral artery occlusion (MCAO) and administered selfotel (N-methyl-d-aspartic acid (NMDA) receptor competitive antagonist), TPEN (a zinc chelator), a combination of the two drugs or vehicle, injected immediately after reperfusion. Animals were killed 14days after MCAO and consecutive brain sections used to measure aromatase expression, cerebral infarct volume and neuroinflammation. Quantitative immunohistochemistry (IHC) demonstrated increased brain aromatase expression in the peri-infarct area relative to contralesional area, which was partially abrogated by neuroprotective agents. There was no correlation between aromatase expression in the peri-infarct zone and infarct volume, which was reduced by neuroprotective agents. Microglial activation, measured by quantitative autoradiography, was positively correlated with infarct and inversely correlated with aromatase expression in the peri-infarct zone. Our findings indicate that focal ischemia upregulates brain aromatase in the male rat brain at 14days post surgery, which is within the time frame documented in females. However, the lack of negative correlation between aromatase expression and infarct volume and lack of positive correlation between microgliosis and aromatase do not support a major role for aromatase as a mediator of neuroprotection or a causal relationship between microglial activation and increased aromatase expression in male focal ischemia.
http://ift.tt/2h9siax
Corrigendum to “1, 25-Dihydroxyvitamin-D3 prevents the development of diabetic cardiomyopathy in type 1 diabetic rats by enhancing autophagy via inhibiting the β-catenin/TCF4/GSK-3β/mTOR pathway” [J. Steroid. Biochem. Mol. Biol. 168 (2017) 71–90]
Publication date: November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 174
Author(s): Huili Wei, Hua Qu, Hang Wang, Baolan Ji, Yao Ding, Dan Liu, Yang Duan, Huimin Liang, Chuan Peng, Xiaoqiu Xiao, Huacong Deng
http://ift.tt/2iz1qAT
Role of G-protein-coupled estrogen receptor (GPER/GPR30) in maintenance of meiotic arrest in fish oocytes
Publication date: Available online 1 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Peter Thomas
An essential role for GPER (formerly known as GPR30) in regulating mammalian reproduction has not been identified to date, although it has shown to be involved in the regulation a broad range of other estrogen-dependent functions. In contrast, an important reproductive role for GPER in the maintenance of oocyte meiotic arrest has been identified in teleost fishes, which is briefly reviewed here. Recent studies have clearly shown that ovarian follicle production of estradiol-17β (E2) maintains meiotic arrest in several teleost species through activation of GPER coupled to a stimulatory G protein (Gs) on oocyte plasma membranes resulting in stimulation of cAMP production and maintenance of elevated cAMP levels. Studies with denuded zebrafish oocytes and with microinjection of GPER antisense oligonucleotides into oocytes have demonstrated the requirement for both ovarian follicle production of estrogens and expression of GPER on the oocyte surface for maintenance of meiotic arrest. This inhibitory action of E2 on the resumption of meiosis is mimicked by the GPER-selective agonist G-1, by the GPER agonists and nuclear ER antagonists, ICI 182,780 and tamoxifen, and also by the xenoestrogen bisphenol-A (BPA) and related alkylphenols. GPER also maintains meiotic arrest of zebrafish oocytes through estrogen- and BPA-dependent GPER activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling. Interestingly, progesterone receptor component 1 (PGRMC1) is also involved in estrogen maintenance of meiotic arrest through regulation of EGFR expression on the oocyte plasma membrane. The preovulatory surge in LH secretion induces the ovarian synthesis of progestin hormones that activate a membrane progestin receptor alpha (mPRα)/inhibitory G protein (Gi) pathway. It also increases ovarian synthesis of the catecholestrogen, 2-hydroxy-estradiol-17β (2-OHE2) which inhibits the GPER/Gs/adenylyl cyclase pathway. Both of these LH actions cause declines in oocyte cAMP levels resulting in the resumption of meiosis. GPER is also present on murine oocytes but there are no reports of studies investigating its possible involvement in maintaining meiotic arrest in mammals.
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Development of a highly sensitive in vitro system to detect and discriminate between vitamin D receptor agonists and antagonists based on split-luciferase technique
Publication date: Available online 1 November 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Hiroki Mano, Shinichi Ikushiro, Nozomi Saito, Atsushi Kittaka, Toshiyuki Sakaki
Split-luciferase techniques are widely used to detect protein-protein interaction and bioactive small molecules including some hormones and vitamins. Previously, we successfully expressed chimeric proteins of luciferase and the ligand binding domain (LBD) of the vitamin D receptor (VDR), LucC-LBD-LucN in COS-7 cells. The LucC-LBD-LucN biosensor was named split-luciferase vitamin D biosensor (SLDB). This biosensor can detect and discriminate between VDR agonists and antagonists in mammalian cells. In this study, we established an in vitro screening system for VDR ligands using the SLDB proteins expressed in Escherichia coli (E. coli) cells. Our in vitro screening system using cell lysate of recombinant E. coli cells could be completed within 30min, and its activity was unchanged after 10 freeze-thaw cycles. This highly sensitive and convenient system would be quite useful to screen VDR ligands with therapeutic potential for various bone-related diseases, age-related cognitive disorders, cancer, and immune disorders. In addition, our system might be applicable to diagnostic measurement of serum concentrations of 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3.
http://ift.tt/2iz59hU
Absence of vitamin D receptor in mature osteoclasts results in altered osteoclastic activity and bone loss.
Publication date: Available online 28 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Yolandi Starczak, Daniel C. Reinke, Kate R. Barratt, Jackson W. Ryan, René St-Arnaud, Howard A. Morris, Rachel A. Davey, Gerald J. Atkins, Paul H. Anderson
Mature osteoclasts express the vitamin D receptor (VDR) and are able to synthesise and respond to 1,25(OH)2D3 via CYP27B1 enzyme activity. Whether vitamin D signalling within osteoclasts is necessary for the regulation of osteoclastic bone resorption in an in vivo setting is unclear. To determine the requirement for the VDR- and CYP27B1-mediated activity in mature osteoclasts, conditional deletion mouse models were created whereby either Vdr or Cyp27b1 gene was inactivated by breeding either Vdrfl/fl or Cyp27b1fl/fl mice with Cathepsin K-Cre transgenic mice (CstkCre) to generate CtskCre/Vdr−/− and CtskCre/Cyp27b1−/− mice respectively. To account for potential CtskCre-meaited off-target deletion of Vdr, Dmp1Cre were also used determine the effect of Vdr deletion in osteocytes. Furthermore, CtskCre/Vdr−/− mice were ovariectomised (OVX) to assess the role of VDR in osteoclasts under bone-loss conditions and bone marrow precursor cells were cultured under osteoclastogenic conditions to assess osteoclast formation. Six-week-old CtskCre/Vdr−/− female mice demonstrated a 15% decrease in femoral BV/TV (p<0.05). In contrast, BV/TV remained unchanged in CtskCre/Cyp27b1−/− mice as well as in Dmp1Cre/VDR−/− mice. When CtskCre/Vdr−/− mice were subjected to OVX, the bone loss that occurred in CtskCre/Vdr−/− was predominantly due to a diminished volume of thinner trabeculae when compared to control levels. These changes in bone volume in CtskCre/Vdr−/− mice occurred without an observable histological change in osteoclast numbers or size. However, while cultured bone marrow-derived osteoclasts from CtskCre/Vdr−/− mice were marginally increased when compared to VDRfl/fl mice, elevated expression of genes such as Cathepsin K, Nfatc1 and VATPase was observed. Collectively, these data indicate that the absence of VDR in mature osteoclasts causes exacerbated bone loss in young mice and during OVX which is associated with enhanced osteoclastic activity and without increased osteoclastogenesis.
http://ift.tt/2h6kypv
1,25-DIHYDROXYCHOLECALCIFEROL (CALCITRIOL) MODIFIES UPTAKE AND RELEASE OF 25-HYDROXYCHOLECALCIFEROL IN SKELETAL MUSCLE CELLS IN CULTURE
Publication date: Available online 26 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): M. Abboud, M.S. Rybchyn, Y.J. Ning, T.C. Brennan-Speranza, C.M. Girgis, J.E. Gunton, D.R. Fraser, R.S. Mason
The major circulating metabolite of vitamin D3, 25-hydroxycholecalciferol [25(OH)D], has a remarkably long half-life in blood for a (seco)steroid. Data from our studies and others are consistent with the hypothesis that there is a role for skeletal muscle in the maintenance of vitamin D status. Muscle cells internalise vitamin D-binding protein (DBP) from the circulation by means of a megalin/cubilin plasma membrane transport mechanism. The internalised DBP molecules then bind to actin and thus provide an intracellular array of high affinity binding sites for its specific ligand, 25(OH)D. There is evidence that the residence time for DBP in muscle cells is short and that it undergoes proteolytic degradation, releasing bound 25(OH)D. The processes of internalisation of DBP and its intracellular residence time, bound to actin, appear to be regulated. To explore whether 1,25-dihydroxycholecalciferol (calcitriol) has any effect on this process, cell cultures of myotubes and primary skeletal muscle fibers were incubated in a medium containing 10−10M calcitriol but with no added DBP. After 3hours pre-incubation with calcitriol, the net uptake of 25(OH)D by these calcitriol-treated cells over a further 4hours was significantly greater than that in vehicle-treated control cells. This was accompanied by a significant increase in intracellular DBP protein. However, after 16hours of pre-incubation with calcitriol, the muscle cells showed a significantly depressed ability to accumulate 25(OH)D compared to control cells over a further 4 or 16hours. These effects of pre-incubation with calcitriol were abolished in fibers from VDR-knockout mice. The effect was also abolished by the addition of 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), which inhibits chloride channel opening. Incubation of C2 myotubes with calcitriol also significantly reduced retention of previously accumulated 25(OH)D after 4 or 8h. It is concluded from these in vitro studies that calcitriol can modify the DBP-dependent uptake and release of 25(OH)D by skeletal muscle cells in a manner that suggests some inducible change in the function of these cells.
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Proteomics in plasma of ovariectomized rats and those exposed to estradiol valerate
Publication date: Available online 18 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Hai Jiang, Wenpei Bai, Wenjuan Wang, Ke Wang, Jing Jia, Jing Zhang, He Diao, Lihua Qin
The menopausal period, an inevitable physiological process for women, is frequently associated with physiological and psychological dysfunction attributable to substantial fluctuation and gradual decrease in female hormones induced by ovarian failure, leading to corresponding symptoms and diseases that impact multiple systems in the body to varying degrees. As prior studies have focused primarily on menopausal syndrome-related pathophysiological changes and hormone replacement therapy effects, here we approached menopausal disease incidence risk and pathogenesis through systemic plasma proteomics analysis. Female Sprague-Dawley rats were randomly divided into sham, ovariectomized, and estrogen treatment after ovariectomy groups (n=9 per group). Tandem Mass Tag quantitative proteomics analysis of their plasma identified over 900 proteins by MS. Between group fold change of >1.2 and p<0.05 (Student's t test) identified 121 (including 36 up-regulated and 85 down-regulated), 117 (69 up-regulated and 48 down-regulated), and 109 (41 up-regulated and 68 down-regulated) differentially expressed proteins between groups, respectively. Of these, 5 (GHR, LIFR, apoA IV, RTN, and Lin28b) were verified by parallel reaction monitoring to be reliable. Further application of optimized screening criteria and performance of a series of bioinformatics analyses allowed the selection of 35 optimal differentially expressed proteins. Gene ontology annotation results suggested that the differentially expressed proteins are mainly annotated as protein binding, cell, and single organism process in terms of molecular function, cell composition, and biological process, respectively. KEGG pathway analysis indicated that the PI3-Akt pathway has the highest aggregation degree of differentially expressed proteins. Protein-protein interaction analysis noted GLUT4 as an important node protein. This research is the first to comprehensively analyze plasma protein changes, together with estrogen efficacy, in ovariectomized rats. The findings facilitate our understanding of the molecular mechanism of systemic menopausal changes and provide valuable clues for developing diagnostic biomarkers for menopausal dysfunctions and selecting clinical therapeutic strategies.
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Long-term optical imaging of neurovascular coupling in mouse cortex using GCaMP6f and intrinsic hemodynamic signals
Source:NeuroImage, Volume 165
Author(s): Xiaochun Gu, Wei Chen, Jiang You, Alan P. Koretsky, N.D. Volkow, Yingtian Pan, Congwu Du
Cerebral hemodynamics are modulated in response to changes in neuronal activity, a process termed neurovascular coupling (NVC), which can be disrupted by neuropsychiatric diseases (e.g., stroke, Alzheimer's disease). Thus, there is growing interest to image long-term NVC dynamics with high spatiotemporal resolutions. Here, by combining the use of a genetically-encoded calcium indicator with optical techniques, we develop a longitudinal multimodal optical imaging platform (MIP) that enabled time-lapse tracking of NVC over a relatively large field of view in the mouse somatosensory cortex at single cell and single vessel resolutions. Specifically, GCaMP6f was used as marker of neuronal activity, which along with MIP allowed us to simultaneously measure the changes in neuronal [Ca2+]i fluorescence, cerebral blood flow velocity (CBFv) and hemodynamics longitudinally for more than eight weeks. We show that [Ca2+]i fluorescence was detectable one week post viral injection and the damage to local microvasculature and perfusion recovered two weeks after injection. By three weeks post viral injection, maximal neuronal and CBFv responses to hindpaw stimulations were observed. Moreover, single neuronal activation in response to hindpaw stimulation was consistently recorded, followed by ∼2 s delayed dilation of contiguous microvessels. Additionally, resting-state spontaneous neuronal and hemodynamic oscillations were detectable throughout the eight weeks of study. Our results demonstrate the capability of MIP for longitudinal investigation of the organization and plasticity of the neurovascular network during resting state and during stimulation-evoked neuronal activation at high spatiotemporal resolutions.
http://ift.tt/2zA30x9
Anterior insular thickness predicts speech sound learning ability in bilinguals
Source:NeuroImage, Volume 165
Author(s): Stephen Matthew Rodriguez, Pilar Archila-Suerte, Kelly A. Vaughn, Christine Chiarello, Arturo E. Hernandez
A previous fMRI study of novel speech sound learning, tied to the methods and results presented here, identified groups of advanced and novice learners and related their classification to neural activity. To complement those results and better elucidate the role of the entire neural system in speech learning, the current study analyzed the neuroanatomical data with the goals of 1) uncovering the regions of interest (ROIs) that predicted speech learning performance in a sample of monolingual and bilingual adults, and 2) examining if the relationship between cortical thickness from selected ROIs and individual learning ability depends on language group. The ROIs selected were brain regions well-established in the literature as areas associated with language and speech processing (i.e., Transverse Superior Temporal Gyrus, anterior insula and posterior insula, all bilaterally). High-resolution brain scans (T1-weighted) were acquired from 23 Spanish-English bilinguals and 20 English monolingual adults. The thickness of the left anterior insula significantly predicted speech sound learning ability in bilinguals but not monolinguals. These results suggest that aptitude for learning a new language is associated with variations in the cortical thickness of the left anterior insula in bilinguals. These findings may provide insight into the higher order mechanisms involved in speech perception and advance our understanding of the unique strategies employed by the bilingual brain during language learning.
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Volumetric reconstruction from printed films: Enabling 30 year longitudinal analysis in MR neuroimaging
Publication date: 15 January 2018
Source:NeuroImage, Volume 165
Author(s): Michael Ebner, Karen K. Chung, Ferran Prados, M. Jorge Cardoso, Declan T. Chard, Tom Vercauteren, Sébastien Ourselin
Hospitals often hold historical MR image data printed on films without being able to make it accessible to modern image processing techniques. Having the possibility to recover geometrically consistent, volumetric images from scans acquired decades ago will enable more comprehensive, longitudinal studies to understand disease progressions. In this paper, we propose a consistent framework to reconstruct a volumetric representation from printed films holding thick single-slice brain MR image acquisitions dating back to the 1980's. We introduce a flexible framework based on semi-automatic slice extraction, followed by automated slice-to-volume registration with inter-slice transformation regularisation and slice intensity correction. Our algorithm is robust against numerous detrimental effects being present in archaic films. A subsequent, isotropic total variation deconvolution technique revitalises the visual appearance of the obtained volumes. We assess the accuracy and perform the validation of our reconstruction framework on a uniquely long-term MRI dataset where a ground-truth is available. This method will be used to facilitate a robust longitudinal analysis spanning 30 years of MRI scans.
Graphical abstract
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BOLD-fMRI in the mouse auditory pathway
Publication date: 15 January 2018
Source:NeuroImage, Volume 165
Author(s): Guilherme Blazquez Freches, Cristina Chavarrias, Noam Shemesh
The auditory pathway is widely distributed throughout the brain, and is perhaps one of the most interesting networks in the context of neuroplasticity. Accurate mapping of neural activity in the entire pathway, preferably noninvasively, and with high resolution, could be instrumental for understanding such longitudinal processes. Functional magnetic resonance imaging (fMRI) has clear advantages for such characterizations, as it is noninvasive, provides relatively high spatial resolution and lends itself for repetitive studies, albeit relying on an indirect neurovascular coupling to deliver its information. Indeed, fMRI has been previously used to characterize the auditory pathway in humans and in rats. In the mouse, however, the auditory pathway has insofar only been mapped using manganese-enhanced MRI. Here, we describe a novel setup specifically designed for high-resolution mapping of the mouse auditory pathway using high-field fMRI. Robust and consistent Blood-Oxygenation-Level-Dependent (BOLD) responses were documented along nearly the entire auditory pathway, from the cochlear nucleus (CN), through the superior olivary complex (SOC), nuclei of the lateral lemniscus (LL), inferior colliculus (IC) and the medial geniculate body (MGB). By contrast, clear BOLD responses were not observed in auditory cortex (AC) in this study. Diverse BOLD latencies were mapped ROI- and pixel-wise using coherence analysis, evidencing different averaged BOLD time courses in different auditory centers. Some degree of tonotopy was identified in the IC, SOC, and MGB in the pooled dataset though it could not be assessed per subject due to a lack of statistical power. Given the importance of the mouse model in plasticity studies, animal models, and optogenetics, and fMRI's potential to map dynamic responses to specific cues, this first fMRI study of the mouse auditory pathway paves the way for future longitudinal studies studying brain-wide auditory-related activity in vivo.
Graphical abstract
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Human torque is not present in chimpanzee brain
Source:NeuroImage, Volume 165
Author(s): Xiang Li, Timothy J. Crow, William D. Hopkins, Qiyong Gong, Neil Roberts
We searched for positional brain surface asymmetries measured as displacements between corresponding vertex pairs in relation to a mid-sagittal plane in Magnetic Resonance (MR) images of the brains of 223 humans and 70 chimpanzees. In humans deviations from symmetry were observed: 1) a Torque pattern comprising right-frontal and left-occipital "petalia" together with downward and rightward "bending" of the occipital extremity, 2) leftward displacement of the anterior temporal lobe and the anterior and central segments of superior temporal sulcus (STS), and 3) posteriorly in the position of left occipito-temporal surface accompanied by a clockwise rotation of the left Sylvian Fissure around the left-right axis. None of these asymmetries was detected in the chimpanzee, nor was associated with a sex difference. However, 4) an area of cortex with its long axis parallel to the olfactory tract in the orbital surface of the frontal lobe was found in humans to be located higher on the left in females and higher on the right in males. In addition whereas the two hemispheres of the chimpanzee brain are equal in extent in each of the three dimensions of space, in the human brain the left hemisphere is longer (p = 3.6e-12), and of less height (p = 1.9e-3), but equal in width compared to the right. Thus the asymmetries in the human brain are potential correlates of the evolution of the faculty of language.
http://ift.tt/2zAjUMf
Combining region- and network-level brain-behavior relationships in a structural equation model
Source:NeuroImage, Volume 165
Author(s): Taylor Bolt, Emily B. Prince, Jason S. Nomi, Daniel Messinger, Maria M. Llabre, Lucina Q. Uddin
Brain-behavior associations in fMRI studies are typically restricted to a single level of analysis: either a circumscribed brain region-of-interest (ROI) or a larger network of brain regions. However, this common practice may not always account for the interdependencies among ROIs of the same network or potentially unique information at the ROI-level, respectively. To account for both sources of information, we combined measurement and structural components of structural equation modeling (SEM) approaches to empirically derive networks from ROI activity, and to assess the association of both individual ROIs and their respective whole-brain activation networks with task performance using three large task-fMRI datasets and two separate brain parcellation schemes. The results for working memory and relational tasks revealed that well-known ROI-performance associations are either non-significant or reversed when accounting for the ROI's common association with its corresponding network, and that the network as a whole is instead robustly associated with task performance. The results for the arithmetic task revealed that in certain cases, an ROI can be robustly associated with task performance, even when accounting for its associated network. The SEM framework described in this study provides researchers additional flexibility in testing brain-behavior relationships, as well as a principled way to combine ROI- and network-levels of analysis.
http://ift.tt/2zncoDB
PAM50: Unbiased multimodal template of the brainstem and spinal cord aligned with the ICBM152 space
Source:NeuroImage, Volume 165
Author(s): Benjamin De Leener, Vladimir S. Fonov, D. Louis Collins, Virginie Callot, Nikola Stikov, Julien Cohen-Adad
Template-based analysis of multi-parametric MRI data of the spinal cord sets the foundation for standardization and reproducibility, thereby helping the discovery of new biomarkers of spinal-related diseases. While MRI templates of the spinal cord have been recently introduced, none of them cover the entire spinal cord. In this study, we introduced an unbiased multimodal MRI template of the spinal cord and the brainstem, called PAM50, which is anatomically compatible with the ICBM152 brain template and uses the same coordinate system. The PAM50 template is based on 50 healthy subjects, covers the full spinal cord (C1 to L2 vertebral levels) and the brainstem, is available for T1-, T2-and T2*-weighted MRI contrasts and includes a probabilistic atlas of the gray matter and white matter tracts. Template creation accuracy was assessed by computing the mean and maximum distance error between each individual spinal cord centerline and the PAM50 centerline, after registration to the template. Results showed high accuracy for both T1- (mean = 0.37 ± 0.06 mm; max = 1.39 ± 0.58 mm) and T2-weighted (mean = 0.11 ± 0.03 mm; max = 0.71 ± 0.27 mm) contrasts. Additionally, the preservation of the spinal cord topology during the template creation process was verified by comparing the cross-sectional area (CSA) profile, averaged over all subjects, and the CSA profile of the PAM50 template. The fusion of the PAM50 and ICBM152 templates will facilitate group and multi-center studies of combined brain and spinal cord MRI, and enable the use of existing atlases of the brainstem compatible with the ICBM space.
http://ift.tt/2zAWy9r
Mapping human brain lesions and their functional consequences
Source:NeuroImage, Volume 165
Author(s): Hans-Otto Karnath, Christoph Sperber, Christopher Rorden
Neuroscience has a long history of inferring brain function by examining the relationship between brain injury and subsequent behavioral impairments. The primary advantage of this method over correlative methods is that it can tell us if a certain brain region is necessary for a given cognitive function. In addition, lesion-based analyses provide unique insights into clinical deficits. In the last decade, statistical voxel-based lesion behavior mapping (VLBM) emerged as a powerful method for understanding the architecture of the human brain. This review illustrates how VLBM improves our knowledge of functional brain architecture, as well as how it is inherently limited by its mass-univariate approach. A wide array of recently developed methods appear to supplement traditional VLBM. This paper provides an overview of these new methods, including the use of specialized imaging modalities, the combination of structural imaging with normative connectome data, as well as multivariate analyses of structural imaging data. We see these new methods as complementing rather than replacing traditional VLBM, providing synergistic tools to answer related questions. Finally, we discuss the potential for these methods to become established in cognitive neuroscience and in clinical applications.
http://ift.tt/2zmCbf1
Default mode network connectivity of fear- and anxiety-related cue and context conditioning
Source:NeuroImage, Volume 165
Author(s): Francesca Zidda, Jamila Andoh, Sebastian Pohlack, Tobias Winkelmann, Ramona Dinu-Biringer, Juliana Cavalli, Michaela Ruttorf, Frauke Nees, Herta Flor
Classical fear conditioning is an important mechanism to adequately respond and adapt to environmental threats and has been related to the development of fear and anxiety. Both cue and context conditioning have been studied but little is known about their relation to relevant resting state networks. The default mode network (DMN) has been reported to be involved in affective learning and described as facilitating a state of readiness in responding to environmental changes.We examined resting state brain connectivity patterns of the default mode network (DMN) in 119 healthy volunteers. Specifically, we carried out correlation analyses between the DMN and skin conductance responses (SCRs) as well as arousal, valence and contingency ratings during learning. In addition, we examined the role of trait anxiety. Two different DMN patterns were identified in which stronger connectivity was linked to lower differential SCRs during fear and anxiety learning. One was related to cue conditioning and involved the amygdala and the medial prefrontal cortex, and one was associated with context conditioning and included the hippocampal formation and sensorimotor areas. These results were replicated in an independent sample. Functional connectivity of the DMN with these key regions at rest was also predictive of trait anxiety but this association could not be replicated in the second sample.We showed that DMN connectivity is differently associated with cued versus contextual learning mechanisms. Uncovering individual differences in baseline network connectivity of the DMN with these key regions might lead to a better understanding of fear and anxiety. Such findings could indeed help to identify vulnerability factors linked to network alterations at rest with dysregulation of learning processes involved in the pathophysiology of stress and anxiety disorders.
http://ift.tt/2zyveZb
Histological validation of diffusion MRI fiber orientation distributions and dispersion
Publication date: 15 January 2018
Source:NeuroImage, Volume 165
Author(s): Kurt G. Schilling, Vaibhav Janve, Yurui Gao, Iwona Stepniewska, Bennett A. Landman, Adam W. Anderson
Diffusion magnetic resonance imaging (dMRI) is widely used to probe tissue microstructure, and is currently the only non-invasive way to measure the brain's fiber architecture. While a large number of approaches to recover the intra-voxel fiber structure have been utilized in the scientific community, a direct, 3D, quantitative validation of these methods against relevant histological fiber geometries is lacking. In this study, we investigate how well different high angular resolution diffusion imaging (HARDI) models and reconstruction methods predict the ground-truth histologically defined fiber orientation distribution (FOD), as well as investigate their behavior over a range of physical and experimental conditions. The dMRI methods tested include constrained spherical deconvolution (CSD), Q-ball imaging (QBI), diffusion orientation transform (DOT), persistent angular structure (PAS), and neurite orientation dispersion and density imaging (NODDI) methods. Evaluation criteria focus on overall agreement in FOD shape, correct assessment of the number of fiber populations, and angular accuracy in orientation. In addition, we make comparisons of the histological orientation dispersion with the fiber spread determined from the dMRI methods. As a general result, no HARDI method outperformed others in all quality criteria, with many showing tradeoffs in reconstruction accuracy. All reconstruction techniques describe the overall continuous angular structure of the histological FOD quite well, with good to moderate correlation (median angular correlation coefficient > 0.70) in both single- and multiple-fiber voxels. However, no method is consistently successful at extracting discrete measures of the number and orientations of FOD peaks. The major inaccuracies of all techniques tend to be in extracting local maxima of the FOD, resulting in either false positive or false negative peaks. Median angular errors are ∼10° for the primary fiber direction and ∼20° for the secondary fiber, if present. For most methods, these results did not vary strongly over a wide range of acquisition parameters (number of diffusion weighting directions and b value). Regardless of acquisition parameters, all methods show improved successes at resolving multiple fiber compartments in a voxel when fiber populations cross at near-orthogonal angles, with no method adequately capturing low to moderate angle (<60°) crossing fibers. Finally, most methods are limited in their ability to capture orientation dispersion, resulting in low to moderate, yet statistically significant, correlation with histologically-derived dispersion with both HARDI and NODDI methodologies. Together, these results provide quantitative measures of the reliability and limitations of dMRI reconstruction methods and can be used to identify relative advantages of competing approaches as well as potential strategies for improving accuracy.
http://ift.tt/2znMP5v
High-alpha band synchronization across frontal, parietal and visual cortex mediates behavioral and neuronal effects of visuospatial attention
Source:NeuroImage, Volume 165
Author(s): Muriel Lobier, J. Matias Palva, Satu Palva
Visuospatial attention prioritizes processing of attended visual stimuli. It is characterized by lateralized alpha-band (8–14 Hz) amplitude suppression in visual cortex and increased neuronal activity in a network of frontal and parietal areas. It has remained unknown what mechanisms coordinate neuronal processing among frontoparietal network and visual cortices and implement the attention-related modulations of alpha-band amplitudes and behavior. We investigated whether large-scale network synchronization could be such a mechanism. We recorded human cortical activity with magnetoencephalography (MEG) during a visuospatial attention task. We then identified the frequencies and anatomical networks of inter-areal phase synchronization from source localized MEG data. We found that visuospatial attention is associated with robust and sustained long-range synchronization of cortical oscillations exclusively in the high-alpha (10–14 Hz) frequency band. This synchronization connected frontal, parietal and visual regions and was observed concurrently with amplitude suppression of low-alpha (6–9 Hz) band oscillations in visual cortex. Furthermore, stronger high-alpha phase synchronization was associated with decreased reaction times to attended stimuli and larger suppression of alpha-band amplitudes. These results thus show that high-alpha band phase synchronization is functionally significant and could coordinate the neuronal communication underlying the implementation of visuospatial attention.
http://ift.tt/2zC5Amk
Do body build and composition influence striae distensae occurrence and visibility in women?
Summary
Background
Striae have been reported to be one of the most common skin changes and a commonly encountered esthetic problem.
Objectives
To analyze risk factors of striae not associated with pregnancy and verify if body build and composition influence striae distensae (SD) occurrence and visibility.
Methods
Eighty female students (40 with striae (the mean age 23.9 years, SD 2.05 years) and 40 without these lesions (24.7 years, SD 6.2 years)) were included in the study. The subjects were asked to fill out a questionnaire including questions concerning risk factors of SD. Body build and composition were examined using Tanita SC-331S Body Composition Analyzer.
Results
Women without striae more often reported a history of intended weight loss (P < .0001), less frequently had a history of contraceptives intake (P < .001) and more often their family history of striae was negative or unknown (P = .01). Multivariate analysis including body build and composition parameters indicated BMI as risk factor of SD (P = .021; OR =1.155, 95% CI 1.006; 1.325).
Conclusions
History of contraceptives intake and a family history of striae are risk factors of SD occurrence, while weight loss can reduce the risk of these lesions. BMI appeared to be the risk factor of striae visibility, especially in abdomen, but not on the buttocks. Further clinical researches are needed to examine the pathophysiology of this condition and to inform patients about the possibility to reduce the risk of striae occurrence.
http://ift.tt/2znicgk
Κυριακή 5 Νοεμβρίου 2017
Alexithymia and problematic alcohol use: A critical update
Source:Addictive Behaviors, Volume 77
Author(s): K.E. Cruise, R. Becerra
There has been a substantial growth in empirical research aimed at examining the co-occurrence of alexithymia and problematic alcohol use and alcohol use disorder (AUD) since Thorberg, Young, Sullivan, and Lyvers (2009) original review article. The objective of the present paper is therefore to provide a critical update review of research on alexithymia and problematic alcohol use published since 2009. A systematic search was conducted through PsychINFO, Medline, and ProQuest databases to obtain relevant literature published between 2009 and 2016. Studies that involved measures of alexithymia and problematic alcohol use among clinical and non-clinical samples were included. Prevalence rates of alexithymia among Alcohol Dependent (AD) samples were identified between 30 and 49%, and were therefore much lower than originally reported. The findings of this update review highlight an indirect relationship between alexithymia and alcohol problem severity that is mediated by a number of psychological drinking constructs (e.g., alcohol expectancy, drinking motives, craving and alcohol related intrusive thoughts) and psychological risk factors for the development of alcohol related problems (e.g., mood and emotion dysregulation, attachment, trauma, and cognitive function). In addition, this review provides reasonable evidence to support alexithymia as an independent risk factor for alcohol related problems among clinical samples only. In conclusion, alexithymia is a multifaceted construct that has a complex relationship with various risk factors and psychological drinking constructs. The growing body of research highlights the demand for understanding the interrelationships between alexithymia, psychosocial risk factors, and problematic alcohol use in order to tailor and target therapeutic interventions.
http://ift.tt/2j3QQ95
Defining the phenotype of young adults with family histories of alcohol and other substance use disorders: Studies from the family health patterns project
Publication date: February 2018
Source:Addictive Behaviors, Volume 77
Author(s): Ashley Acheson, Andrea S. Vincent, Andrew J. Cohoon, William R. Lovallo
Individuals with a family history of alcohol and other drug use disorders (FH+) are at increased risk for developing substance use disorders themselves relative to those with no such histories (FH−). Here we sought to identify key characteristics associated with FH+ status and alcohol and other drug use disorder status in a large cohort of FH+ and FH− young adults.We conducted principal component analyses on demographic, temperament, and cognitive measures differentiating 506 FH+ and 528 FH− young adults. Three principal components were identified, and these component scores were then used to predict the odds of being FH+ and the odds of having an alcohol or other drug use disorder. Component 1 consisted of measures indexing internalizing traits, with higher component scores indicating greater depressive, anxious, and emotional instability tendencies. Component 2 consisted of measures of externalizing traits as well as exposure to early life adversity (ELA), with higher scores indicating less impulse control, more antisocial behavior, and greater ELA exposure. Component 3 consisted of estimated intelligence, delay discounting, and demographic characteristics, with higher scores indicating lower estimated intelligence, greater discounting of delayed rewards, less education, and lower childhood socioeconomic status. For each 1-point increase in the Component 1, 2, and 3 scores, the odds of being classified FH+ increased by 2%, 8%, and 4%, respectively. Similar findings were observed when individuals with alcohol or other drug use disorders were removed from the analyses. Finally, greater Component 2 scores were also associated with increased odds of having an alcohol or other drug use disorder. Collectively, these findings provide a more comprehensive understanding of the FH+ phenotype in young adults and help form a basis for further studies on biological mechanisms underlying risk for substance use disorders. The present findings also provide further support for a prominent role of ELA in promoting risk for problem alcohol and other drug use.
http://ift.tt/2An340o
The impact of the legalization of recreational marijuana on college students
Publication date: February 2018
Source:Addictive Behaviors, Volume 77
Author(s): Jacob Jones, K. Nicole Jones, Jenny Peil
In January of 2014 the Regulate Marijuana like Alcohol Act or, Amendment 64, went into effect in Colorado. Even though it was the first state to enact recreational legalization, attitudes towards marijuana use have been changing for decades. Prompted by medical marijuana legalization, studies have found mixed results in regards to the impact that legalization has on frequency of use and abuse. With college students having the highest rates of use in the United States (U.S.), whether legal or not, it was important to explore the impact that legalization has on this population. In the current study, rates of marijuana and alcohol use in college students before and after recreational legalization were explored. Data was collected in four waves from October 2013 to March 2015, to be able to determine the trends in marijuana and alcohol use, and relationship between the substances. In addition, grade point average was measured as a possible consequence of marijuana use. We found the frequency of marijuana use in Colorado college students is much higher than the national average t(94445)=24.424, p<0.001, especially the percentage of daily or almost daily users, t(2191)=10.373, p<0.001. There were significant differences between the marijuana non-users and the once a week or more often but not daily marijuana users in grade point average, F(6, 227)=2.935, p<0.001. In addition, it seems that the relationship between alcohol and marijuana use in general is decreasing since the passing of Amendment 64, but not among the binge drinkers.
http://ift.tt/2j6dAVD
The crop-residue of fiber hemp cv. Futura 75: from a waste product to a source of botanical insecticides
Abstract
In the attempt to exploit the potential of the monoecious fiber hemp cv. Futura 75 in new fields besides textile, cosmetics and food industry, its crop-residue given by leaves and inflorescences was subjected to hydrodistillation to obtain the essential oils. These are niche products representing an ideal candidate for the development of natural insecticides for the control and management of mosquito vectors, houseflies and moth pests. After GC-MS analysis highlighting a safe and legal chemical profile (THC in the range 0.004–0.012% dw), the leaf and inflorescence essential oils were investigated for the insecticidal potential against three insect targets: the larvae of Culex quinquefasciatus and Spodoptera littoralis and the adults of Musca domestica. The essential oil from inflorescences, showing (E)-caryophyllene (21.4%), myrcene (11.3%), cannabidiol (CBD, 11.1%), α-pinene (7.8%), terpinolene (7.6%), and α-humulene (7.1%) as the main components, was more effective than leaf oil against these insects, with LD50 values of 65.8 μg/larva on S. littoralis, 122.1 μg/adult on M. domestica, and LC50 of 124.5 μl/l on C. quinquefasciatus larvae. The hemp essential oil moderately inhibited the acetylcholinesterase (AChE), which is a target enzyme in pesticide science. Overall, these results shed light on the future application of fiber hemp crop-residue for the development of effective, eco-friendly and sustainable insecticides.
http://ift.tt/2zk5H3e
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Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
