The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood.
http://ift.tt/2eUHB9t
Παρασκευή 8 Σεπτεμβρίου 2017
Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry
Genotoxic potential of diesel exhaust particles from the combustion of first- and second-generation biodiesel fuels—the FuelHealth project
Abstract
Epidemiological data indicate that exposure to diesel exhaust particles (DEPs) from traffic emissions is associated with higher risk of morbidity and mortality related to cardiovascular and pulmonary diseases, accelerated progression of atherosclerotic plaques, and possible lung cancer. While the impact of DEPs from combustion of fossil diesel fuel on human health has been extensively studied, current knowledge of DEPs from combustion of biofuels provides limited and inconsistent information about its mutagenicity and genotoxicity, as well as possible adverse health risks. The objective of the present work was to compare the genotoxicity of DEPs from combustion of two first-generation fuels, 7% fatty acid methyl esters (FAME) (B7) and 20% FAME (B20), and a second-generation 20% FAME/hydrotreated vegetable oil (SHB: synthetic hydrocarbon biofuel) fuel. Our results revealed that particulate engine emissions from each type of biodiesel fuel induced genotoxic effects in BEAS-2B and A549 cells, manifested as the increased levels of single-strand breaks, the increased frequencies of micronuclei, or the deregulated expression of genes involved in DNA damage signaling pathways. We also found that none of the tested DEPs showed the induction of oxidative DNA damage and the gamma-H2AX-detectable double-strand breaks. The most pronounced differences concerning the tested particles were observed for the induction of single-strand breaks, with the greatest genotoxicity being associated with the B7-derived DEPs. The differences in other effects between DEPs from the different biodiesel blend percentage and biodiesel feedstock were also observed, but the magnitude of these variations was limited.
http://ift.tt/2xkJDYa
A systematic review of synthetic CT generation methodologies for use in MRI-only radiotherapy
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Emily Johnstone, Jonathan J. Wyatt, Ann M. Henry, Susan C. Short, David Sebag-Montefiore, Louise Murray, Charles G. Kelly, Hazel M. McCallum, Richard Speight
MRI offers superior soft tissue contrast as compared to CT, which is conventionally used for radiotherapy treatment planning (RTP) and patient positioning verification, resulting in improved target definition. The two modalities are co-registered for RTP, however this introduces a systematic error. Implementing an MRI-only radiotherapy workflow would be advantageous as this error would be eliminated, the patient pathway simplified and patient dose reduced. Unlike CT, in MRI there is no direct relationship between signal intensity and electron density, however various methodologies for MRI-only RTP have been reported. A systematic review of these methods was undertaken.The PRISMA guidelines(1) were followed. Embase and Medline databases were searched (1996-03/2017) for studies which generated synthetic CTs (sCT)s for MRI-only radiotherapy. 61 articles met the inclusion criteria.This review showed that MRI-only RTP techniques could be grouped into three categories: i]bulk density override ii]atlas-based and iii]voxel-based techniques, which all produce an sCT scan from MR image(s).Bulk density override techniques either used a single homogeneous or multiple tissue override. The former produced large dosimetric errors (>2%) in some cases and the latter frequently required manual bone contouring. Atlas-based techniques used both single and multiple atlases and included methods incorporating pattern recognition techniques. Clinically acceptable sCTs were reported, but atypical anatomy led to erroneous results in some cases. Voxel-based techniques included methods using routine and specialised MRI sequences, namely ultra-short echo time imaging. High quality sCTs were produced, however use of multiple sequences led to long scanning times increasing the chances of patient movement. Using non-routine sequences would currently be problematic in most radiotherapy centres.Atlas-based and voxel-based techniques were found to be the most clinically useful methods, with some studies reporting dosimetric differences of <1% between planning on the sCT and CT and <1mm deviations when using sCTs for positional verification.
http://ift.tt/2xkGkAb
IGRT strategies for pelvic lymph node irradiation in high-risk prostate cancer: motion and margins
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Lucy Kershaw, Laila van Zadelhoff, Wilma Heemsbergen, Floris Pos, Marcel van Herk
PurposeFor optimal irradiation of pelvic lymph nodes (LN) in high-risk prostate cancer, definition of margins to determine the planning target volume(s) is essential. Detailed quantification of the relative motion of the LN, seminal vesicles (SV) and prostate is currently lacking. This work aimed to quantify these motions and define margins for image-guided radiotherapy based on bony anatomy or prostate correction strategies for a 3 or 6 degrees-of-freedom couch.Material and MethodsNineteen patients had a planning CT followed by a mean of 11 repeated CTs during radiotherapy. The prostate, SV, external and internal iliac LN regions on the left and right were outlined on each CT. Systematic and random uncertainties were determined along with correlations between the motion of these regions. CTV-PTV margins required to take only motion into account were calculated for each guidance method.ResultsFor bone guidance, motion of prostate and LNs was largely uncorrelated. Margins to compensate for motion ((LR, SI, AP) in cm) based on a 3 degrees-of-freedom couch were; prostate: (0.2, 0.6, 0.8), SV: (0.4, 0.9, 1.0) and LN: (0.3, 0.4, 0.6). For prostate guidance, margins were calculated for correlated motion; prostate: (0, 0, 0), SV: (0.3, 0.5, 0.4) and LN: (0.3, 0.5, 0.9). For a 6 degrees-of-freedom couch, these margins were; prostate: (0.2, 0.6, 0.8), SV: (0.3, 0.9, 1.0) and LN: (0.3, 0.4, 0.3) for bone guidance. For prostate guidance, margins were; prostate: (0, 0, 0), SV: (0.2, 0.5, 0.4) and LN: (0.3, 0.6, 0.6)ConclusionsImage-guided radiotherapy based on bony anatomy requires larger prostate and SV margins, and guidance on prostate requires larger LN margins. Neither guidance strategy is optimal, and a combination of the two, or treatment adaption after a number of fractions might be preferable. Calculation of the total margin should also include delineation uncertainties.
Teaser
Definition of margins to determine the optimal image-guided radiotherapy (IGRT) strategy for pelvic lymph node irradiation is essential in high-risk prostate cancer. In this work, these margins were derived from systematic and random motions measured using repeated CT scans in 19 patients, based on matching to either bony anatomy or prostate for a 3 or 6 degrees-of-freedom (DOF) couch. When matching to bony anatomy, margins were smaller for lymph nodes than when matching to prostate, but larger for prostate and seminal vesicles. The prostate and seminal vesicle margins were unchanged when using a 3 vs 6 DOF couch, but lymph node margins were smaller in the anterior-posterior direction.http://ift.tt/2gQCvI7
Subcutaneous implant-based breast reconstruction, a modern challenge in post mastectomy radiation planning
Source:Practical Radiation Oncology
Author(s): Melissa P. Mitchell, Jamie Wagner, James Butterworth
As survival rates for breast cancer continue to improve, there has been increasing interest in reducing toxicity of therapy. In the field of breast surgery, we have seen advancements in the surgical approach from total mastectomy to skin and nipple sparing mastectomy. Nodal surgery has also been significantly impacted by a "less is more" approach, sparing patients with healthy lymph nodes the side effect of axillary lymph node dissection by performing sentinel lymph node dissection to accurately assess the draining nodal basin. More recently, there have been increasing reports of techniques to improve options for reconstruction. A growing trend has been use of acellular dermal matrix (ADM). This has been reported to improve cosmesis and reduce the number of surgical procedures required to obtain desired aesthetic results. Additionally, there have been increasing reports of use of prepectoral ADM covered implants. As compared to traditional methods of using submuscular tissue expanders, devices placed in the prepectoral plane have been reported to reduce animation deformities and postoperative pain. There is also the benefit that muscular function will be preserved with a subcutaneous expander. Furthermore, there is a growing push for single stage procedures made possible through the use of ADM. This benefits the patient by subjecting them to less operations and benefits the health care system by decreasing health care costs, as compared to multiple stage surgeries.
http://ift.tt/2gRQVvs
Factors Associated with Fatigue in Prostate Cancer (PC) Patients Undergoing External Beam Radiation Therapy (EBRT)
Source:Practical Radiation Oncology
Author(s): Hann-Hsiang Chao, Abigail Doucette, David M. Raizen, Neha Vapiwala
PurposeFatigue is a common adverse effect among cancer patients undergoing external beam radiation therapy (EBRT), yet the underlying disease- and treatment-related factors influencing its development are poorly understood. We hypothesized that clinical, demographic, and treatment-related factors differentially affect fatigue and aimed to better characterize variables related to fatigue development in prostate cancer (PC) patients during EBRT.MethodsWe identified a 681 patient cohort with non-metastatic PC undergoing a 6–9week EBRT course. Patient fatigue scores (range 0–3) were prospectively recorded by providers during treatment visits using standardized criteria. Clinical and demographic factors including age, race, EBRT details, disease staging, smoking status, comorbidities, urinary symptoms, employment status, weight, and concurrent medication use were assessed for their relationship to fatigue levels. Significant differences in fatigue severity by each variable at the beginning and end of EBRT were assessed by non-parametric-means testing, and differences in the level of fatigue increase over the treatment course were assessed using an ordered logistic regression model.ResultsSignificant increases in reported fatigue severity were seen in patients with: age<60years (p=0.006), depressive symptoms (p<0.001) and use of androgen deprivation therapy prior to radiation start (p=0.04). In addition, the prescription of antiemetics prior to radiation start was associated with reduced fatigue severity (p=0.03).ConclusionsWe identify factors associated with increased (young age, depressive symptoms, androgen deprivation therapy) and decreased (antiemetic prescription) fatigue in a large cohort of PC patients receiving EBRT. Continued investigation is needed to further elucidate clinical drivers and biological underpinnings of increased fatigue to guide potential interventions.
http://ift.tt/2vMBUxe
HPV related Nasopharyngeal and Cervical Cancer in a Married Couple in North America
Source:Practical Radiation Oncology
Author(s): Daniel B. Vanderbilt, Quoc-Anh Ho, Uma Goyal, Robert C. Bell, Robert R. Klein, Sun K. Yi
http://ift.tt/2vMgBw4
Pancreatic injury in children: a case report and review of the literature
Trauma is the main cause of morbidity and mortality in the pediatric population. Blunt trauma to the abdomen accounts for the majority of abdominal injuries in children. Pancreatic injury, although uncommon (2...
http://ift.tt/2wR46k3
Plasma-rich plasma, the ultimate secret for youthful skin elixir and hair growth triggering
Summary
The clinical application of platelet-rich plasma (PRP) is based on the increase in the concentration of growth factors that are released from alpha-granule of the concentrated platelets and in the secretion of proteins which are able to capitalize on the healing process at the cellular level. It has been invented to restore the natural beauty by starting the natural rejuvenation process of the skin and aiming to make it function as a younger one and to keep the skin youthful and maintain it. Besides that, it is also emerged to include hairs as a new injectable procedure to enable stimulating hair growth locally and topically; preventing its fall; improving hair shaft, hair stem, and its caliber; increasing its shine, vitality, and pliability; and declining hair splitting and breakage. Thus, youth is in your blood as it has a magical power imposed in the platelet factors. There is, however, no standardization of the techniques besides insufficient description of the adopted procedures. Not long, autologous platelet-rich plasma (PRP) has surfaced strongly in diverse medical specialties including plastic, wound healing and diabetic ulcers, orthopedic, trauma, ocular surgery, dry eye for eyelid injection, urology for urinary incontinence, sexual wellness, cutaneous surgery, sport medicine, dentistry and dermatology, and aesthetic applications. PRP proved to promote wound healing and aid in facelift, volumetric skin, skin rejuvenation, regeneration, and reconstruction; improve wrinkling; stimulate hair growth; increase hair follicle viability and its survival rate; prevent apoptosis; increase and prolong the anagen hair growth stage; and delay the progression to catagen hair cycle stage with increased density in hair loss and hair transplantation. The aims of this extensive review were to cover all PRP application aspects that are carried out in aesthetic dermatology and to assess the literature on platelet-rich plasma outcomes on main aesthetic practices of general dermatology. A literature review was conducted by searching through PubMed, Biomedical Library database, Google Scholar, and Research Gate for the terms PRP, platelet-rich plasma, platelet-rich fibrin matrix, platelet preparations, platelet application therapy, platelet growth factors, platelet facial, platelet facial rejuvenation, platelet hairs, and platelet wound healing, from inception till 2017, and they were combined using Boolean operators. All those retrieved articles in English language were looked at and explored thoroughly.
http://ift.tt/2wPy9Kt
Seasonally-induced alterations of some facial signs in Caucasian women. Impact of a daily application of a photo-protective product
Abstract
Objectives
These were two-fold: i) to record through standardized pictures, the possible changes in 14 facial signs induced, in a 6-month period, by the periodical shift from winter to summer in a group of 42 Caucasian women residing in Paris and ii) to appraise the preventive effects of a strong photo-protective product, daily applied to their face by an additional group (N=40) of women of same age-range and presenting same severities of facial signs in winter.
Methods
Facial signs (structural and pigmentation-related) were graded in blind by a panel of 12 experts from photographs taken under standard conditions. Grading was performed under specific scales as previously published. A global and focused analysis of the skin colour or dark spots, when present, was carried out through spectro-radiometry under diffuse and standardized visible light, using the L*, a*, b* referential system.
Results
The unprotected group showed significant changes in summer as compared to winter on 10 facial signs (2/3 of the studied signs) that presented an increased severity, of variable respective amplitude. 5 signs among the 10 were particularly and significantly affected by the seasonal transition, of an amplitude above the precision of the grading scale. Three of these 5 signs concerned structural elements (wrinkles), the two others being related to vascular disorders (redness). These season-induced alterations appear efficiently alleviated in the photo-protected group. The colour of the facial skin then appears more homogeneous, less red, less dull, all criteria being quantified by the L*, a*, b* referential system. The comparison with a previous work carried out on Chinese women, through a similar protocol, shows that the photo-protective product brings, in Caucasian women, a more important effect upon structural and vascular features than upon pigmentation disorders, inversely to the results previously observed in Chinese women.
Conclusion
The alterations in some facial signs occurring in a 6-month period between winter and summer are confirmed in Caucasian women, mostly related to structural (wrinkles) and vascular elements. Such changes appear alleviated or prevented by daily applications of a strong sun photo-protective product.
This article is protected by copyright. All rights reserved.
http://ift.tt/2wPQfft
Plasma-rich plasma, the ultimate secret for youthful skin elixir and hair growth triggering
Summary
The clinical application of platelet-rich plasma (PRP) is based on the increase in the concentration of growth factors that are released from alpha-granule of the concentrated platelets and in the secretion of proteins which are able to capitalize on the healing process at the cellular level. It has been invented to restore the natural beauty by starting the natural rejuvenation process of the skin and aiming to make it function as a younger one and to keep the skin youthful and maintain it. Besides that, it is also emerged to include hairs as a new injectable procedure to enable stimulating hair growth locally and topically; preventing its fall; improving hair shaft, hair stem, and its caliber; increasing its shine, vitality, and pliability; and declining hair splitting and breakage. Thus, youth is in your blood as it has a magical power imposed in the platelet factors. There is, however, no standardization of the techniques besides insufficient description of the adopted procedures. Not long, autologous platelet-rich plasma (PRP) has surfaced strongly in diverse medical specialties including plastic, wound healing and diabetic ulcers, orthopedic, trauma, ocular surgery, dry eye for eyelid injection, urology for urinary incontinence, sexual wellness, cutaneous surgery, sport medicine, dentistry and dermatology, and aesthetic applications. PRP proved to promote wound healing and aid in facelift, volumetric skin, skin rejuvenation, regeneration, and reconstruction; improve wrinkling; stimulate hair growth; increase hair follicle viability and its survival rate; prevent apoptosis; increase and prolong the anagen hair growth stage; and delay the progression to catagen hair cycle stage with increased density in hair loss and hair transplantation. The aims of this extensive review were to cover all PRP application aspects that are carried out in aesthetic dermatology and to assess the literature on platelet-rich plasma outcomes on main aesthetic practices of general dermatology. A literature review was conducted by searching through PubMed, Biomedical Library database, Google Scholar, and Research Gate for the terms PRP, platelet-rich plasma, platelet-rich fibrin matrix, platelet preparations, platelet application therapy, platelet growth factors, platelet facial, platelet facial rejuvenation, platelet hairs, and platelet wound healing, from inception till 2017, and they were combined using Boolean operators. All those retrieved articles in English language were looked at and explored thoroughly.
http://ift.tt/2wPy9Kt
Assessing the potential role of next generation tyrosine kinase inhibitors in the treatment of cancers with acquired kinase domain mutations
Past few decades have seen the gradual replacement of standard cytotoxic therapy with molecular therapeutics, as the former was associated with significant general cell loss. Although molecular targeted therapies had proven to be highly effective, the duration of treatment efficacy is challenged by the growing resistance of cancer cells. The tyrosine kinase receptors are one of the better explored molecular targets in oncology. Cancer-positive for tyrosine kinase fusion genes has been targeted effectively with tyrosine kinase inhibitors (TKI).
http://ift.tt/2jd4HcM
Downregulation of FOXP3 inhibits cell proliferation and enhances chemosensitivity to cisplatin in human lung adenocarcinoma
Publication date: Available online 8 September 2017
Source:Pathology - Research and Practice
Author(s): Chun Li, Liwei Sun, Rui Jiang, Peng Wang, Haogang Xue, Yudong Zhan, Xiaodong Gai
Our study aimed to investigate the biological role of FOXP3 expression in human lung adenocarcinoma (LAD) tissues and evaluate its involvement in cell proliferation and chemosensitivity to cisplatin in LAD cells. Paraffin-embedded tissues from 50 LAD patients were collected to detect FOXP3 and Ki-67 expression using immunohistochemistry (IHC). Downregulation of FOXP3 in A549 cells was performed using siRNA transfection. Real-time PCR or western blot assay was performed to analyze FOXP3 expression in A549 cells. Cell proliferation and cisplatin cytotoxicity test were assessed by CCK-8 assay. The expression of FOXP3 was significantly associated with lymph node metastasis and TNM stage of LAD patients. The FOXP3 expression was positively correlated with Ki-67 labelling index(LI)in LAD tissues. The downregulated expression of FOXP3 by siRNA transfection significantly inhibited cell proliferation and enhanced chemosensitivity to cisplatin in A549 cells. The expression of FOXP3 was significantly upregulated following cisplatin treatment in A549 cells. Our study indicates that FOXP3 may potentially be a novel molecular target in combating drug resistance in the chemotherapy of LAD.
http://ift.tt/2xSM8gh
Calibration of a lactic-acid model for simulating biofilm-induced degradation of the dentin-composite interface
Source:Dental Materials
Author(s): Laikuan Zhu, Yuping Li, Carola A. Carrera, Yung-Chung Chen, Mingyu Li, Alex Fok
ObjectiveTo verify and calibrate a chemical model for simulating the degradation of the dentin-composite interface induced by multi-species oral biofilms in vitro.MethodsDentin-composite disks (5-mm dia.×2-mm thick) were made from bovine incisor roots and filled with either Z100™ (Z100) or Filtek™ LS (LS) composite. The disks, which were covered with nail varnish, but with one of the dentin-composite margins exposed, were immersed in lactic acid solution at pH 4.5 for up to 48h. Diametral compression was performed to measure the reduction in bond strength of the dentin-composite disks following acid challenge. Scanning electron microscopy (SEM) was used to examine decalcification of dentin and fracture modes of the disks. To better understand the degradation process, micro-computed tomography, in combination with a radiopaque dye (AgNO3), was used to assess interfacial leakage in 3D longitudinally, while SEM was used to determine the path of leakage. One-way analysis of variance (ANOVA) was used to analyze the results, with the level of statistical significance set at p<0.05. The results were compared with those obtained previously using multi-species biofilms for verification and calibration purposes.ResultsAfter 48h of acid challenge, the debonding load of both the LS- and Z100-filled disks reduced significantly (p<0.05). In the Z100-filled disks, debonding mostly occurred at the adhesive-dentin interface, while in the LS-filled disks, this happened at the adhesive-composite interface, instead. The degree of dentin demineralization, the reduction in debonding load and the modes of failure observed were very similar to those induced by multi-species oral biofilms found in the previous work. Leakage of AgNO3 occurred mainly along the hybrid layer. The specimens filled with Z100 had a thicker hybrid layer (∼6.5μm), which exhibited more interfacial leakage than those filled with LS.SignificanceThe chemical model with lactic acid used in this study can induce degradation to the dentin-composite interface similar to those produced by multi-species biofilms. With appropriate calibration, this could provide an effective in vitro method for ageing composite restorations in assessing their potential clinical performance.
http://ift.tt/2wP5fLw
IGF system targeted therapy: therapeutic opportunities for ovarian cancer
Source:Cancer Treatment Reviews
Author(s): J.A.L. Liefers-Visser, R.A.M. Meijering, A.K.L. Reyners, A.G.J. van der Zee, S. de Jong
The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential.
http://ift.tt/2jcLlV8
Extracellular vesicles from oral squamous carcinoma cells display pro- and antiangiogenic properties
Abstract
Background
A new intercellular communication mode established by neoplastic cells and tumor microenvironment components is based on extracellular vesicles (EVs). However, the biological effects of the EVs released by tumor cells on angiogenesis are not completed understood. Here we aimed to understand the biological effects of EVs isolated from two cell lines of oral squamous cell carcinoma (OSCC) (SCC15 and HSC3) on endothelial cell tubulogenesis.
Methods
OSCC-derived EVs were isolated with a polymer-based precipitation method, quantified using nanoparticle tracking analysis and verified for EV markers by dot-blot. Functional assays were performed to assess the angiogenic potential of the OSCC-derived EVs.
Results
The results showed that EVs derived from both cell lines displayed typical spherical-shaped morphology and expressed the EV markers CD63 and Annexin II. Although the average particle concentration and size were quite similar, SCC15-derived EVs promoted a pronounced tubular formation associated with significant migration and apoptosis rates of the endothelial cells, whereas EVs derived from HSC3 cells inhibited significantly endothelial cell tubulogenesis and proliferation.
Conclusion
The findings of this study reveal that EVs derived from different OSCC cell lines by a polymer-based precipitation method promote pro- or antiangiogenic effects.
This article is protected by copyright. All rights reserved.
http://ift.tt/2vUtTdT
Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain
Objective
Prenatal androgen exposure has been suggested to play a role in polycystic ovary syndrome. Given the limited information on what maternal characteristics influence maternal testosterone levels, and the even less explored routes by which female fetus androgen exposure would occur, the aim of this study was to investigate the impact of maternal age, BMI, weight gain, depressed mood and aromatase SNPs on testosterone levels in maternal serum and amniotic fluid of female fetuses.
MethodsBlood samples from pregnant women (n = 216) obtained in gestational weeks 35–39, and pre-labor amniotic fluid samples from female fetuses (n = 56), taken at planned Caesarean section or in conjunction with amniotomy for induction of labor, were analyzed. Maternal serum testosterone and amniotic fluid testosterone and cortisol were measured by tandem mass spectrometry.
ResultsMultiparity (β = –0.28, P < 0.001), self-rated depression (β = 0.26, P < 0.001) and weight gain (β = 0.18, P < 0.05) were independent explanatory factors for the maternal total testosterone levels. Maternal age (β = –0.34, P < 0.001), weight gain (β = 0.19, P < 0.05) and amniotic fluid cortisol levels (β = 0.44, P < 0.001) were independent explanatory factors of amniotic fluid testosterone in female fetuses, explaining 64.3% of the variability in amniotic fluid testosterone.
Wider implications of the findingsYoung maternal age and excessive maternal weight gain may increase the prenatal androgen exposure of female fetuses. Further studies are needed to explore this finding.
http://ift.tt/2xk0Hxm
Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency
Background
It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC).
Aims and methodsTo explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation.
ResultsMedian pre- and post-hCG testosterone for the overall group was 0.7 nmol/L (<0.5, 6) and 7.9 nmol/L (<0.5, 31.5), respectively. Of the 12 boys, 3 (25%) did not respond to hCG stimulation with a pre and post median serum testosterone of <0.5 nmol/L and <0.5 nmol/L, respectively. When corrected for gene expression changes in the non-responders to exclude hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR-37153 and piR-39248, non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5. On comparing fold-change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 (P = 0.01).
ConclusionsThe identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency.
http://ift.tt/2gPNTEj
MANAGEMENT OF ENDOCRINE DISEASE: Suicide risk in patients with diabetes: a systematic review and meta-analysis
Background
Previous studies investigating the risk of suicide in diabetes patients reported controversial findings. We did a systematic review and meta-analysis to comprehensively estimate the risk and incidence rate of suicide in diabetic patients.
MethodsPubMed, EMBASE and PsycINFO were searched for eligible studies. Random-effects meta-analysis was used to calculate the relative risk (RR) and the incidence rate of suicide in diabetes patients. We also calculated the proportion of deaths attributable to suicide among diabetes patients.
Results54 studies were finally included, including 28 studies on the suicide risk associated with diabetes, 47 studies on the incidence rate of suicide and 45 studies on the proportion of deaths attributable to suicide. Meta-analysis showed that diabetes could significantly increase the risk of suicide (RR = 1.56; 95% CI: 1.29–1.89; P < 0.001). Subgroup analysis showed that the RR of suicide associated with type 1 diabetes was 2.25 (95% CI: 1.50–3.38; P < 0.001). The pooled incidence rate of suicide in patients with diabetes was 2.35 per 10 000 person-years (95% CI: 1.51–3.64). The pooled proportions of long-term deaths attributable to suicide in type 1 diabetes patients and type 2 diabetes patients were 7.7% (95% CI: 6.0–9.8) and 1.3% (95% CI: 0.6–2.6), respectively.
ConclusionThis meta-analysis suggests that diabetes can significantly increase the risk of suicide. Suicide has an obvious contribution to mortality in diabetic patients, especially among type 1 diabetes patients. Effective strategies to decrease suicide risk and improve mental health outcomes in diabetes patients are needed.
http://ift.tt/2xkTU6E
Childhood thyroid function, body composition and cardiovascular function
Objective
The cardiovascular system is a known target for thyroid hormone. Early-life cardiovascular alterations may lead to a higher risk of cardiovascular disease in adulthood. Little is known about the effects of thyroid hormone on cardiovascular function during childhood, including the role of body composition in this association.
DesignPopulation-based prospective cohort of children (n = 4251, median age 6 years, 95% range: 5.7–8.0 years).
MethodsThyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured to assess thyroid function. Left ventricular (LV) mass was assessed with echocardiography. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (CFPWV). Systolic and diastolic blood pressure (BP) was measured. Body composition was assessed by dual-energy X-ray absorptiometry scan.
ResultsFT4 was inversely associated with LV mass (P = 0.002), and with lean body mass (P < 0.0001). The association of FT4 with LV mass was partially mediated through variability in lean body mass (55% mediated effect). TSH was inversely associated with LV mass (P = 0.010), predominantly in boys. TSH was positively associated with systolic and diastolic BP (both P < 0.001). FT4 was positively associated with CFPWV and diastolic BP (P < 0.0001, P = 0.008, respectively), and the latter association attenuated after adjustment for CFPWV.
ConclusionsAt the age of 6 years, higher FT4 is associated with lower LV mass (partially through effects on lean body mass) and with higher arterial stiffness, which may lead to higher BP. Our data also suggest different mechanisms via which TSH and FT4 are associated with cardiovascular function during early childhood.
http://ift.tt/2gQnwxL
DIAGNOSIS OF ENDOCRINE DISEASE: Diagnostic approach to TSH-producing pituitary adenoma
Thyrotropin (TSH)-secreting adenomas (TSHomas) are the rarest form of pituitary adenomas, and most endocrinologists will see few cases in a lifetime, if any. In most cases, the diagnostic approach is complicated and cases may be referred after being presented as a syndrome of inappropriate TSH secretion or as a pituitary mass. This review aims to cover the past, present and possible future diagnostic approaches to TSHomas, including different clinical presentations, laboratory assessment and imaging advances. The differential diagnoses will be discussed, as well as possible coexisting disorders. By evaluating the existing reports and reviews describing this rare condition, this review aims to present a clinically practical suggestion on the diagnosic workup for TSHomas, Major advances and scientific breakthroughs in the imaging area in recent years, facilitating diagnosis of TSHomas, support the belief that future progress within the imaging field will play an important role in providing methods for a more efficient diagnosis of this rare condition.
http://ift.tt/2xk0z0Q
Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma
Objective
Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic–pituitary–adrenal axis in patients with ACC receiving mitotane.
Design and methodsWe prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test.
ResultsWe demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04–275.00) vs 24.53 (6.16–121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32–275.00) vs 67.43 (8.8–179.52) pmol/L P = 0.016).
ConclusionsThe observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.
http://ift.tt/2gQL1qF
MANAGEMENT OF ENDOCRINE DISEASE: L-Thyroxine replacement therapy in the frail elderly: a challenge in clinical practice
The number of elderly people, mostly aged over 85 years (the 'oldest old'), is increasing worldwide. As a consequence, accompanying morbidity and disability have been increasing, and frailty, defined as an age-related condition of decline of physiological reserves and vulnerability, represents an emerging problem. Caring for older frail people may represent a challenge, since the elderly differ significantly from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions. Specific criteria of therapeutic appropriateness and modified goals of care are needed in such patients, also in endocrine care settings. Indeed, thyroid dysfunctions are among the most common conditions in older, multimorbid populations. The prevalence of overt and subclinical hypothyroidism is as high as 20% and thyroid hormone prescription is common in the elderly, with a trend toward levothyroxine treatment of more marginal degrees of hypothyroidism. In addition, older patients have the highest rate of overtreatment during replacement therapy and are more susceptible to developing adverse effects from thyroid hormone excess. Recently, results of a multicentric randomized controlled trial, the TRUST–IEMO collaboration trial, added further insights to the debated question of whether and when levothyroxine treatment is required and if it is beneficial in the elderly. With this in mind, we revised the relevant literature on the impact of thyroid dysfunction and replacement therapy among older people, with the aim to better define indications, benefits and risks of l-T4 replacement therapy in the frail elderly.
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MECHANISMS IN ENDOCRINOLOGY: Towards the clinical translation of stem cell therapy for type 1 diabetes
Insulin-producing cells derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) have for long been a promising, but elusive treatment far from clinical translation into type 1 diabetes therapy. However, the field is now on the verge of moving such insulin-producing cells into clinical trials. Although stem cell therapies provide great opportunities, there are also potential risks such as teratoma formation associated with the treatment. Many considerations are needed on how to proceed with clinical translation, including whether to use hESCs or iPSCs, and whether encapsulation of tissue will be needed. This review aims to give an overview of the current knowledge of stem cell therapy outcomes in animal models of type 1 diabetes and a proposed road map towards the clinical setting with special focus on the potential risks and hurdles which needs to be considered. From a clinical point of view, transplantation of insulin-producing cells derived from stem cells must be performed without immune suppression in order to be an attractive treatment option. Although costly and highly labour intensive, patient-derived iPSCs would be the only solution, if not clinically successful encapsulation or tolerance induction protocols are introduced.
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Independent and opposite associations of serum levels of omentin-1 and adiponectin with increases of glycaemia and incident type 2 diabetes in an older population: KORA F4/FF4 study
Objective
Cross-sectional studies found that higher levels of the novel adipokine omentin-1 were associated with higher adiponectin and lower levels of risk factors for type 2 diabetes, but its relevance for incident type 2 diabetes is currently not understood. Therefore this study investigated whether serum omentin-1 was associated with changes in glycaemia and incident type 2 diabetes independently of adiponectin.
Design and methodsThe study was based on participants aged 62–81 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort. Associations of baseline serum levels of omentin-1 and adiponectin with changes in glycaemia were assessed in 471 non-diabetic participants, and associations between both adipokines and incident type 2 diabetes were assessed in 76 cases and 430 non-cases (follow-up time 6.5 years). Multivariable linear and logistic regression models were adjusted for multiple potential confounders.
ResultsHigher serum levels of omentin-1 were associated with increases in fasting glucose, 2-h glucose and HbA1c (all P < 0.001) and with incident type 2 diabetes (adjusted odds ratio (OR) (95% CI): 1.40 (1.03; 1.90) per s.d. of log2-transformed omentin-1; P = 0.032). These associations were independent from adiponectin levels, which showed associations with changes in glycaemia and risk of type 2 diabetes in the opposite direction. We found no statistically significant interactions of omentin-1 with adiponectin or sex in the association with incident type 2 diabetes (all P > 0.1).
ConclusionsSystemic levels of omentin-1 were positively associated with increases in glycaemia and incident type 2 diabetes in this older population. These associations were independent of potential confounders including adiponectin.
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Natural history of autoimmune primary ovarian insufficiency in patients with Addisons disease: from normal ovarian function to overt ovarian dysfunction
Context
Women with autoimmune Addison's disease with normal ovulatory cycles but positive for steroid cell antibodies (StCA) have been considered at risk of premature ovarian insufficiency (POI).
DesignThirty-three women younger than 40 years, with subclinical-clinical autoimmune Addison's disease but with normally ovulatory menses, were followed up for 10 years to evaluate the long-term time-related variations of StCA, ovarian function and follicular reserve. All patients and 27 control women were investigated at the start and every year for the presence and titre of StCA (by indirect immunofluorescence), serum concentrations of anti-Mullerian hormone (AMH) and ovarian function at four consecutive menses every year.
ResultsAt the start of the study StCA were present in 16 women (group 1), at low/middle titres (≤1:32) in seven of them (43.8%, group 1A), at high titres (>1:32) in the remaining nine patients (group 1B, 56.2%), while they were absent from 17 patients (group 2). During the follow-up period, all women in group 1A remained StCA-positive at low/middle titres with normal ovulatory menses and normal gonadotrophin and AMH levels, while all patients in group 1B showed a further increase of StCA titres (1:128–1:256) and progressed through three stages of ovarian function. None of the patients in group 2 and controls showed the appearance of StCA or ovarian dysfunction during the follow-up.
ConclusionsThe presence of StCA at high titres can be considered a good predictive marker of subsequent development of autoimmune POI. To single out the stages of autoimmune POI may allow a timely therapeutic choice in the subclinical and early clinical stages.
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Adrenal insufficiency is seen in more than one-third of patients during ongoing low-dose prednisolone treatment for rheumatoid arthritis
Objective
Patients receiving long-term glucocorticoid treatment are at risk of developing adrenal insufficiency during treatment. We investigated the prevalence of prednisolone-induced adrenal insufficiency in the particular clinical situation where patients receive ongoing low-dose (5 mg/day) prednisolone treatment, a dose by itself too low to cover glucocorticoid needs during stress.
Design and methodsCross-sectional study in 42 patients with rheumatoid arthritis (29 women, aged 36–86 years) treated with 5 mg prednisolone/day, who had received prednisolone for ≥6 months (median: 66, range: 6–444 months). Adrenal function was evaluated by a 250 μg Synacthen test performed after mean 48.7 h prednisolone pause. Local assay-specific cut-off for normal adrenal function was P-cortisol ≥420 nmol/L 30 min after Synacthen injection.
ResultsOverall, 20 of the 42 patients (48%, 95% CI: 33–62%) had an insufficient adrenal response to the Synacthen test. Including only patients who had not received concomitant treatment with any other glucocorticoid formulas within the last 3 months, 13 of 33 patients (39%, 95% CI: 25–56%) had an insufficient response. Adrenocorticotrophic hormone (ACTH) concentrations were generally low and anti-adrenal antibodies were negative indicating secondary adrenal insufficiency as the most likely diagnosis. There was no correlation between duration of treatment and 30 min P-cortisol (P = 0.62). Adrenal function did not depend on sex or seropositivity of rheumatoid arthritis.
ConclusionWe demonstrate a high prevalence of adrenal insufficiency during ongoing low-dose prednisolone treatment. The results urge to increase focus on the condition to ensure identification and correct management of insufficient patients during stress and withdrawal. Strategies for adrenal function evaluation during ongoing low-dose glucocorticoid treatment need to be established.
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The association of autoimmune thyroid disease (AITD) with psoriatic disease: a prospective cohort study, systematic review and meta-analysis
Objective
Autoimmune thyroid disease (AITD) and psoriatic disease share auto-immunological components. Few studies have investigated the link between both, yielding inconclusive results.
DesignWe assessed the association of AITD with psoriatic disease in a prospective cohort study and performed a systematic review and meta-analysis.
Methods8214 participants of the Rotterdam Study (RS) with thyroid peroxidase antibodies (TPO-Abs), thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and information on psoriatic disease were included. We performed logistic and Cox regression analyses and a systematic literature search in several electronic databases on AITD and psoriatic disease. We pooled odds ratios (ORs) of included studies using the Mantel-Haenszel method, while adding RS data on prevalent psoriatic disease.
ResultsWithin the RS, we found no association between TPO-Ab positivity and psoriatic disease. There was a positive trend between TSH and prevalent psoriatic disease, and between FT4 and incident psoriatic disease, although not significant. Out of 1850 articles identified, seven were included in the systematic review and four in the meta-analysis. The risk of psoriatic disease (pooled OR) was 1.71 (confidence interval (CI): 1.27–2.31) for TPO-Ab positivity, 1.25 (CI: 1.14–1.37) for AITD and 1.34 (CI: 1.16–1.54) respectively, and 1.17 (CI: 1.03–1.32) for hypothyroidism and hyperthyroidism.
ConclusionsOur meta-analysis suggests that TPO-Ab positivity, hypothyroidism and hyperthyroidism might be associated with prevalent psoriatic disease. However, there are only few studies with large heterogeneity regarding psoriatic disease definition and indication of publication bias. Additional prospective data are needed to assess the association of AITD with incident psoriatic disease.
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Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer
Context
Thyroid hormones modulate proliferative, metabolic and angiogenic pathways. However few studies have examined associations of thyroid hormones with cancer risk.
ObjectivesTo explore associations of thyrotropin (TSH), free thyroxine (FT4) and anti-thyroperoxidase antibodies (TPOAb) with the incidence of all (non-skin) cancers and specific common cancers.
Design and settingA prospective cohort study of a community-dwelling population aged 25–84 years in Western Australia.
Main outcome measuresArchived sera from 3649 participants in the 1994/1995 Busselton Health Survey were assayed for TSH, FT4 and TPOAb. Cancer outcomes until 30 June 2014 were ascertained using data linkage. Longitudinal analyses were performed using Cox proportional hazards regression.
ResultsDuring 20-year follow-up, 600 participants were diagnosed with non-skin cancer, including 126, 100, 103 and 41 prostate, breast, colorectal and lung cancers respectively. Higher TSH was associated with a lower risk of prostate cancer after adjusting for potential confounders, with a 30% lower risk for every 1 mIU/L increase in TSH (adjusted hazard ratio (HR): 0.70, 95% confidence interval (CI): 0.55–0.90, P = 0.005). Similarly, higher FT4 was associated with an increased risk of prostate cancer (adjusted HR: 1.11 per 1 pmol/L increase, 95% CI: 1.03–1.19, P = 0.009). There were no associations of TSH, FT4 or TPOAb with all non-skin cancer events combined, or with breast, colorectal or lung cancer.
ConclusionIn a community-dwelling population, lower TSH and higher FT4 were associated with an increased risk of prostate cancer. Further studies are required to assess if thyroid function is a biomarker or risk factor for prostate cancer.
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Birth defects after use of antithyroid drugs in early pregnancy: a Swedish nationwide study
Objective
Antithyroid drugs (ATDs) may have teratogenic effects, but more evidence is needed on the risk and types of birth defects after the use of methimazole (MMI) and propylthiouracil (PTU). This study aimed to evaluate the association between the use of ATDs in early pregnancy and birth defects.
DesignSwedish nationwide register-based cohort study.
MethodsThe study included 684 340 children live-born in Sweden from 2006 to 2012. Exposure groups defined by maternal ATD use in early pregnancy were MMI (n = 162); PTU (n = 218); MMI and PTU (n = 66); ATD before or after, but not in pregnancy (n = 1551) and non-exposed (never ATD (n = 682 343)). Outcome was cumulative incidence of birth defects diagnosed before two years of age.
ResultsThe cumulative incidence of birth defects was not significantly different in children exposed to MMI (6.8%, P = 0.6) or PTU (6.4%, P = 0.4) vs non-exposed (8.0%). For subtypes of birth defects, MMI was associated with an increased incidence of septal heart defects (P = 0.02). PTU was associated with ear (P = 0.005) and obstructive urinary system malformations (P = 0.006). A case of choanal atresia was observed after exposure to both MMI and PTU. The incidence of birth defects in children born to mothers who received ATD before or after, but not in pregnancy, was 8.8% and not significantly different from non-exposed (P = 0.3), MMI exposed (P = 0.4) or PTU exposed (P = 0.2).
ConclusionsMMI and PTU were associated with subtypes of birth defects previously reported, but the frequency of ATD exposure in early pregnancy was low and severe malformations described in the MMI embryopathy were rarely observed.
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Axitinib treatment in advanced RAI-resistant differentiated thyroid cancer (DTC) and refractory medullary thyroid cancer (MTC)
Background
Axitinib, an antiangiogenic multikinase inhibitor (MKI), was evaluated in the compassionate use programme (CUP) in Spain (October 2012–November 2014).
Subjects and Methods47 patients with advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC, n = 34) or medullary thyroid cancer (MTC, n = 13) with documented disease progression were treated with axitinib 5 mg b.i.d. The primary efficacy endpoint was objective response rate (ORR) by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Progression-free survival (PFS) and adverse events (AEs) were secondary objectives. Regulatory authorities validated the CUP, and all patients signed informed consent form.
ResultsAxitinib was administered as first-line therapy in 17 patients (36.2%), as second-line in 18 patients (38.3%) and as third/fourth-line in 12 patients (25.5%). With a median follow-up of 11.5 months (0–24.3), ORR was 27.7% (DTC: 29.4% and MTC: 23.1%) and median PFS was 8.1 months (95% CI: 4.1–12.2) (DTC: 7.4 months (95% CI: 3.1–11.8) and MTC: 9.4 months (95% CI: 4.8–13.9)). Better outcomes were reported with first-line axitinib, with an ORR of 53% and a median PFS of 13.6 months compared with 16.7% and 10.6 months as second-line treatment. Twelve (25.5%) patients required dose reduction to 3 mg b.i.d. All-grade AEs included asthenia (53.2%), diarrhoea (36.2%), hypertension (31.9%) and mucositis (29.8%); grade 3/4 AEs included anorexia (6.4%), diarrhoea (4.3%) and cardiac toxicity (4.3%).
ConclusionAxitinib had a tolerable safety profile and clinically meaningful activity in refractory and progressive thyroid cancer regardless of histology as first-line therapy. To our knowledge, this is the first time that cross-resistance between MKIs is suggested in thyroid cancer, highlighting the importance of prospective sequential clinical studies.
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Analysis of genetic and clinical characteristics of a Chinese Kallmann syndrome cohort with ANOS1 mutations
Objective
To analyze ANOS1 gene mutations in a large Chinese Kallmann syndrome (KS) cohort and to characterize the clinical presentation of the disease in patients with ANOS1 mutations.
Patients and methodsChinese patients with KS, including 187 sporadic and 23 pedigree cases were recruited. Patients' ANOS1 gene sequences were analyzed by direct sequencing of PCR-amplified products. In silico analysis was used to assess functional relevance of newly identified missense mutations. Patients' clinical characteristics were analyzed retrospectively.
Result(s)Fifteen nonsynonymous rare ANOS1 variants were found in 13 out of 187 sporadic and 8 out of 23 familial IHH probands. Seven novel (C86F, C90Y, C151W, Y379X, c.1062 + 1G > A, Y579L fs 591X, R597X) and eight recurrent ANOS1 mutations (S38X, R257X, R262X, R423X, R424X, V560I, c.1843-1G > A, p.R631X) were identified. All the novel mutations were predicted to be pathogenic. The prevalence of cryptorchidism was high (38.1%) and occurred in patients with different kind of ANOS1 mutations, while the patients with the same mutation did not present with cryptorchidism uniformly.
Conclusion(s)The prevalence of ANOS1 gene mutations is low in sporadic KS patients, but is much higher in familial KS patients. In the present study, we identify seven novel ANOS1 mutations, including two mutations in the CR domain, which are probably pathogenic. These mutations expand the ANOS1 mutation spectrum and provide a foundation for prenatal diagnosis and genetic counseling.
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Variation of the epidermal expression of glucocorticoid receptor-beta as potential predictive marker of bullous pemphigoid outcome
Abstract
Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease in Western countries. Although topical and/or systemic glucocorticoids treatment efficacy is widely recognized, up to 30% of patients with BP may undergo a relapse during the first year of treatment. We investigated the protein expression of the total glucocorticoid receptor and GRβ isoform in the skin biopsy specimens from patients with BP, and wondered whether such investigation at baseline provided a tool to predict disease outcome. Total GR and GRβ protein expressions were detected by immunohistochemistry at baseline on 12 patients who later relapse and 11 patients who remained on remission in comparison with 14 control patients. The expression of GRβ in the epidermis of patients with BP who later relapse was significantly higher than that in the epidermis of patients with BP controlled upon corticosteroid treatment, which was also higher than control patients. Thus, our results suggest that increased protein expression of GRβ in skin epithelial cells is predictive of reduced steroid treatment efficacy, and therefore of increased risk of disease relapse in patients with BP.
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Monitoring UV-induced signaling pathways in an ex vivo skin organ culture model using phospho-antibody array
Abstract
We investigated UV-induced signaling in an ex vivo skin organ culture model using phospho-antibody array. Phosphorylation modulations were analyzed in time-course experiments following exposure to solar-simulated UV and validated by western blot analyses. We found that UV induced P-p38 and its substrates, P-ERK1/2 and P-AKT which were previously shown to be upregulated by UV in cultured keratinocytes and in vivo human skin. This indicates that phospho-antibody array applied to ex vivo skin organ culture is a relevant experimental system to investigate signaling events following perturbations. Since the identified proteins are components of pathways implicated in skin tumorigenesis, UV-exposed skin organ culture model could be used to investigate the effect on these pathways of NMSC cancer drug candidates. In addition, we found that phospho-HCK is induced upon UV exposure, producing a new candidate for future studies investigating its role in the skin response to UV and UV-induced carcinogenesis.
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Activation of NLRP3 signaling accelerates skin wound healing
Abstract
The process of skin wound healing involves the following three steps: inflammation, tissue formation, and tissue remodeling. These optimal steps are required for the development of normal wound healing. Recent reports demonstrated that inflammasomes are involved in the innate immune response. In the present study, we examined whether the activation of inflammasomes affects the process of skin wound repair. The skin wound repair model was established using wild-type (WT), NACHT, LRR and PYD domains-containing protein 3 (NALP3) knockout (KO) and ASC-KO mice. The wounds were observed every other day and changes in wound size over time were calculated using photography. Wound repair in NALP3-KO and ASC-KO mice was significantly impaired compared with WT mice. Isoliquiritigenin, an inhibitor of NALP3, decreased the rate of wound repair in WT mice. mRNA expression of pro-inflammatory cytokines in the wound sites of NALP3-KO mice was markedly decreased compared with WT mice. Treatment with adenosine triphosphate (ATP), a ligand of NALP3, up-regulated the mRNA expression of pro-inflammatory cytokines at the wound site and accelerated wound healing in the WT mice. Scratch assay revealed that ATP accelerated wound closure in mouse embryonic fibroblasts from WT mice but not from NALP3-KO mice. In conclusion, the present study demonstrated that NALP3 pathway activation is involved in wound repair, and the topical use of ATP may be useful as an effective treatment for accelerating wound healing.
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Human Tissue Inhibitor of Metalloproteinases-1 Improved Wound Healing in Diabetes through Its Anti-apoptotic Effect
Abstract
Impaired wound healing accompanies severe cell apoptosis in diabetic patients. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) was known to have effects on promoting growth and anti-apoptosis for cells. we aimed to determine the actual levels of TIMP-1 and cell apoptosis in: 1) the biopsies of diabetic and non-diabetic foot tissue; 2) the human fibroblasts with or without treatments of Advanced Glycation End Products (AGEs). Next, in both human fibroblasts and the animal model of diabetic rats, to determine the improved levels of cell apoptosis and wound healing after the treatments of either active protein of TIMP-1 or in vivo expression of gene therapy vector-mediated TIMP-1. The levels of TIMP-1 were significantly reduced in diabetic skin tissues and in AGEs-treated fibroblasts. Both AGEs-treated cells were effectively protected from apoptosis by active protein of TIMP-1 at appropriate dose level. So did the induced in vivo TIMP-1 expression after gene delivery. Similar effects were also found on the significant improvement of impaired wound healing in diabetic rats. We concluded that TIMP-1 improved wound healing through its anti-apoptotic effect. Treatments with either active protein TIMP-1 or TIMP-1 gene therapy delivered in local wound sites may be used as a strategy for accelerating diabetic wound healing.
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Evidence for a contributory role of a xenogeneic immune response in experimental epidermolysis bullosa acquisita
Abstract
Autoimmune diseases affect a large fraction of the population in Western countries. To elucidate the underlying causes, autoantibody transfer-induced mouse models have been established that greatly contributed to the understanding of the pathophysiology of these diseases. However, the role of a potentially co-occurring murine xenogeneic immune response to commonly utilized rabbit anti-mouse IgG remains poorly understood. Using the established rabbit anti-mouse type VII collagen (COL7) IgG-induced mouse model of the mucocutaneous blistering disorder epidermolysis bullosa acquisita (EBA), we found in this study a profound T and B cell response along with an altered cytokine expression profile in draining lymph nodes of mice injected with the xenogeneic IgG. This was associated with the formation of circulating and skin-bound mouse anti-rabbit IgG in wild-type but not CD154-deficient or B-cell deficient JHT mice challenged with pathogenic rabbit IgG. Development of EBA skin lesions was attenuated in the two mouse strains lacking a B cell response at later observation time points, but was not affected in mice treated with the T cell trafficking blocker FTY720. Collectively, our results implicate a host's xenoreactive immune response to rabbit anti-mouse COL7 IgG, a confounding effect that may contribute to immune complex-driven inflammation and tissue damage in this antibody transfer-induced EBA mouse model, especially at later time points. In this regard, it may be recommended to finish the evaluation of results obtained by experiments employing antibody-transferred mouse models within the first 2 weeks after the pathogenic antibody injection.
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Ultrasonic Characteristics and Cellular Properties of Anabaena Gas Vesicles
Source:Ultrasound in Medicine & Biology
Author(s): Yaoheng Yang, Zhihai Qiu, Xuandi Hou, Lei Sun
Ultrasound imaging is a common modality in clinical examination and biomedical research, but has not played a significant role in molecular imaging for lack of an appropriate contrast agent. Recently, biogenic gas vesicles (GVs), naturally formed by cyanobacteria and haloarchaea, have exhibited great potential as an ultrasound molecular imaging probe with a much smaller size (∼100 nm) and improved imaging contrast. However, the basic acoustic and biological properties of GVs remain unclear, which hinders future application. Here, we studied the fundamental acoustic properties of a rod-shaped gas vesicle from Anabaena, a kind of cyanobacterium, including attenuation, oscillation resonance, and scattering, as well as biological behaviors (cellular internalization and cytotoxicity). We found that GVs have two resonance peaks (85 and 120 MHz). We also observed a significant non-linear effect and its pressure dependence as well. Ultrasound B-mode imaging reveals sufficient echogenicity of GVs for ultrasound imaging enhancement at high frequencies. Biological characterization also reveals endocytosis and non-toxicity.
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Pancreatic injury in children: a case report and review of the literature
Trauma is the main cause of morbidity and mortality in the pediatric population. Blunt trauma to the abdomen accounts for the majority of abdominal injuries in children. Pancreatic injury, although uncommon (2...
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Neuroendocrine mechanisms underlying bariatric surgery - insights from human studies and animal models
Abstract
Obesity has reached epidemic proportions and to date, bariatric surgery remains the only effective treatment for morbid obesity in terms of its capacity to achieve durable weight loss. Bariatric surgery procedures, including Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB) and sleeve gastrectomy (SG) have been the primary procedures conducted over the past decade, with SG increasing in popularity over the past five years at the expense of both RYGB and AGB. Although these procedures were initially proposed to function via restrictive or malabsorptive mechanisms, it is now clear that profound physiological changes underlie the metabolic improvements in patients who undergo bariatric surgery. Data generated in human patients and animal models highlights the rapid and sustained changes in gut hormones that coincide with these procedures. Furthermore, recent studies highlight the involvement of the nervous system, specifically the vagus nerve, in mediating the reduction in appetite and food intake following bariatric surgery. What is unclear is where these pathways converge and interact within the gut-brain axis and whether vagally-mediated circuits are sufficient to drive the metabolic sequalae following bariatric surgery.
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The Hypothalamic Regulation of Metabolic Adaptations to Exercise
Abstract
Our modern lifestyle is characterized by easy access to nutrient dense foods combined with limited physical activity. A sedentary lifestyle is one of several factors that have contributed to the global obesity epidemic and also predisposes to chronic illnesses such as diabetes and cardiovascular disease. While many studies have focused on the benefits of exercise in peripheral tissues, the contributions of the central nervous system to these exercise-induced metabolic adaptations are relatively unknown. This review will highlight the role of the ventromedial hypothalamus (VMH) in regulating the metabolic response to exercise.
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Berberine suppresses LPS-induced inflammation through modulating Sirt1/NF-κB signaling pathway in RAW264.7 cells
Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Hao Zhang, Yun Shan, Yun Wu, Chuanchong Xu, Xizhong Yu, Juan Zhao, Jing Yan, Wenbin Shang
Chronic inflammation is a major contributing factor in the pathogenesis of many diseases. Natural product berberine (BBR) exhibits potent anti-inflammatory effect in vitro and in vivo, while the underlying mechanisms remain elusive. Sirt1, a NAD+-dependent protein deacetylase, was recently found to play an important role in modulating the development and progression of inflammation. Thus, we speculate that Sirt1 might mediate the inhibitory effect of BBR on inflammation. In LPS-stimulated RAW264.7 macrophages, BBR treatment significantly downregulated the expression of proinflammatory cytokines such as MCP-1, IL-6 and TNF-α. Importantly, BBR potently reversed LPS-induced down-regulation of Sirt1. Consistently, the inhibitory effects of BBR on proinflammatory cytokines expression was largely abrogated by Sirt1 inhibition either by EX527, a Sirt1 inhibitor or Sirt1 siRNA. Further mechanistic studies revealed that BBR-induced inhibition of NF-κB is Sirt1-dependent, as either pharmacologically or genetically inactivating Sirt1 enhanced the IκΒα degradation, IKK phosphorylation, NF-κB p65 acetylation and DNA-binding activity. Taken together, our results provide the first evidence that BBR potently suppressed inflammatory responses in macrophages through inhibition of NF-κB signaling via Sirt1-dependent mechanisms.
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Mincle inhibits neutrophils and macrophages apoptosis in A. fumigatus keratitis
Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Jing Lin, Kun He, Guiqiu Zhao, Cui Li, Liting Hu, Guoqiang Zhu, Yawen Niu, Guipei Hao
PurposeTo determine whether macrophage inducible C-type lectin (Mincle) regulates neutrophils and macrophages apoptosis in A. fumigatus keratitis.Materials and methodsA murine model (C57BL/6) of fungal keratitis (AF) was established by gently scraping corneal central epithelium, smearing A. fumigatus on the epithelium surface and covering the eye with contact lenses. AF cell model was established by extracting neutrophils (PMN) and macrophages, and then infecting cells with A. fumigatus. Animals and cells were randomly divided into control and A. fumigatus keratitis group, which were treated with Mincle ligand Trehalose-6,6-dibehenate (TDB), Mincle neutralizing antibody (MincleAb) or PBS before infection. The cornea infection was monitored using a slit lamp and further analyzed using H&E assay. PCR, Western blot, immunostaining, TUNEL staining and flow cytometry were used to examine the expression of Mincle and apoptosis factors, PMN infiltration and cell apoptosis, respectively.ResultsHigher levels of Mincle mRNA and protein, as well as epithelial thickness and presence of inflammatory cells in the stroma, were observed in the AF group compared to control. In addition, higher Mincle mRNA levels were observed in normal and stimulated neutrophils and macrophages. Furthermore, Fas, FasL and CASP3 mRNA levels, neutrophils infiltration rate and TUNEL-positive cells were significantly increased in AF+MincleAb mice compared with the control. Similar results, as well as significantly higher neutrophils and macrophages apoptosis, were observed by treating cells with MincleAb in vitro. Most importantly, opposite results i.e. lower mRNA levels, neutrophils infiltration rate and TUNEL-positive cells, as well as lower cell apoptosis in vitro, were observed in mice and cells treated with TDB.ConclusionMincle-participated in inflammatory process which inhibits neutrophils and macrophages apoptosis induced by A. fumigatus involved in Fas-dependent apoptotic pathways.
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Anti-inflammatory and antioxidant potential of Guaianolide isolated from Cyathocline purpurea: Role of COX-2 inhibition
Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Urmila U. Tambewagh, Amit D. Kandhare, Varsha S. Honmore, Parag P. Kadam, Vijay M. Khedkar, Subhash L. Bodhankar, Supada R. Rojatkar
BackgroundInflammation activated by oxidative stress can cause various diseases, such as asthma, rheumatoid arthritis, cancer, diabetes, etc. Plant constituents with sesquiterpene lactones possess antioxidant and anti-inflammatory properties.AimTo determine the antioxidant and anti-inflammatory potential of isolated phytoconstituent from Cyathocline purpurea Buch-Ham ex D (CP). Don in laboratory animals. Furthermore, to understand the interactions involved in the binding of this compound to cyclooxygenase-2 (COX-2) via computational docking.MethodsPhytoconstituent was isolated, purified and well characterized (using IR, NMR, and MS) from ethyl acetate fraction of CP methanolic extract. It was then evaluated for its in-vitro antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2) and hydroxyl (OH) radical assays as well as in-vivo anti-inflammatory potential against carrageenan-induced paw edema model in rats. The molecular docking study was performed against the crystal structure of COX-2 to evaluate the binding potential of phytoconstituent towards this enzyme.ResultsThe isolated compound 6α-hydroxy-4 [14], 10 [15]-guainadien-8α, 12-olide (HGN) showed significant (p<0.001) antioxidant activity with IC50 values of 76μg/mL. Administration of HGN (10 and 20mg/kg) significantly (p<0.001) reduced the increased paw volume after subplantar administration of carrageenan. It also exhibits good binding affinity towards with COX-2 with a docking score of −8.98 and Glide binding energy of −36.488kcal/mol shedding light on the potential mechanism of anti-inflammatory action.ConclusionsThe presence of hydroxyl group in HGN provides a credential to its in-vivo anti-inflammatory and in-vitro antioxidant activities. Furthermore, the good binding affinity of HGN for the active site of COX-2 may open novel vistas in therapeutic option with natural antioxidants like Cyathocline purpurea to treat various inflammatory disorders.
http://ift.tt/2xSKJ9L
A comprehensive approach to evaluating and classifying sun-protective clothing
Abstract
Background
National standards for clothing designed to protect the wearer from the harmful effects of solar ultraviolet radiation (UVR) have been implemented in Australia/New Zealand, Europe, and the USA. Industry standards reflect the need to protect the skin by covering a considerable proportion of the potentially exposed body surface area (BSA) and by reducing UVR-transmission through fabric (the Ultraviolet Protection Factor; UPF).
Objectives
This research aimed to develop a new index for rating sun-protective clothing that incorporates the BSA coverage of the garment in addition to the UPF of the fabric.
Methods
A mannequin model was fixed to an optical bench and marked with horizontal lines at 1 cm intervals. An algorithm (the Garment Protector Factor; GPF) was developed based on the number of lines visible on the clothed versus unclothed mannequin and the UPF of the garment textile. This data was collected in 2015-16 and analysed in 2016.
Results
The GPF weights fabric UPF by BSA coverage above the minimum required by international sun-protective clothing standards for upper-body, lower-body and full-body garments. GPF increases with BSA coverage of the garment and fabric UPF. Three nominal categories are proposed for the GPF: 0 ≤ GPF < 3 for garments that 'meet' minimum standards; 3 ≤ GPF < 6 for garments providing 'good' sun-protection; and GPF ≥ 6 indicating 'excellent' protection.
Conclusions
Adoption of the proposed rating scheme should encourage manufacturers to design sun-protective garments that exceed the minimum standard for BSA coverage, with positive implications for skin cancer prevention, consumer education and sun-protection awareness.
This article is protected by copyright. All rights reserved.
http://ift.tt/2xSGIC1
A comprehensive approach to evaluating and classifying sun-protective clothing
Abstract
Background
National standards for clothing designed to protect the wearer from the harmful effects of solar ultraviolet radiation (UVR) have been implemented in Australia/New Zealand, Europe, and the USA. Industry standards reflect the need to protect the skin by covering a considerable proportion of the potentially exposed body surface area (BSA) and by reducing UVR-transmission through fabric (the Ultraviolet Protection Factor; UPF).
Objectives
This research aimed to develop a new index for rating sun-protective clothing that incorporates the BSA coverage of the garment in addition to the UPF of the fabric.
Methods
A mannequin model was fixed to an optical bench and marked with horizontal lines at 1 cm intervals. An algorithm (the Garment Protector Factor; GPF) was developed based on the number of lines visible on the clothed versus unclothed mannequin and the UPF of the garment textile. This data was collected in 2015-16 and analysed in 2016.
Results
The GPF weights fabric UPF by BSA coverage above the minimum required by international sun-protective clothing standards for upper-body, lower-body and full-body garments. GPF increases with BSA coverage of the garment and fabric UPF. Three nominal categories are proposed for the GPF: 0 ≤ GPF < 3 for garments that 'meet' minimum standards; 3 ≤ GPF < 6 for garments providing 'good' sun-protection; and GPF ≥ 6 indicating 'excellent' protection.
Conclusions
Adoption of the proposed rating scheme should encourage manufacturers to design sun-protective garments that exceed the minimum standard for BSA coverage, with positive implications for skin cancer prevention, consumer education and sun-protection awareness.
This article is protected by copyright. All rights reserved.
http://ift.tt/2xSGIC1
Hepatoprotective effects of crocin on biochemical and histopathological alterations following acrylamide-induced liver injury in Wistar rats
Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Sema Gedik, Mehmet Erman Erdemli, Mehmet Gul, Birgul Yigitcan, Harika Gozukara Bag, Zeynep Aksungur, Eyup Altinoz
The objective of the present study is the treatment of oxidative damage caused by acrylamide induced oxidative stress in rats with the administration of a strong antioxidant, namely crocin. High acrylamide (AA) levels have genotoxic, carcinogenic and neurotoxic effects on living organisms. In the present study, 40 Wistar rats were randomly divided into four equal groups. These groups were control, acrylamide (25mg/kg), crocin (50mg/kg), acrylamide+crocin (25mg/kg acrylamide and 50mg/kg crocin) groups. At the end of the application, biochemical and histological variations were examined in liver and blood samples. It was observed that acrylamide administration significantly decreased liver GSH and TAS levels when compared to the control group. On the contrary, it was also observed that AST, ALT, ALP, SOD and CAT activities and TOS and MDA levels increased as a result of acrylamide administration. Histopathological examinations demonstrated inflammatory cell infiltration, hepatocellular necrosis and hemorrhage areas in AA group liver sections. Furthermore, intracytoplasmic vacuolization was detected in hepatocytes. After crocin treatment, it was observed that GSH and TAS levels increased while AST, ALT, ALP, SOD and CAT activities and TOS and MDA levels decreased. Significant decreases were observed in inflammatory cell infiltration and vascular congestion in liver sections and intracytoplasmic vacuolization in hepatocytes after the crocin treatment, while no hepatocellular necrosis and hemorrhages were observed. In the present study, it was demonstrated that crocin treatment removed acrylamide induced liver damage due to the strong antioxidant properties of crocin.
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Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats
Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Norsharina Ismail, Maznah Ismail, Nur Hanisah Azmi, Muhammad Firdaus Abu Bakar, Zhang Yida, Maizaton Atmadini Abdullah, Hamidon Basri
Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-β (Aβ) accumulation due to abnormal amyloid-β precursor protein (APP) processing and Aβ metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Aβ metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis. Despite the neuropharmacological attributes of black cumin seed (Nigella sativa) extracts and its main active compound, thymoquinone (TQ), limited records are available in relation to AD research. Nanoemulsion (NE) is exploited as drug delivery systems due to their capacity of solubilising non-polar active compounds and is widely examined for brain targeting. Herewith, the effects of thymoquinone-rich fraction nanoemulsion (TQRFNE), thymoquinone nanoemulsion (TQNE) and their counterparts' conventional emulsion in response to high fat/cholesterol diet (HFCD)-induced rats were investigated. Particularly, the Aβ generation; APP processing, β-secretase 1 (BACE1), γ-secretases of presenilin 1 (PSEN1) and presenilin 2 (PSEN2), Aβ degradation; insulin degrading enzyme (IDE), Aβ transportation; low density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) were measured in brain tissues. TQRFNE reduced the brain Aβ fragment length 1–40 and 1–42 (Aβ40 and Aβ42) levels, which would attenuate the AD pathogenesis. This reduction could be due to the modulation of β- and γ-secretase enzyme activity, and the Aβ degradation and transportation in/out of the brain. The findings show the mechanistic actions of TQRFNE in response to high fat and high cholesterol diet associated to Aβ generation, degradation and transportation in the rat's brain tissue.
Graphical abstract
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MicroRNA-20a participates in the aerobic exercise-based prevention of coronary artery disease by targeting PTEN
Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Dongwei Wang, Yi Wang, Juan Ma, Wenping Wang, Bingbing Sun, Tengfei Zheng, Ming Wei, Yangli Sun
BackgroundExercise can reduce the coronary artery disease (CAD) incidence. MiRNA-20a has been reported to distinctly expressed after sustain physical activity. However, its expression and regulation pattern in CAD model with or without exercise has not been reported.ObjectiveIn present study, we aim to investigate regulatory mechanism of miR-20a in exercise-associated reduced-CAD incidence and miR-20a-dependent signaling pathways.MethodsEight weeks old male ApoE/LDLR double knock out mice were recruited for this study. CAD model was established in mice fed with or without western diet and cholesterol levels were measured using detection kit as well as fast protein liquid chromatography. Relative mRNA levels were determined using quantitative RT-PCR while the protein levels were analyzed using western blotting. Luciferase assay was used to determine the miRNA binding site on target genes. CCK-8 assay and flow cytometry (FCM) were used for assessing the proliferative and apoptotic rate.ResultsOverall cholesterol level was significantly increased in CAD model group, compared to normal control group. Expression of miR-20 was significantly lower in CAD group where the VEGF and PTEN were upregulated, compared to non-CAD group. Increased miR-20a was induced after exercise in CAD model group, and miR-20a agomir group. Overexpression of miR-20a decreased the expression level of ET-1, TxA2, ANGII, PTEN and increased the eNOS, PGI2, and VEGF, at both transcriptional and translational levels. In vitro examination further confirmed these findings in human umbilical vein endothelial cells (HUVEC). MiR-20a specifically binds to the 3′UTR of PTEN and mediated the cell survival and proliferation through activating the PI3K/Akt signaling pathways.ConclusionMiRNA-20a may have great potential as therapeutic target for CAD, since its participation can induce alteration of functional genes as well as PTEN, which is specifically targeted by miR-20a, and promote the survival and proliferation of vein endothelial cells.
http://ift.tt/2xSucmb
Triptolide suppresses growth and hormone secretion in murine pituitary corticotroph tumor cells via NF-kappaB signaling pathway
Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Ran Li, Zhuo Zhang, Junwen Wang, Yiming Huang, Wei Sun, Ruifan Xie, Feng Hu, Ting Lei
Triptolide is a principal diterpene triepoxide from the Chinese medical plant Tripterygium wilfordii Hook. f., whose extracts have been utilized in dealing with diverse diseases in traditional Chinese medicine for centuries. Recently, the antitumor effect of triptolide has been found in several pre-clinical neoplasm models, but its effect on pituitary corticotroph adenomas has not been investigated so far. In this study, we are aiming to figure out the antitumor effect of triptolide and address the underlying molecular mechanism in AtT20 murine corticotroph cell line. Our results demonstrated that triptolide inhibited cell viability and colony number of AtT20 cells in a dose- and time-dependent pattern. Triptolide also suppressed proopiomelanocortin (Pomc) mRNA expression and extracellular adrenocorticotropic hormone (ACTH) secretion in AtT20 cells. Flow cytometry prompted that triptolide leaded to G2/M phase arrest, apoptosis program and mitochondrial membrane depolarization in AtT20 cells. Moreover, dose-dependent activation of caspase-3 and decreased Bcl2/Bax proportion were observed after triptolide treatment. By western blot analysis we found that triptolide impeded phosphorylation of NF-κB p65 subunit and extracellular signal-regulated kinase (ERK), along with reduction of cyclin D1, without any impact on other NF-κB related protein expression like total p65, p50, IκB-α, p-IκB-α. Furthermore, the mouse xenograft model revealed the inhibition of tumor growth and hormone secretion after triptolide administration. Altogether this compound might be a potential pharmaceutical choice in managing Cushing's disease.
Graphical abstract
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Risk of exclusion from stroke rehabilitation in the oldest-old
Publication date: Available online 7 September 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Paola Forti, Fabiola Maioli, Elisabetta Magni, Letizia Regazzoni, Roberto Piperno, Marco Zoli, Maura Coveri, Gaetano Procaccianti
ObjectiveTo investigate whether oldest-old age (≥85 yr) is an independent predictor of exclusion from stroke rehabilitation.DesignRetrospective cohort study.SettingStroke Unit (SU) of an Italian tertiary hospital.Participants1055 elderly patients (age 65-74 yr, n=230; age, 75-84 yr, n=432; age ≥ 85 yr, n=393), who, between 2009 and 2012, were admitted to SU with acute stroke and evaluated by a multiprofessional team for access to rehabilitation. The study excluded patients for whom rehabilitation was unnecessary or inappropriate.InterventionsNot applicable.Main Outcome MeasuresAccess to an early mobilization (EM) protocol during SU stay and subsequent access to post-acute rehabilitation after SU discharge. Analyses were adjusted for prestroke and stroke-related characteristics.Results32.2% of patients were excluded from EM. Multivariable-adjusted Odds Ratio (OR) of EM exclusion was 1.30 (95% CI: 0.76, 2.21) for age 75-84 yr and 2.07 (95% CI: 1.19, 3.59) for age ≥85 yr compared to age 65-74 yr. Of 656 patients admitted to EM and who, at SU discharge, had not yet fully recovered their prestroke functionally status, 18.4% were excluded from post-acute rehabilitation. For patients able to walk unassisted at SU discharge, probability of exclusion did not change across age groups. For patients unable to walk unassisted at SU discharge, OR of exclusion from post-acute rehabilitation was 3.74 (95% CI: 1.26, 11.13) for age 75-84 yr and 9.15 (95% CI: 3.05, 27.46) for age ≥85 yr compared to age 65-74 yr.ConclusionOldest-old age is an independent predictor of exclusion from stroke rehabilitation.
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The link between Parkinson’s disease and rapid eye movement sleep behavior disorder with dream enactment: Possible implications for early rehabilitation
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Brian P. Johnson, Kelly P. Westlake
The purpose of this paper is twofold. First, to inform readers of the link between the loss of motor inhibition during rapid eye movement (REM) sleep dreaming, diagnosed as REM sleep behavior disorder (RBD), and the future onset of neurodegenerative disorders, such as Parkinson's Disease and dementia with lewy bodies. It has been reported that motor disinhibition during rapid eye movement sleep often precedes onset of these disorders by years or even decades. Second, to consider that identification of RBD and the early involvement of rehabilitation and/or development of home exercise plans may aid in prolonging and even increasing function, independence, and quality of life should such neurodegenerative disorders develop later in life.
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Masthead
Source:Archives of Physical Medicine and Rehabilitation, Volume 98, Issue 9
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Editorial Board
Source:Archives of Physical Medicine and Rehabilitation, Volume 98, Issue 9
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Table of Contents
Source:Archives of Physical Medicine and Rehabilitation, Volume 98, Issue 9
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Anti-inflammatory effect of Astaxanthin in phthalic anhydride-induced atopic dermatitis animal model
Abstract
In this study, we investigated anti-dermatitic effects of Astaxanthin (AST) in phthalic anhydride (PA)-induced atopic dermatitis (AD) animal model as well as in vitro model. AD-like lesion was induced by the topical application of 5% PA to the dorsal skin or ear of Hos:HR-1 mouse. After AD induction, 100 μl of 1 mg/ml and 2 mg/ml of AST (10 μg or 20 μg/cm2) was spread on the dorsum of ear or back skin three times a week for four weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor-κB (NF-κB) activity. We also measured tumor necrosis factor- α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and immunoglobulinE (IgE) concentration in the blood of AD mice by enzyme-linked immunosorbent assay (ELISA). AST treatment attenuated the development of PA-induced AD. Histological analysis showed that AST inhibited hyperkeratosis, mast cells and infiltration of inflammatory cells. AST treatment inhibited expression of iNOS and COX-2, and NF-κB activity as well as release of TNF-α, IL-1β, IL-6, and IgE. In addition, AST (5, 10, and 20μM) potently inhibited lipopolysaccharide (LPS) (1 μg/ml)-induced nitric oxide (NO) production, expression of iNOS and COX-2, and NF-κB DNA binding activities in RAW 264.7 macrophage cells. Our data demonstrated that AST could be a promising agent for AD by inhibition of NF-κB signaling.
This article is protected by copyright. All rights reserved.
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Editors' Selections From This Issue: Volume 98 / Number 9 / September 2017
Source:Archives of Physical Medicine and Rehabilitation, Volume 98, Issue 9
http://ift.tt/2eMjlmd
CD8+ lineage dendritic cells determine adaptive immune responses to inflammasome activation upon sterile skin injury
Abstract
The molecular links between sterile inflammation and induction of adaptive immunity have not been fully identified. Here, we examine how damage associated molecular patterns (DAMPs), as opposed to pathogen associated molecules (PAMPs), regulates the immune response to non-self-antigens presented at the site of the physical injury. Heat applied briefly to the skin invokes sterile inflammation, characterised by local cell death and caspase-1 activation without demonstrably disrupting skin integrity. Co-delivery of ovalbumin (OVA) with heat injury induces OVA-specific CD8+ T cell responses and this is dependent on caspase-1 activation and MyD88 signalling. Using Id2flox/flox-CD11cCre+ mice, we demonstrate that CD8+ lineage DCs are required to induce OVA-specific CD8+ T cell responses following heat injury. Consistent with this observation, intradermal administration of CD8+ lineage DCs but not CD11b+ lineage DCs restores priming of CD8+ T cell responses in Casp-1-/- mice. Thus, we conclude that a sterile injury induces CD8+ T cell immune responses to local antigen through caspase-1 activation and requires CD8+ lineage DCs, a finding of significance for immunotherapy and for the pathogenesis of autoimmunity.
This article is protected by copyright. All rights reserved.
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Retraction notice to ”Electrical Stimulation for Hemiplegic Shoulder Function: A Systematic Review and Meta-Analysis of 15 Randomized Controlled Trials“ [Arch Phys Med Rehabil. 97 (2016) 1588-94]
Publication date: September 2017
Source:Archives of Physical Medicine and Rehabilitation, Volume 98, Issue 9
Author(s): Ping Gu, Juan-juan Ran
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://ift.tt/2sF4ZfT).This article has been retracted at the request of the co-Editors-in-Chief. The article plagiarizes a paper that was published in BioMed Research International, Volume 2015 (2015), Article ID 729768, 14 pages, http://ift.tt/2eMJDEM. Nearly the entire introduction and sections of the methods, limitations and conclusions duplicate the BioMed Research International paper. One of the conditions of submission of a paper to Archives of Physical Medicine and Rehabilitation is that authors declare explicitly that the paper is an original work and not duplicative of prior work unless that work is cited properly. The duplication in this manuscript is a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter.
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Structural proteins of the dermal-epidermal junction targeted by autoantibodies in pemphigoid diseases
Abstract
The dermal-epidermal junction consists of a network of several interacting structural proteins which strengthen adhesion and mediate signaling events. This structural network consists of hemidesmosomal-anchoring filament complexes connecting the basal keratinocytes to the basement membrane. The anchoring filaments in turn interact with the anchoring fibrils to attach the basement membrane to the underlying dermis. Several of these structural proteins are recognized by autoantibodies in pemphigoid diseases, a heterogeneous group of clinically and immunopathologically diverse entities. Targeted proteins include the two intracellular plakins plectin isoform 1a and BP230 (also called bullous pemphigoid antigen (BPAG) 1 isoform e (BPAG1e)), which are connected to the intermediate filaments and to the cell surface receptor α6β4 integrin, which in turn is connected to laminin 332, a component of the anchoring filaments. Further essential adhesion proteins are BP180, a transmembrane protein, laminin γ1, and type VII collagen. Latter protein is the major constituent of the anchoring fibrils. Additionally, a 105 kDa protein of the lower lamina lucida has been described as autoantigen. Mutations in the corresponding genes of these adhesion molecules lead to inherited epidermolysis bullosa emphasizing the importance of these proteins for the integrity of the dermal-epidermal junction. This review will provide an overview on the structure and function of the proteins situated in the dermal-epidermal junction targeted by autoantibodies.
This article is protected by copyright. All rights reserved.
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Archives of Physical Medicine and Rehabilitation Supplements
Source:Archives of Physical Medicine and Rehabilitation, Volume 98, Issue 9
http://ift.tt/2eMjia1
Effect of HPV16 L1 virus-like particles on the aggregation of non-functionalized gold nanoparticles
Source:Biosensors and Bioelectronics, Volume 100
Author(s): Giovanni Palomino-Vizcaino, Diana Gabriela Valencia Reséndiz, María Luisa Benítez-Hess, Natalia Martínez-Acuña, Juana Virginia Tapia-Vieyra, Daniel Bahena, Mauricio Díaz-Sánchez, Octavio Patricio García-González, Brenda Arizaí Alvarez-Sandoval, Luis Marat Alvarez-Salas
Colorimetric assays based on gold nanoparticles (GNPs) are of considerable interest for diagnostics because of their simplicity and low-cost. Nevertheless, a deep understanding of the interaction between the GNPs and the intended molecular target is critical for the development of reliable detection technologies. The present report describes the spontaneous interaction between HPV16 L1 virus-like particles (VLPs) and non-functionalized GNPs (nfGNPs) resulting in the inhibition of nfGNPs salt-induced aggregation and the stabilization of purified VLPs. Ionic-competition experiments suggested that the nature of nfGNPs-VLPs interaction is non-covalent. Adsorption of an RNA aptamer on nfGNPs surface showed an additive aggregation-inhibitory effect. The use of mutant VLPs confirmed that the interaction nfGNPs-VLPs is not mediated by the opposing superficial electrostatic charges, suggesting that non-electrostatic forces participate in the arrangement of nfGNPs on the VLPs surface. Competition experiments using increasing ethanol concentrations on nfGNPs-VLPs complexes suggested hydrophobic interactions as the main stabilizing force. Therefore, the nfGNPs-VLPs interaction described here should facilitate the development of adsorption assays based on nfGNPs for HPV detection and cervical cancer prevention.
http://ift.tt/2f9Nv3u
Electrochemical assay for continuous monitoring of dynamic DNA methylation process
Publication date: 15 February 2018
Source:Biosensors and Bioelectronics, Volume 100
Author(s): Li Zhang, Xiaofen Xiao, Yuzhi Xu, Danping Chen, Jun Chen, Yingjun Ma, Zong Dai, Xiaoyong Zou
A simple electrochemical strategy is reported for continuous monitoring of dynamic DNA methylation process over time. An electrochemical sensor was prepared by co-assembling of DNA probe and 6-mercapto-1-hexanol onto a gold electrode. The top of the DNA probe was labeled with 6-ferrocenylhexanethiol modified gold nanoparticle. The charge density between the C•G base pair was verified to be slightly reduced by DNA methylation, and could be further decelerated by ~ 25% upon co-locating a Br group onto methylated cytosine (mC). Therefore, in the presence of NaIO4/LiBr, the progressively methylated DNA on the sensor showed a clearly decreasing current over methylation time. The dynamic DNA methylation process was indicated continuously from the current decrease ratio, with a limit of detection of 0.0372µM. The strategy is convenient, cost-effective, and enable continuous profiling methylation process without distortion. Besides, the strategy was successfully applied for the studies on inhibitor screening and flanking sequence preference of DNA methyltransferase 3a. The results show that the activity of DNA methyltransferase 3a can be mildly inhibited by epigallocatechin gallate, and varies towards different flanking sequence with an order of 5′-CCGG-3′<5′-CGCG-3′<5′-CGCA-3′.
Graphical abstract
http://ift.tt/2wOzbao
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