Influence of sunflower seed oil or baby lotion on the skin barrier function of newborns: A pilot study

Summary

Background

Skin care influences skin barrier function during the first postnatal weeks. Although the use of natural oils in preterms has been investigated, there are currently no data comparing the effect of sunflower oil to an emollient on barrier development in healthy term newborns.

Methods

In a prospective, randomized clinical study, 50 healthy full-term newborns aged ≤72 h were randomly assigned to two groups: group baby lotion (L, n=22) and sunflower seed oil (SSO, n=24). The skin barrier function was evaluated in three anatomical areas (front, abdomen, and thigh) by noninvasive assessment of transepidermal water loss (TEWL), stratum corneum hydration (SCH), sebum, and skin pH at inclusion and after five weeks.

Results

In both groups, skin pH decreased and SCH increased statistically significantly in all measured areas at W5 compared to baseline. TEWL decreased statistically significantly on the forearm in both groups, on the upper leg in group L, and on the abdomen in group SSO.

Conclusions

Both skin care regimes did not harm skin barrier function adaptation in healthy term neonates during the first five weeks of life.

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Recent development of two-dimensional transition metal dichalcogenides and their applications

Publication date: Available online 9 January 2017
Source:Materials Today
Author(s): Wonbong Choi, Nitin Choudhary, Gang Hee Han, Juhong Park, Deji Akinwande, Young Hee Lee
Recent advances in atomically thin two-dimensional transition metal dichalcogenides (2D TMDs) have led to a variety of promising technologies for nanoelectronics, photonics, sensing, energy storage, and opto-electronics, to name a few. This article reviews the recent progress in 2D materials beyond graphene and includes mainly transition metal dichalcogenides (TMDs) (e.g. MoS2, WS2, MoSe2, and WSe2). These materials are finding niche applications for next-generation electronics and optoelectronics devices relying on ultimate atomic thicknesses. Albeit several challenges in developing scalable and defect-free TMDs on desired substrates, new growth techniques compatible with traditional and unconventional substrates have been developed to meet the ever-increasing demand of high quality and controllability for practical applications. The fabrication of novel 2D TMDs that exhibit exotic functionalities and fundamentally new chemistry is highlighted. And finally, in parallel with the electronics, the considerable effort devoted to using these materials for energy and sensing applications is discussed in detail.



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Physical and biological characteristics of multi drug resistance (MDR): An integral approach considering pH and drug resistance in cancer

Publication date: Available online 8 January 2017
Source:Seminars in Cancer Biology
Author(s): Ziad Omran, Paula Scaife, Simon Stewart, Cyril Rauch
The role of the Warburg effect in cancer remains to be elucidated with a resurgence in research efforts over the past decade. Why a cancer cell would prefer to use energy inefficient glycolysis, leading to an alteration of pH both inside and outside of the cell, remains to be uncovered. The development of MDR represents a major challenge in the treatment of cancer and it is explained, so far, by the over expression of drug transporters such as the well-known and archetypal P-glycoprotein (Pgp). However, controversies exist regarding the function of Pgp in multi-drug resistance. We suggest here that Pgp-mediated MDR relies fundamentally on pH alterations mediated by the Warburg effect. Furthermore, we propose that the use of proton pump and/or transporters inhibitors (PPIs/PTIs) in cancer are key to controlling both MDR, i.e. sensitize tumors to antineoplastic agents, and drug-related adverse effects.



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Cancer and Apoptosis: Who Is Built to Last?

Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Douglas R. Green
Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state.

Teaser

Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state.


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Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer

Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Christopher J. Halbrook, Costas A. Lyssiotis
Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.

Teaser

Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.


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Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma

Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Veronica Veschi, Zhihui Liu, Ty C. Voss, Laurent Ozbun, Berkley Gryder, Chunhua Yan, Ying Hu, Anqi Ma, Jian Jin, Sharlyn J. Mazur, Norris Lam, Barbara K. Souza, Giuseppe Giannini, Gordon L. Hager, Cheryl H. Arrowsmith, Javed Khan, Ettore Appella, Carol J. Thiele
Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4^K20me1 methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53^K382me1, leading to activation of the p53 canonical pathway. In pre-clinical xenograft NB models, genetic or pharmacological (UNC0379) SETD8 inhibition conferred a significant survival advantage, providing evidence for SETD8 as a therapeutic target in NB.

Graphical abstract

Teaser

Veschi et al. perform both genetic and chemical screening to identify histone methyltransferase SETD8 as a potential target in neuroblastoma (NB). Chemical or genetic inhibition of SETD8 in NB leads to increased p53 activity and reduced tumor cell growth, resulting in prolonged survival in mouse models of NB.


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Settling a Nervous Stomach: The Neural Regulation of Enteric Cancer

Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Michelle Monje
The nervous system is emerging as a regulator of malignancy. In this issue of Cancer Cell, Hayakawa et al. demonstrate a feedforward signaling loop in which tumor-derived nerve growth factor promotes enteric tumor innervation, and recruited nerves drive cancer growth through acetylcholine-regulated Wnt signaling and stimulation of further NGF release.

Teaser

The nervous system is emerging as a regulator of malignancy. In this issue of Cancer Cell, Hayakawa et al. demonstrate a feedforward signaling loop in which tumor-derived nerve growth factor promotes enteric tumor innervation, and recruited nerves drive cancer growth through acetylcholine-regulated Wnt signaling and stimulation of further NGF release.


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Simultaneous Inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-κB and AKT

Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Juliane Paul, Maurice Soujon, Antje M. Wengner, Sabine Zitzmann-Kolbe, Andrea Sturz, Katja Haike, Koh Hui Keng Magdalene, Sze Huey Tan, Martin Lange, Soo Yong Tan, Dominik Mumberg, Soon Thye Lim, Karl Ziegelbauer, Ningshu Liu
Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79^mut, CARD11^mut, TNFAIP3^mut, or MYD88^mut. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79B^WT/MYD88^mut patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79B^mut-ABC-DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3Kα/δ inhibitor copanlisib produced a sustained complete response in vivo in CD79B^mut/MYD88^mut ABC-DLBCL models.

Graphical abstract

Teaser

Paul et al. reveal that ABC-DLBCL expresses high levels of PI3Kα and PI3Kδ, leading to downstream activation of both NF-κB and AKT signaling. Treatment with the dual PI3Kα/δ inhibitor copanlisib has strong anti-tumor activity and synergizes with the BTK inhibitor ibrutinib, causing tumor remission in DLBCL models.


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BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer

Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Carlos López-García, Laurent Sansregret, Enric Domingo, Nicholas McGranahan, Sebastijan Hobor, Nicolai Juul Birkbak, Stuart Horswell, Eva Grönroos, Francesco Favero, Andrew J. Rowan, Nicholas Matthews, Sharmin Begum, Benjamin Phillimore, Rebecca Burrell, Dahmane Oukrif, Bradley Spencer-Dene, Michal Kovac, Gordon Stamp, Aengus Stewart, Havard Danielsen, Marco Novelli, Ian Tomlinson, Charles Swanton
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.

Graphical abstract

Teaser

López-García et al. find that BCL9L is often genetically inactivated in human colorectal cancers with chromosomal instability. BCL9L dysfunction promotes aneuploidy tolerance by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID independent of TP53 mutation status.


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Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment

Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Jin-Sung Park, Il-Kug Kim, Sangyeul Han, Intae Park, Chan Kim, Jeomil Bae, Seung Ja Oh, Seungjoo Lee, Jeong Hoon Kim, Dong-Cheol Woo, Yulong He, Hellmut G. Augustin, Injune Kim, Doheon Lee, Gou Young Koh




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Antiaging Effect of Metformin on Brain in Naturally Aged and Accelerated Senescence Model of Rat

Rejuvenation Research , Vol. 0, No. 0.


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Effects of stimulus mode and ambient temperature on cerebral responses to local thermal stimulation: An EEG study

Publication date: Available online 10 January 2017
Source:International Journal of Psychophysiology
Author(s): Bin Lv, Chang Su, Lei Yang, Tongning Wu
The physiological responses to human thermal stimulation have been widely investigated, but most of them are mainly concerned about the whole body thermal stimulation. In this study, we investigated the effects of stimulus mode and ambient temperature on cerebral responses during local thermal stimulation on hand. The left hands were stimulated by metal thermostat based and thermostatic water based stimulators at different stimulated temperatures (38°C, 40°C, 42°C and 44°C) and different ambient temperatures (25°C and 32°C). EEG data were recorded over the whole brain during the experiments. Then the statistical comparisons were conducted on the EEG relative power among different experimental sessions. We observed that EEG activities were alternated between thermal stimulated periods and the baseline in all four frequency bands. And there was a higher percentage of delta band power in the right temporal and parietal regions under the ambient temperature of 32°C while compared to 25°C. In addition, the theta band activity under the metal based stimulation showed significantly higher EEG relative power than that under the water based stimulation over the whole brain. Compared with the water based stimulation, there was a lower EEG relative power of the beta band activity during the metal based stimulation in the bilateral frontal and right temporal regions. The experimental results suggested that the neural physiological responses in different EEG frequency bands were sensitive to different influence factors during the local hand thermal stimulation.



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Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect?

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Cosmetics, Vol. 4, Pages 4: Oxidative Stress and Ageing: The Influence of Environmental Pollution, Sunlight and Diet on Skin

Skin ageing is a complex process that is determined by both intrinsic and extrinsic factors, which leads to a progressive loss of structure and function. There is extensive evidence indicating that oxidative stress induced by reactive oxygen species plays an important role in the process of human skin ageing. Mitochondria are the major source of cellular oxidative stress and are widely implicated in cutaneous ageing. Extrinsic skin ageing is driven to a large extent by environmental factors and external stressors such as ultraviolet radiation (UVR), pollution and lifestyle factors which have been shown to stimulate the production of reactive oxygen species and generate oxidative stress. The oxidative damage from these exogenous sources can impair skin structure and function, leading to the phenotypic features of extrinsic skin ageing. The following review highlights the current evidence surrounding the role of mitochondria and oxidative stress in the ageing process and the influence of environmental factors such as ultraviolet radiation, pollution and diet on skin ageing.

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Photodynamic Therapy: The Light Treatment for Cutaneous Non- Melanoma Malignancies

Photodynamic therapy has many treatment applications for malignant and premalignant lesions of the skin. The basic principle involves application of a photosensitizer followed by exposure of the target tissues to light. 5-aminolevulinic acid is a natural occurring compound in the heme biosynthesis pathway. Its metabolite protoporphyrin IX is a photosensitizer that has the ability to selectively damage premalignant, malignant, and certain abnormal tissues, rendering its wide application for use in actinic keratosis, Bowen's disease, and basal cell carcinoma. Adequate lesion preparation is critical for successful treatment. Ongoing research on the clinical use of photodynamic therapy, its potential impact in oncological patient management and on public health and cost is continuously evolving. The perfection of this light therapy on patient treatment awaits results of future clinical trials.

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Clearance of recalcitrant warts in a patient with idiopathic immune deficiency following administration of the quadrivalent human papillomavirus vaccine

Summary

Human papillomavirus (HPV)-induced cutaneous warts are potentially serious and debilitating. In immunosuppressed patients, these warts may be resistant to standard therapies. We report a case of a young patient with a primary immune deficiency whose recalcitrant cutaneous warts regressed completely following administration of a quadrivalent HPV vaccine.

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Unusual skin changes on the neck

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Nursing care management of photodynamic therapy in digestive tract carcinomas at a single cancer center

Publication date: Available online 9 January 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Atsushi Nanashima, Koji Nakashima, Hiroshi Kawakami, Shinya Ashizuka, Yoshimasa Kubota
The primary goal of nursing care in cases of endoscopic photodynamic therapy (PDT) for digestive tract carcinoma is to prevent phototoxicity by the intravenous administration of photosensitizers. The adequate protocol and management of patients should be conducted under the instruction of expert physicians. Our experiences of administering porfimer sodium and talaporfin sodium during clinical PDT provide insight regarding the specific management protocol of each photosensitizer during an in-hospital stay. We herein report our nursing protocol based on 15 years of experience. Under adequate management, PDT can be safely performed.



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Optimizing the effects of Persian gum and carrot pomace powder for development of low-fat donut with high fibre content

Publication date: Available online 10 January 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Mehran Nouri, Behzad Nasehi, Vahid Samavati, Saman Abdanan Mehdizadeh
The objective of present study was to develop and optimize a low-fat high fibre donut formulation using response surface methodology. A 5-level-3-factor central composite rotatable design was employed, where the independent variables were Persian gum (0–1.5g/100g), carrot pomace powder (0–15g/100g) and water (38–53g/100g), while the dependent variables were physicochemical properties of donuts. It was found that Persian gum and carrot pomace powder both effectively contributed to retention of donuts moisture content which in turn led to significant reduction of fat uptake during frying process (p < 0.05). Persian gum decreased the donuts firmness while carrot pomace powder adversely affected the textural properties as well as specific volume (p < 0.05). Image analysis revealed that carrot pomace powder influenced all the image analysis parameters investigated negatively. Response surface methodology described that donuts with optimum formulation of 1.20g/100gPersian gum, 6.45g/100gcarrot pomace powder and 48.16g/100g water had considerably lower fat uptake and acceptable sensory attributes compared to control sample.



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MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults

Objective

Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study's objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults.

Design

54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A.

Results

Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects.

Conclusions

Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.

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Cabergoline for Cushings disease: a large retrospective multicenter study

Objective

The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD.

Design

We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals.

Methods

Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded.

Results

Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19–105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1–240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5–3.5).

Conclusions

About 20–25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

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Clinical characteristics and management of growth hormone excess in patients with McCune-Albright syndrome

Objective

McCune–Albright syndrome (MAS) is a sporadic, postzygotic disease presenting with fibrous dysplasia, cafe-au-lait spots and multiple endocrinopathies. Growth hormone (GH) excess is an uncommon but potentially severe complication of MAS. This study aims to describe the clinical manifestations of GH excess in the context of MAS and analyze the responses of these patients to treatments.

Design

Retrospective clinical study.

Methods

Clinical data from 52 MAS patients were analyzed. Serum GH and IGF1 levels, as well as nadir GH levels after an oral glucose tolerance test and alkaline phosphatase (ALP) levels were determined before and after the treatment.

Results

In total, 13 MAS patients (25%) had the complication of GH excess, including 10 males (76.9%). Among them, all had FD, and 6 patients had sphenoidal bone involvement. Visual deficits were present in 8 patients, and hearing deficits were present in 5. Olfactory dysfunction was observed in 3 patients. Evident pituitary adenomas were confirmed in 9 patients by MRI. These patients underwent surgery with or without pretreatment of long-acting somatostatin analogue octreotide, and 6 achieved complete remission. The serum ALP levels decreased significantly after treatment for GH excess.

Conclusions

MAS with GH excess is more common in male patients. GH excess can lead to more severe skeletal lesions in MAS patients involving more of the craniofacial bones. Complete trans-sphenoidal complete tumor excision with neuronavigational guidance is effective and could lower ALP levels. LAR is recommended as a preoperative treatment and when patients fail to achieve complete remission after surgery.

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Imprecision: Limitations to Interpretation of a Large Randomized Clinical Trial.

Author: FitzGerald, Garret A. MD

Page: 113-115

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Incident Type 2 Myocardial Infarction in a Cohort of Patients Undergoing Coronary or Peripheral Arterial Angiography.

Author: Gaggin, Hanna K. MD, MPH; Liu, Yuyin MS; Lyass, Asya PhD; van Kimmenade, Roland R. J. MD, PhD; Motiwala, Shweta R. MD; Kelly, Noreen P. MD; Mallick, Aditi MD; Gandhi, Parul U. MD; Ibrahim, Nasrien E. MD; Simon, Mandy L. DNP, NP; Bhardwaj, Anju MD; Belcher, Arianna M. BS; Harisiades, Jamie E. BA; Massaro, Joseph M. PhD; D'Agostino, Ralph B. Sr. PhD; Januzzi, James L. Jr. MD

Page: 116-127

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Stroke Treatment With Intravenous Tissue-Type Plasminogen Activator: More Proof That Time Is Brain.

Author: Alberts, Mark J. MD

Page: 140-142

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Treatment With Tissue Plasminogen Activator in the Golden Hour and the Shape of the 4.5-Hour Time-Benefit Curve in the National United States Get With The Guidelines-Stroke Population.

Author: Kim, Joon-Tae MD; Fonarow, Gregg C. MD; Smith, Eric E. MD, MPH; Reeves, Mathew J. PhD; Navalkele, Digvijaya D. MD; Grotta, James C. MD; Grau-Sepulveda, Maria V. MD; Hernandez, Adrian F. MD; Peterson, Eric D. MD; Schwamm, Lee H. MD; Saver, Jeffrey L. MD

Page: 128-139

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Thrombus Aspiration in ST-Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration.

Author: Jolly, Sanjit S. MD, MSc; James, Stefan MD, PhD; Dzavik, Vladimir MD; Cairns, John A. MD; Mahmoud, Karim D. MD, PhD; Zijlstra, Felix MD, PhD; Yusuf, Salim MBBS, DPhil; Olivecrona, Goran K. MD, PhD; Renlund, Henrik PhD; Gao, Peggy MSc; Lagerqvist, Bo MD, PhD; Alazzoni, Ashraf MD; Kedev, Sasko MD, PhD; Stankovic, Goran MD; Meeks, Brandi MEng; Frobert, Ole MD, PhD

Page: 143-152

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Coronary Artery Calcium to Guide a Personalized Risk-Based Approach to Initiation and Intensification of Antihypertensive Therapy.

Author: McEvoy, John W. MB, BCh, BAO, MEHP, MHS; Martin, Seth S. MD, MHS; Dardari, Zeina A. MS; Miedema, Michael D. MD, MPH; Sandfort, Veit MD; Yeboah, Joseph MD, MPH; Budoff, Matthew J. MD; Goff, David C. Jr. MD, PhD; Psaty, Bruce M. MD, PhD; Post, Wendy S. MD, MS; Nasir, Khurram MD, MPH; Blumenthal, Roger S. MD; Blaha, Michael J. MD, MPH

Page: 153-165

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Nitrite and S-Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation: Relationship to Basal and Exercise Blood Flow Responses to Hypoxia.

Author: Bailey, Damian M. PhD; Rasmussen, Peter PhD; Overgaard, Morten MD; Evans, Kevin A. PhD; Bohm, Aske M. MD; Seifert, Thomas PhD; Brassard, Patrice PhD; Zaar, Morten MD; Nielsen, Henning B. MD; Raven, Peter B. PhD; Secher, Niels H. MD, PhD

Page: 166-176

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How Red Blood Cells Process Nitric Oxide: Evidence for the Nitrite Hypothesis.

Author: Gladwin, Mark T. MD

Page: 177-179

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An Evidence-Based Medicine Approach to Antihyperglycemic Therapy in Diabetes Mellitus to Overcome Overtreatment.

Author: Makam, Anil N. MD, MAS; Nguyen, Oanh K. MD, MAS

Page: 180-195

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Clipping It in the Bud.

Author: Lazarus, John J. MD, PhD; Murthy, Venkatesh L. MD, PhD; Yang, Bo MD, PhD

Page: 196-200

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Implantable Cardioverter-Defibrillator for Nonischemic Cardiomyopathy: An Updated Meta-Analysis.

Author: Golwala, Harsh MD; Bajaj, Navkaranbir Singh MD, MPH; Arora, Garima MD; Arora, Pankaj MD

Page: 201-203

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Letter by Vrints Regarding Article, "Coronary Computed Tomography Angiography in the Evaluation of Chest Pain of Suspected Cardiac Origin".

Author: Vrints, Christiaan J. M. MD, PhD

Page: e5-e6

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Response by Hulten et al to Letter Regarding Article, "Coronary Computed Tomography Angiography in the Evaluation of Chest Pain of Suspected Cardiac Origin".

Author: Hulten, Edward MD, MPH; Bittencourt, Marcio Sommer MD, PhD, MPH; Veeranna, Vikas MD; Blankstein, Ron MD

Page: e7-e8

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Letter by Koh Regarding Article, "Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial".

Author: Koh, Kwang Kon MD, PhD

Page: e9-e10

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Letter by Nagele Regarding Article, "Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial".

Author: Nagele, Matthias P. MD

Page: e11-e12

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Response by Heydari et al to Letter Regarding Article, "Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial".

Author: Heydari, Bobak MD, MPH; Harris, William S. PhD; Kwong, Raymond Y. MD, MPH

Page: e13-e14

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Correction to: Diverse Requirements for Efficient Population Screening for Abdominal Aortic Aneurysm: From Program Management to Maintaining Skills in Open Repair.

Author:

Page: e15

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Multiwavelength micromirrors in the cuticle of scarab beetle Chrysina gloriosa

Publication date: 15 January 2017
Source:Acta Biomaterialia, Volume 48
Author(s): Gonzague Agez, Chloé Bayon, Michel Mitov
Beetles from the genus Chrysina show vivid reflections from bright green to metallic silver-gold as a consequence of the cholesteric liquid crystal organization of chitin molecules. Particularly, the cuticle of Chrysina gloriosa exhibits green and silver stripes. By combining confocal microscopy and spectrophotometry, scanning electron microscopy and numerical simulations, the relationship between the reflectance and the structural parameters for both stripes at the micro- and nanoscales are established. Over the visible and near IR spectra, polygonal cells in tessellated green stripes behave as multiwavelength selective micro-mirrors and the silver stripes as specular broadband mirrors. Thermoregulation, conspecifics or intra-species communication, or camouflage against predators are discussed as possible functions. As a prerequisite to bio-inspired artificial replicas, the physical characteristics of the polygonal texture in Chrysina gloriosa cuticle are compared to their equivalents in synthetic cholesteric oligomers and their fundamental differences are ascertained. It is shown that the cuticle has concave cells whereas the artificial films have convex cells, contrary to expectation and assumption in the literature. The present results may provide inspiration for fabricating multiwavelength selective micromirrors or spatial wavelength-specific light modulators.Statement of SignificanceMany insects own a tessellated carapace with bumps, pits or indentations. Little is known on the physical properties of these geometric variations and biological functions are unknown or still debated. We show that the polygonal cells in scarab beetle Chrysina gloriosa behave as multiwavelength selective micromirrors over the visible and infrared spectra, with a variety of spatial patterns. In the context of biomimetic materials, we demonstrate that the carapace has concave cells whereas the artificial films have convex cells, contrary to expectation in the literature. Thermoregulation, communication or camouflage are discussed as advanced functions. Results may provide inspiration for fabricating spatial wavelength-specific light modulators and optical packet switching in routing technologies.

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Poly (3,4-ethylenedioxythiophene) graphene oxide composite coatings for controlling magnesium implant corrosion

Publication date: 15 January 2017
Source:Acta Biomaterialia, Volume 48
Author(s): Kasey Catt, Huaxiu Li, X. Tracy Cui
Magnesium (Mg) is a promising biodegradable implant material because of its appropriate mechanical properties and safe degradation products. However, in vivo corrosion speed and hydrogen gas production need to be controlled for uses in biomedical applications. Here we report the development of a conducting polymer 3,4-ethylenedioxythiphene (PEDOT) and graphene oxide (GO) composite coating as a corrosion control layer. PEDOT/GO was electropolymerized on Mg samples in ethanol media. The coated Mg samples were subjected to various corrosion tests. The PEDOT/GO coating significantly reduced the rate of corrosion as evidenced by lower Mg ion concentration and pH of the corrosion media. In addition, the coating decreased the evolved hydrogen. Electrochemical analysis of the corroding samples showed more positive corrosion potential, a decreased corrosion current, and an increase in the polarization resistance. PEDOT/GO corrosion protection is attributed to three factors; an initial passive layer preventing solution ingress, buildup of negative charges in the film, and formation of corrosion protective Mg phosphate layer through redox coupling with Mg corrosion. To explore the biocompatibility of the coated implants in vitro, corrosion media from PEDOT/GO coated or uncoated Mg samples were exposed to cultured neurons where PEDOT/GO coated samples showed decreased toxicity. These results suggest that PEDOT/GO coating will be an effective treatment for controlling corrosion of Mg based medical implants.Statement of SignificanceCoating Mg substrates with a PEDOT/GO composite coating showed a significant decrease in corrosion rate. While conducting polymer coatings have been used to prevent corrosion on various metals, there has been little work on the use of these coatings for Mg. Additionally, to our knowledge, there has not been a report of the combined used of conducting polymer and GO as a corrosion control layer. Corrosion control is attributed to an initial barrier layer followed by electrochemical coupling of the PEDOT/GO coating with the substrate to facilitate the formation of a protective phosphate layer. This coupling also resulted in a decrease in hydrogen produced during corrosion, which could further improve the host tissue integration of Mg implants. This work elaborates on the potential for electroactive polymers to serve as corrosion control methods.

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2017 Acta Biomaterialia Gold Medal Award

Publication date: 15 January 2017
Source:Acta Biomaterialia, Volume 48





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Dual delivery of VEGF and ANG-1 in ischemic hearts using an injectable hydrogel

Publication date: 15 January 2017
Source:Acta Biomaterialia, Volume 48
Author(s): Abdul Jalil Rufaihah, Nurul Azizah Johari, Srirangam Ramanujam Vaibavi, Marian Plotkin, Do Thi Di Thien, Theodoros Kofidis, Dror Seliktar
Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor therapy is promising, the retention in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. VEGF and ANG-1 were incorporated in PF hydrogels and their in vitro characteristics were studied. Acute MI was generated in a rodent model with rats randomly assigned to 4 groups; sham, saline, PF and PF-VEGF-ANG1 (n=10 each group). Saline or hydrogel was injected in infarct and peri-infarct areas of the myocardium. After 4weeks, myocardial function was assessed using echocardiography. Tissue samples were harvested for Hematoxylin and Eosin, Masson Trichrome and capillary staining to assess the extent of fibrotic scar and arteriogenesis. Both VEGF and ANG-1 were released in a sustained and controlled manner over 30days. PF-VEGF-ANG1 treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI. The utility of this synergistic, biomaterial-based growth factor delivery may have clinical implications in the prevention of post-MI cardiac dysfunction.Statement of SignificanceAcute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. Treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI.

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Editorial Board

Publication date: 15 January 2017
Source:Acta Biomaterialia, Volume 48





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Gadolinium accumulation in organs of Sprague–Dawley® rats after implantation of a biodegradable magnesium-gadolinium alloy

Publication date: 15 January 2017
Source:Acta Biomaterialia, Volume 48
Author(s): Anastasia Myrissa, Simone Braeuer, Elisabeth Martinelli, Regine Willumeit-Römer, Walter Goessler, Annelie Martina Weinberg
Biodegradable magnesium implants are under investigation because of their promising properties as medical devices. For enhancing the mechanical properties and the degradation resistance, rare earth elements are often used as alloying elements.In this study Mg10Gd pins were implanted into Sprague–Dawley® rats. The pin volume loss and a possible accumulation of magnesium and gadolinium in the rats' organs and blood were investigated in a long-term study over 36weeks. The results showed that Mg10Gd is a fast disintegrating material. Already 12weeks after implantation the alloy is fragmented to smaller particles, which can be found within the intramedullary cavity and the cortical bones. They disturbed the bone remodeling until the end of the study.The results concerning the elements' distribution in the animals' bodies were even more striking, since an accumulation of gadolinium could be observed in the investigated organs over the whole time span. The most affected tissue was the spleen, with up to 3240μgGd/kg wet mass, followed by the lung, liver and kidney (up to 1040, 685 and 207μgGd/kg). In the brain, muscle and heart, the gadolinium concentrations were much smaller (less than 20μg/kg), but an accumulation could still be detected. Interestingly, blood serum samples showed no accumulation of magnesium and gadolinium.This is the first time that an accumulation of gadolinium in animal organs was observed after the application of a gadolinium-containing degradable magnesium implant. These findings demonstrate the importance of future investigations concerning the distribution of the constituents of new biodegradable materials in the body, to ensure the patients' safety.Statement of SignificanceIn the last years, biodegradable Mg alloys are under investigation due to their promising properties as orthopaedic devices used for bone fracture stabilization. Gadolinium as Rare Earth Element enhances the mechanical properties of Mg-Gd alloys but its toxicity in humans is still questionable. Up to now, there is no study investigating the elements' metabolism of a REE-containing Magnesium alloy in an animal model. In this study, we examined the gadolinium distribution and accumulation in rat organs during the degradation of Mg10Gd. Our findings showed that Gd is accumulating in the animal organs, especially in spleen, liver and kidney. This study is of crucial benefit regarding a safe application of REE-containing Magnesium alloys in humans.

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Light triggered formation of photo-responsive epoxy based networks

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Simone Radl, Ignazio Roppolo, Karina Pölzl, Markus Ast, Josef Spreitz, Thomas Griesser, Wolfgang Kern, Sandra Schlögl, Marco Sangermano
Taking advantage of versatile o-nitrobenzyl chemistry, the present study highlights the design of photocurable epoxy networks that undergo spatially controlled bond cleavage in response to UV irradiation. The synthetic strategy involves the preparation of epoxy monomers with photolabile o-nitrobenzyl ester (o-NBE) links that are cured via photoinduced cationic ring opening reaction. Two different photoinitiation systems are employed which do not interfere with the absorbance of the o-NBE groups. The first initiation mechanism exploits the direct photolysis of N-hydroxynaphthalimide triflate upon deep UV exposure and the second mechanism follows a free radical promoted cationic polymerization upon visible light illumination. The crosslinking and cleavage kinetics of the photodegradable epoxy networks are characterized by spectroscopic techniques. In thin films, the UV induced increase in solubility is confirmed by sol-gel analysis and used for the fabrication of positive tone photoresists. Patterned films are obtained by photolithographic processes and microscopic analyses reveal that the resists provide a resolution of 4 μm and a good contrast behavior.

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Testing of a palatable bait and compatible vaccine carrier for the oral vaccination of European badgers (Meles meles) against tuberculosis

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Sonya Gowtage, Gareth A. Williams, Ray Henderson, Paul Aylett, Duncan MacMorran, Si Palmer, Andy Robertson, Sandrine Lesellier, Stephen P. Carter, Mark A. Chambers
The oral vaccination of wild badgers (Meles meles) with live Bacillus Calmette–Guérin (BCG) is one of the tools being considered for the control of bovine tuberculosis (caused by Mycobacterium bovis) in the UK. The design of a product for oral vaccination requires that numerous, and often competing, conditions are met. These include the need for a highly palatable, but physically stable bait that will meet regulatory requirements, and one which is also compatible with the vaccine formulation; in this case live BCG. In collaboration with two commercial bait companies we have developed a highly attractive and palatable bait recipe designed specifically for European badgers (Meles meles) that meets these requirements. The palatability of different batches of bait was evaluated against a standardised palatable control bait using captive badgers. The physical properties of the bait are described e.g. firmness and colour. The microbial load in the bait was assessed against European and US Pharmacopoeias. The bait was combined with an edible vaccine carrier made of hydrogenated peanut oil in which BCG vaccine was stable during bait manufacture and cold storage, demonstrating <0.5 log10 reduction in titre after 117weeks' storage at −20°C. BCG stability in bait was also evaluated at +4°C and under simulated environmental conditions (20°C, 98% Relative Humidity; RH). Finally, iophenoxic acid biomarkers were utilised as a surrogate for the BCG vaccine, to test variants of the vaccine-bait design for their ability to deliver biomarker to the gastrointestinal tract of individual animals. These data provide the first detailed description of a bait-vaccine delivery system developed specifically for the oral vaccination of badgers against Mycobacterium bovis using live BCG.



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The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Jennifer E. Cornick, Özlem Tastan Bishop, Feyruz Yalcin, Anmol M. Kiran, Benjamin Kumwenda, Chrispin Chaguza, Shanil Govindpershad, Sani Ousmane, Madikay Senghore, Mignon du Plessis, Gerd Pluschke, Chinelo Ebruke, Lesley McGee, Beutel Sigaùque, Jean-Marc Collard, Stephen D. Bentley, Aras Kadioglu, Martin Antonio, Anne von Gottberg, Neil French, Keith P. Klugman, Robert S. Heyderman, Mark Alderson, Dean B. Everett
Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (<2%). The vast majority of the observed variation was predicted to have no impact on the efficaciousness of a protein vaccine incorporating a single variant of SP0148, SP1912 and/or SP2108 from S. pneumoniae TIGR4. Our findings emphasise the importance of taking geographic differences into account when designing global vaccine interventions and support the continued development of SP0148, SP1912 and SP2108 as protein vaccine candidates against this important pneumococcal serotype.



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Influenza in the Asia-Pacific region: Findings and recommendations from the Global Influenza Initiative

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Benjamin J. Cowling, Saverio Caini, Tawee Chotpitayasunondh, Samsuridjal Djauzi, Salvacion R. Gatchalian, Q. Sue Huang, Parvaiz A. Koul, Ping-Ing Lee, Abdul Razak Muttalif, Stanley Plotkin
The fourth roundtable meeting of the Global Influenza Initiative (GII) was held in Hong Kong, China, in July 2015. An objective of this meeting was to gain a broader understanding of the epidemiology, surveillance, vaccination policies and programs, and obstacles to vaccination of influenza in the Asia-Pacific region through presentations of data from Australia, Hong Kong, India, Indonesia, Malaysia, New Zealand, the Philippines, Taiwan, Thailand, and Vietnam.As well as a need for improved levels of surveillance in some areas, a range of factors were identified that act as barriers to vaccination in some countries, including differences in climate and geography, logistical challenges, funding, lack of vaccine awareness and education, safety concerns, perceived lack of vaccine effectiveness, and lack of inclusion in national guidelines. From the presentations at the meeting, the GII discussed a number of recommendations for easing the burden of influenza and overcoming the current challenges in the Asia-Pacific region. These recommendations encompass the need to improve surveillance and availability of epidemiological data; the development and publication of national guidelines, where not currently available and/or that are in line with those proposed by the World Health Organization; the requirement for optimal timing of vaccination programs according to local or country-specific epidemiology; and calls for advocacy and government support of vaccination programs in order to improve availability and uptake and coverage.In conclusion, in addition to the varied epidemiology of seasonal influenza across this diverse region, there are a number of logistical and resourcing issues that present a challenge to the development of optimally effective vaccination strategies and that need to be overcome to improve access to and uptake of seasonal influenza vaccines. The GII has developed a number of recommendations to address these challenges and improve the control of influenza.



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Replacement of in vivo human rabies vaccine potency testing by in vitro glycoprotein quantification using ELISA – Results of an international collaborative study

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Sylvie Morgeaux, Bertrand Poirier, C. Ian Ragan, Dianna Wilkinson, Ulrich Arabin, Françoise Guinet-Morlot, Robin Levis, Heidi Meyer, Patrice Riou, Shahjahan Shaid, Dmitriy Volokhov, Noël Tordo, Jean-Michel Chapsal
Three different ELISAs quantifying rabies glycoprotein were evaluated as in vitro alternatives to the National Institutes of Health (NIH) in vivo potency test for batch release of human rabies vaccines. The evaluation was carried out as an international collaborative study supported by the European Partnership for Alternatives to Animal Testing (EPAA). This pre-validation study, the results of which are presented in this paper, compared three different ELISA designs, assessing their within- and between-laboratory precision. One of the ELISA designs was proposed to the European Directorate for the Quality of Medicines & HealthCare (EDQM) and accepted for an international collaborative study under the umbrella of the Biological Standardisation Programme.



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Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Meliha C. Kapetanovic, Johanna Nagel, Inger Nordström, Tore Saxne, Pierre Geborek, Anna Rudin
BackgroundTreatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccination. The mechanisms by which MTX exerts these effects in RA are unknown. We aimed to evaluate whether MTX reduces vaccine-specific serum Ig levels and their functionality in RA patients following vaccination with pneumococcal conjugate vaccine, and if numbers of antigen-specific circulating plasmablasts are affected.MethodsTen patients with RA on MTX and 10 RA patients without disease modifying anti-rheumatic drug (DMARD) were immunized with a dose 13-valent pneumococcal conjugate vaccine (Prevenar13). Circulating plasmablasts producing total IgG and IgA as well as specific IgG and IgA against two pneumococcal capsular serotypes (6B and 23F) were enumerated using ELISPOT 6days after vaccination. IgG levels against both these serotypes were determined with ELISA before and 4–6weeks after vaccination. Positive antibody response was defined as ⩾2-fold increase of pre-vaccination antibody levels. The functionality of vaccine specific antibodies to serotype 23F was evaluated by measuring their ability to opsonize bacteria using opsonophagocytic assay (OPA) in 4 randomly chosen RA patients on MTX and 4 RA patients without DMARD.ResultsAfter vaccination, RA patients on MTX showed significant increase in pre- to postvaccination antibody levels for 6B (p<0.05), while patients without DMARD had significant increases for both 6B and 23F (p<0.05 and p<0.01, respectively). Only 10% of RA on MTX and 40% of RA patients without DMARD showed positive post-vaccination antibody responses for both serotypes. Increased opsonizing ability after vaccination was detected in 1 of 4 RA patients on MTX and 3 of 4 patients on RA without DMARD. However, numbers of circulating total and vaccine-specific IgG- or IgA-producing plasmablasts did not differ between RA patients with or without MTX.ConclusionsMTX treatment in RA leads to reduced vaccine-specific antibody responses and their functionality compared to untreated RA following pneumococcal vaccination using polysaccharide-protein conjugate vaccine. However, since there was no reduction in numbers of circulating total or vaccine-specific antibody-producing plasmablasts after vaccination this effect is probably not due to reduced activation of B cells in lymphoid tissue.Clinical trial registration: NCT02240888.



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Demand- and supply-side determinants of diphtheria-pertussis-tetanus nonvaccination and dropout in rural India

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Arpita Ghosh, Ramanan Laxminarayan
BackgroundAlthough 93% of 12- to 23-month-old children in India receive at least one vaccine, typically Bacillus Calmette–Guérin, only 75% complete the recommended three doses of diphtheria-pertussis-tetanus (DPT, also referred to as DTP) vaccine. Determinants can be different for nonvaccination and dropout but have not been examined in earlier studies. We use the three-dose DPT series as a proxy for the full sequence of recommended childhood vaccines and examine the determinants of DPT nonvaccination and dropout between doses 1 and 3.MethodsWe analyzed data on 75,728 6- to 23-month-old children in villages across India to study demand- and supply-side factors determining nonvaccination with DPT and dropout between DPT doses 1 and 3, using a multilevel approach. Data come from the District Level Household and Facility Survey 3 (2007–08).ResultsIndividual- and household-level factors were associated with both DPT nonvaccination and dropout between doses 1 and 3. Children whose mothers had no schooling were 2.3 times more likely not to receive any DPT vaccination and 1.5 times more likely to drop out between DPT doses 1 and 3, compared with children whose mothers had 10 or more years of schooling. Although supply-side factors related to availability of public health facilities and immunization-related health workers in villages were not correlated with dropout between DPT doses 1 and 3, children in districts where 46% or more villages had a healthcare subcentre were 1.5 times more likely to receive at least one dose of DPT vaccine compared with children in districts where 30% or fewer villages had subcentres.ConclusionsNonvaccination with DPT in India is influenced by village- and district-level contextual factors over and above individuals' background characteristics. Dropout between DPT doses 1 and 3 is associated more strongly with demand-side factors than with village- and district-level supply-side factors.



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Perfusion of the uterine junctional zone in nulliparous and primiparous women assessed by DCE-MRI, as a function of menstrual cycle and hormonal contraception

Publication date: May 2017
Source:Magnetic Resonance Imaging, Volume 38
Author(s): L.J. Meylaerts, L. Wijnen, M. Bazot, M. Grieten, W. Ombelet, M. Vandersteen
PurposeTo evaluate the perfusion parameters of inner and outer myometrium in healthy nulliparous and primiparous women who are and who are not currently using hormonal contraceptives by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Material and methodsWe performed pelvic 1.5T DCE-MRI on 98 women: 18 nulliparous non-users, 30 nulliparous users, 12 primiparous non-users and 38 primiparous users of hormonal contraception (mean age respectively 26.4, 25.8, 30.23 and 28.18years). The nulliparous non-users underwent DCE-MRI investigations during their follicular, ovulatory and luteal phase. Perfusion parameters (iAUC/volume, Ktrans, Kep and Ve) were assessed in the anterior and posterior junctional zone (JZ), outer myometrium and cervix.ResultsIn nulliparous non-users, the mean Ktrans and iAUC/volume showed a decrease from follicular to luteal phase (0.82 vs 0.55min⁻¹ for Ktrans, p=0/027 and 1.28 vs 0.68 for iAUC/volume, p<0.001). The anterior JZ demonstrated lower Ktrans (p=0.050) and higher Kep (p=0.012), in nulliparous non-users, lower Ktrans in nulliparous users (p<0.001) and lower Ve in primiparous users (p=0.012) than the anterior outer myometrium. Ktrans at the anterior and posterior JZ wall in nulliparous users was lower than in non-users (p=0.001 and p=0.013) and Ve at the anterior JZ wall in primiparous users was lower than in non-users (p=0.044).ConclusionThis study provides data on normal perfusion parameters of inner and outer myometrium, which may be potentially useful in assisted reproductive therapy.



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Spectral characterization, thermal and biological activity studies of Schiff base complexes derived from 4,4′-Methylenedianiline, ethanol amine and benzil

Publication date: 15 April 2017
Source:Journal of Molecular Structure, Volume 1134
Author(s): Sanaa Moustafa Emam
Some new metal(II) complexes of asymmetric Schiff base ligand were prepared by template technique. The shaped complexes are in binuclear structures and were explained through elemental analysis, molar conductivity, various spectroscopic methods (IR, U.V–Vis, XRD, ESR), thermal (TG) and magnetic moment measurements. The IR spectra were done demonstrating that the Schiff base ligand acts as neutral tetradentate moiety in all metal complexes. The electronic absorption spectra represented octahedral geometry for all complexes, while, the ESR spectra for Cu(II) complex showed axially symmetric g-tensor parameter with g׀׀ > g⊥ > 2.0023 indicating to ²B1g ground state with (dx2−y2)¹ configuration. The nature of the solid residue created from TG estimations was affirmed utilizing IR and XRD spectra. The biological activity of the prepared complexes was studied against Land Snails. Additionally, the in vitro antitumor activity of the synthesized complexes with Hepatocellular Carcinoma cell (Hep-G2) was examined. It was observed that Zn(II) complex (5), exhibits a high inhibition of growth of the cell line with IC50 of 7.09 μg/mL.

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Hassle free synthesis of nanodimensional Ni, Cu and Zn sulfides for spectral sensing of Hg, Cd and Pb: A comparative study

Publication date: 5 April 2017
Source:Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 176
Author(s): Zarina Ansari, Shib Shankar Singha, Abhijit Saha, Kamalika Sen
A simple room temperature synthesis method of Ni, Cu and Zn sulfide nanoparticles (NPs) in aqueous medium is reported here. The NPs stabilized in aqueous medium by the citrate ions were characterized by UV–vis, ζ potentials, TEM and Raman spectroscopic techniques. The solid NPs could be isolated from the aqueous medium when allowed to stand for a prolonged time (~20h). The solids were also characterized by IR and powder X-ray analysis. The nanoparticles were further used for the development of facile optical sensing and detection of heavy metal ions at trace scale. Alterations in the absorption spectra of the generated NPs were indicative of their interactions with heavy metal ions. Raman spectral measurements further validate the detection technique. It is found that out of the three synthesized nanoparticles, nickel sulfide NP is a specific sensor for mercury ions whereas zinc sulfide and copper sulfide NPs act as sensors for Hg²⁺, Cd²⁺ and Pb²⁺.

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Novel synthesis of metal sulfides-loaded porous carbon as anode materials for lithium-ion batteries

Publication date: 15 April 2017
Source:Chemical Engineering Journal, Volume 314
Author(s): Siqi Zhang, Rong Lin, Wenbo Yue, Fangzhou Niu, Jie Ma, Xiaojing Yang
Many metal sulfides with high theoretical capacities are potential anode materials for lithium-ion batteries. However, the low electronic conductivity and large volume change of metal sulfides during cycling seriously hamper their practical applications. Herein, we report a novel and scalable strategy to synthesize well-dispersed Ni3S2 (∼5nm) inside porous carbon (CMK-3) by using mesoporous silica (SBA-15) as the template. CMK-3 offers not only good electronic conductivity but also mesopores to accommodate the volume variation of Ni3S2, leading to outstanding electrochemical performance of Ni3S2-loaded CMK-3. To show the versatility of this novel method, ZnS-loaded CMK-3 is also prepared. However, most ZnS nanoparticles are formed outside the pores of CMK-3 with regard to high loading amount. It is inferred that the intermediate product Zn would melt and migrate to the outer surface of CMK-3 prior to the formation of ZnS. This novel synthesis method may offer an attractive pathway to metal sulfide-loaded porous carbon with high lithium storage capacity.

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Ameliorating Effects of Herbal Formula Hemomine on Experimental Subacute Hemorrhagic Anemia in Rats

Publication date: Available online 9 January 2017
Source:Journal of Ethnopharmacology
Author(s): Sae Kwang Ku, Hyemee Kim, Joo Wan Kim, Ki Sung Kang, Hae-Jeung Lee
Ethnopharmacological relevanceHemomine (HM) is an herbal mixture consisting of 5 varieties of the hematopoietic herbal extracts (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia lactiflora Pall., Rehmannia glutinosa Liboschitz ex Stueudel, Glycyrrhiza uralensis Fischer).Aim of the studyAnemia has been treated with iron supplements, whereas it could cause adverse side effects such as digestive discomfort. In the present study, HM was applied to SHA rats to test for several activities so as to verify its therapeutic potentials on anemia and digestive discomfort.Materials and methodsSprague-Dawley rats were assigned to seven groups: (Two controls, two references (ferric hydroxide polymatose (FM) and ferritin extract glycerin hydrate (FA)), three different concentrations of HM, n=8 per groups), and induced subacute hemorrhagic anemia (SHA) through blood exsanguinations once a day for 7 days.ResultsThe SHA animal model showed changes in the markers related to classic iron-deficient and regenerative anemia in this experiment. However, the SHA related anemic signs were dose-dependently inhibited by the administration of HM 2, 1, and 0.5ml/kg for 7 days, and more favorably than the equal dosages of FM and FA. In addition, FM and FA showed the typical constipation signs, including reduction of in thickness of the colonic mucosa, in contrast, HM 2, 1, and 0.5ml/kg groups had no effects on the gastrointestinal motilities and the colonic mucous components when compared to the controls. The results suggested that the HM significantly showed to have therapeutic effects in the experimental SHA in rats, and is more potent than the commercial iron supplement through the proliferation of hematopoietic stem cells with reduced digestive discomfort.ConclusionsTherefore, Hemomine may prove to be a promising hematopoietic and therapeutic agent for anemia.

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A characterization of the antimalarial activity of the bark of Cylicodiscus gabunensis Harms

Publication date: Available online 9 January 2017
Source:Journal of Ethnopharmacology
Author(s): Omar Aldulaimi, Fidelia I. Uche, Hamza Hameed, Haddijatou Mbye, Imran Ullah, Falko Drijfhout, Timothy D.W. Claridge, Paul Horrocks, Wen-Wu Li
Ethnopharmacological relevance and aimA decoction of the bark of Cylicodiscus gabunensis Harms is used as a traditional medicine in the treatment of malaria in Nigeria. This study aims to validate the antimalarial potency of this decoction in vitro against Plasmodium falciparum and define potential bioactive constituents within the C. gabunensis bark.Materials and methodsA bioassay-guided separation and fractionation protocol was applied to C. gabunensis extracts, exploiting the use of a Malaria Sybr Green I Fluorescence assay method to monitor antiproliferative effects on parasites as well as define 50% inhibition concentrations. Spectroscopic techniques, including GC-MS, TOF LC-MS and ¹H NMR were used to identify phytochemicals present in bioactive fractions. Analogues of gallic acid were synthesized de novo to support the demonstration of the antimalarial action of phenolic acids identified in C. gabunensis bark. In vitro cytotoxicity of plant extracts, fractions and gallate analogues was evaluated against the HepG2 cell line.ResultsThe antimalarial activity of ethanolic extracts of C. gabunensis bark was confirmed in vitro, with evidence for phenolic acids, primarily gallic acid and close analogues such as ethyl gallate, likely providing this effect. Further fraction produced the most potent fraction with a 50% inhibitory concentration of 4.7µg/ml. Spectroscopic analysis, including ¹H NMR, LC-MS and GC-MS analysis of this fraction and its acid hydrolyzed products, indicated the presence of conjugates of gallic acid with oligosaccharides. The extracts/fractions and synthetic alkyl gallate showed moderate selectivity against P. falciparum.ConclusionsThese results support the use of the bark of C. gabunensis as a traditional medicine in the treatment of human malaria, with phenolic acid oligosaccharide complexes evident in the most bioactive fractions.

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Role of cAMP/PKA pathway and T-type calcium channels in the mechanism of action of serotonin in human adrenocortical cells

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Estelle Louiset, Céline Duparc, Sébastien Lenglet, Celso E. Gomez-Sanchez, Hervé Lefebvre
In human adrenal, serotonin (5-HT), produced by mast cells located in zona glomerulosa, stimulates production of corticosteroids through a paracrine mechanism involving the 5-HT receptor type 4 (5-HT4). The aim of the present study was to investigate the transduction mechanisms associated with activation of 5-HT4 receptors in human adrenocortical cells. Our results show that 5-HT4 receptors are present in the outer adrenal cortex, both in glomerulosa and fasciculata zonae. In the zona glomerulosa. 5-HT4 receptor was detected both in immunopositive and immunonegative cells for 11β-hydroxylase, an enzyme involved in cortisol synthesis. The data demonstrate that 5-HT4 receptors are positively coupled to adenylyl cyclases and cAMP-dependent protein kinases (PKA). The activation of the cAMP-PKA pathway is associated with calcium influx through T-type calcium channels. Both the adenylyl cyclase/PKA pathway and the calcium influx are involved in 5-HT-induced cortisol secretion.

Graphical abstract

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GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Julia Dörner, Verena Martinez Rodriguez, Ricarda Ziegler, Theresa Röhrig, Rebecca S. Cochran, Ronni M. Götz, Mark D. Levin, Marjut Pihlajoki, Markku Heikinheimo, David B. Wilson
As certain strains of mice age, hyperplastic lesions resembling gonadal tissue accumulate beneath the adrenal capsule. Gonadectomy (GDX) accelerates this heterotopic differentiation, resulting in the formation of wedge-shaped adrenocortical neoplasms that produce sex steroids. Stem/progenitor cells that reside in the adrenal capsule and retain properties of the adrenogonadal primordium are thought to be the source of this heterotopic tissue. Here, we demonstrate that GLI1⁺ progenitors in the adrenal capsule give rise to gonadal-like cells that accumulate in the subcapsular region. A tamoxifen-inducible Cre driver (Gli1-creER^T2) and two reporters (R26R-lacZ, R26R-confetti) were used to track the fate of GLI1⁺ cells in the adrenal glands of B6D2F2 mice, a strain that develops both GDX-induced adrenocortical neoplasms and age-dependent subcapsular cell hyperplasia. In gonadectomized B6D2F2 mice GLI1⁺ progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers. Pdgfra, a gene expressed in adrenocortical stromal cells, was upregulated in the GDX-induced neoplasms. In aged non-gonadectomized B6D2F2 mice GLI1⁺ progenitors gave rise to patches of subcapsular cell hyperplasia. Treatment with GANT61, a small-molecule GLI antagonist, attenuated the upregulation of gonadal-like markers (Gata4, Amhr2, Foxl2) in response to GDX. These findings support the premise that GLI1⁺ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic tissue.



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Electrochemistry of cytochrome P450 17α-hydroxylase/17,20-lyase (P450c17)

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Lisandra L. Martin, Clemens Kubeil, Alexandr N. Simonov, Vladimir L. Kuznetsov, C. Jo Corbin, Richard J. Auchus, Alan J. Conley, Alan M. Bond, Raymond J. Rodgers
Within the superfamily of cytochrome P450 enzymes (P450s), there is a small class which is functionally employed for steroid biosynthesis. The enzymes in this class appear to have a small active site to accommodate the steroid substrates specifically and snuggly, prior to the redox transformation or hydroxylation to form a product. Cytochrome P450c17 is one of these and is also a multi-functional P450, with two activities, the first 17α-hydroxylation of pregnenolone is followed by a subsequent 17,20-lyase transformation to dehydroepiandrosterone (DHEA) as the dominant pathways to cortisol precursors or androgens in humans, respectively. How P450c17 regulates these two redox reactions is of special interest. There is a paucity of direct electrochemical studies on steroidogenic P450s, and in this mini-review we provide an overview of these studies with P450c17. Historical consideration as to the difficulties in obtaining reliable electrochemistry due to issues of handling proteins on an electrode, together with advances in the electrochemical techniques are addressed. Recent work using Fourier transformed alternating current voltammetry is highlighted as this technique can provide both catalytic information simultaneously with the underlying redox transfer with the P450 haem.



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Somatic KCNJ5 mutation occurring early in adrenal development may cause a novel form of juvenile primary aldosteronism

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Ai Tamura, Koshiro Nishimoto, Tsugio Seki, Yoko Matsuzawa, Jun Saito, Masao Omura, Celso E. Gomez-Sanchez, Kohzoh Makita, Seishi Matsui, Nobukazu Moriya, Atsushi Inoue, Maki Nagata, Hironobu Sasano, Yasuhiro Nakamura, Yuto Yamazaki, Yasuaki Kabe, Kuniaki Mukai, Takeo Kosaka, Mototsugu Oya, Sachiko Suematsu, Tetsuo Nishikawa
We report a case of non-familial juvenile primary aldosteronism (PA). Super-selective adrenal venous sampling identified less aldosterone production in the right inferior adrenal segment than others. Bilateral adrenalectomy sparing the segment normalized blood pressure and improved PA. Both adrenals had similar histologies, consisting of a normal adrenal cortex and aldosterone synthase-positive hyperplasia/adenoma. An aldosterone-driving KCNJ5 mutation was detected in the lesions, but not in the histologically normal cortex. After taking into account that the two adrenal glands displayed a similar histological profile, as well as the fact that hyperplastic lesions in both glands exhibited a common KCNJ5 mutation, we conclude that the specific mutation may have occurred at an adrenal precursor mesodermal cell, at an early stage of development; its daughter cells were mixed with non-mutant cells and dispersed into both adrenal glands, resulting into a form of the condition known as genetic mosaicism.



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A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Elzette Pretorius, Wiebke Arlt, Karl-Heinz Storbeck
The abundant adrenal C19 steroid 11β-hydroxyandrostenedione (11OHA4) has been written off as a dead-end product of adrenal steroidogenesis. However, recent evidence has demonstrated that 11OHA4 is the precursor to the potent androgenic 11-oxygenated steroids, 11-ketotestosterone and 11-ketodihydrotestosterone, that bind and activate the human androgen receptor similarly to testosterone and DHT. The significance of this discovery becomes apparent when considering androgen dependent diseases such as castration resistant prostate cancer and diseases associated with androgen excess, e.g. congenital adrenal hyperplasia and polycystic ovary syndrome. In this review we describe the production and metabolism of 11-oxygenated steroids. We subsequently discuss their androgenic activity and highlight the putative role of these androgens in disease states.



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Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Nesa Marti, José A. Galván, Amit V. Pandey, Mafalda Trippel, Coya Tapia, Michel Müller, Aurel Perren, Christa E. Flück
Recently, dihydrotestosterone biosynthesis through the backdoor pathway has been implicated for the human testis in addition to the classic pathway for testosterone (T) synthesis. In the human ovary, androgen precursors are crucial for estrogen synthesis and hyperandrogenism in pathologies such as the polycystic ovary syndrome is partially due to ovarian overproduction. However, a role for the backdoor pathway is only established for the testis and the adrenal, but not for the human ovary. To investigate whether the backdoor pathway exists in normal and PCOS ovaries, we performed specific gene and protein expression studies on ovarian tissues.We found aldo-keto reductases (AKR1C1-1C4), 5α-reductases (SRD5A1/2) and retinol dehydrogenase (RoDH) expressed in the human ovary, indicating that the ovary might produce dihydrotestosterone via the backdoor pathway. Immunohistochemical studies showed specific localization of these proteins to the theca cells. PCOS ovaries show enhanced expression, what may account for the hyperandrogenism.

Graphical abstract

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Regulation of zonation and homeostasis in the adrenal cortex

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Emanuele Pignatti, Sining Leng, Diana L. Carlone, David T. Breault
The adult adrenal cortex is organized into concentric zones, each specialized to produce distinct steroid hormones. Cellular composition of the cortex is highly dynamic and subject to diverse signaling controls. Cortical homeostasis and regeneration rely on centripetal migration of steroidogenic cells from the outer to the inner cortex, which is accompanied by direct conversion of zona glomerulosa (zG) into zona fasciculata (zF) cells. Given the important impact of tissue structure and growth on steroidogenic function, it is essential to understand the mechanisms governing adrenal zonation and homeostasis. Towards this end, we review the distinctions between each zone by highlighting their morphological and ultra-structural features, discuss key signaling pathways influencing zonal identity, and evaluate current evidence for long-term self-renewing stem cells in the adult cortex. Finally, we review data supporting zG-to-zF transdifferentiation/direct conversion as a major mechanism of adult cortical renewal.



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Function of CYP11A1 in the mitochondria

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Yu Chien, Karen Rosal, Bon-chu Chung
Steroids are synthesized from the adrenal glands and gonads by enzymes of the cytochromes P450 and hydroxysteroid dehydrogenase in nature. These enzymes are located in the membrane of endoplasmic reticulum and mitochondria to catalyze redox reactions using electrons transported from the membrane. In the mitochondria, steroidogenic enzymes are inserted into the inner membrane with the bulk of the protein facing the matrix. They are not only important for steroid biosynthesis, their presence also affects mitochondrial morphology. Mitochondria undergo constant fission and fusion; they play important roles in energy production, apoptosis, and metabolism. Their defects often lead to human diseases. Mitochondrial cristae are usually lamellar in shape, but can also assume different shapes. Cristae in the mitochondria of steroidogenic cells are tubular-vesicular in shape. This cristae shape is also related to the degree of steroidogenic cell differentiation. Steroidogenic enzymes in the mitochondria appear to have a dual role in shaping the morphology of mitochondria and in steroid production.



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Structural insights into the function of steroidogenic cytochrome P450 17A1

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Rahul Yadav, Elyse M. Petrunak, D. Fernando Estrada, Emily E. Scott
Cytochrome P450 17A1 (CYP17A1) operates at the core of human steroidogenesis, directing precursors into mineralocorticoids, glucocorticoids, or sex steroids. Although the 17α−hydroxylase and 17,20-lyase activities of this dual function enzyme have been investigated extensively, until recently no CYP17A1 structures were available to inform our understanding. Structures of CYP17A1 with a range of steroidal inhibitors and substrates are now available. This review relates functional knowledge of this enzyme to structural features defining the selective differentiation between its various substrates. While both hydroxylase and lyase substrates have similar orientations with respect to the heme, subtle differences in hydrogen bonding between CYP17A1 and the C3 substituent at the opposite end of ligands appear to correlate with differential substrate utilization and product formation. Complementary structural information from solution NMR supports cytochrome b5 allosteric modulation of the lyase reaction, implicating regions involved in ligand access to the otherwise buried active site.



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The metabolic fate and receptor interaction of 16α-hydroxyprogesterone and its 5α-reduced metabolite, 16α-hydroxy-dihydroprogesterone

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Desmaré van Rooyen, Therina du Toit, Renate Louw-du Toit, Donita Africander, Pieter Swart, Amanda C. Swart
16α-hydroxyprogesterone (16OHP4) is not well characterised in terms of metabolism and receptor interaction. We therefore investigated its metabolism by adrenal CYP11B and peripheral steroidogenic enzymes, SRD5A and AKR1C2. UHPLC-MS/MS analyses identified novel steroids: the biosynthesis of 4-pregnen-11β,16α-diol-3,20-dione catalysed by CYP11B2; the 5α-reduction of the latter and 16OHP4 catalysed by SRD5A yielding 5α-pregnan-11β,16α-diol-3,20-diovne and 5α-pregnan-16α-ol-3,20-dione (16OH-DHP4); and 16OH-DHP4 converted by AKR1C2 to 5α-pregnan-3α,16α-diol-20-one. Receptor studies showed 16OHP4, 16OH-DHP4, progesterone and dihydroprogesterone (DHP4) were weak partial AR agonists; 16OHP4, 16OH-DHP4 and DHP4 exhibited weak partial agonist activity towards PR-B with DHP4 also exhibiting partial agonist activity towards PR-A. Data showed that while the 5α-reduction of P4 decreased PR activation significantly, 16OHP4 and 16OH-DHP4 exhibited comparable receptor activation. Although the clinical relevance of 16OHP4 remains unclear the elevated 16OHP4 levels characteristic of 21OHD, CAH, PCOS, prostate cancer, testicular feminization syndrome and cryptorchidism likely contribute towards these clinical conditions, inducing receptor-activated target genes.



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Endothelial cells regulate β-catenin activity in adrenocortical cells via secretion of basic fibroblast growth factor

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Carolin Schwafertz, Sven Schinner, Markus C. Kühn, Matthias Haase, Amelie Asmus, Birgit Mülders-Opgenoorth, Ishrath Ansurudeen, Peter J. Hornsby, Henning Morawietz, Elke Oetjen, Matthias Schott, Holger S. Willenberg
Endothelial cell-derived products influence the synthesis of aldosterone and cortisol in human adrenocortical cells by modulating proteins such as steroidogenic acute-regulatory (StAR) protein, steroidogenic factor (SF)-1 and CITED2. However, the potential endothelial cell-derived factors that mediate this effect are still unknown. The current study was perfomed to look into the control of β-catenin activity by endothelial cell-derived factors and to identify a mechanism by which they affect β-catenin activity in adrenocortical NCIH295R cells.Using reporter gene assays and Western blotting, we found that endothelial cell-conditioned medium (ECCM) led to nuclear translocation of β-catenin and an increase in β-catenin-dependent transcription that could be blocked by U0126, an inhibitor of the mitogen-activated protein kinase pathway. Furthermore, we found that a receptor tyrosin kinase (RTK) was involved in ECCM-induced β-catenin-dependent transcription. Through selective inhibition of RTK using Su5402, it was shown that receptors responding to basic fibroblast growth factor (bFGF) mediate the action of ECCM.Adrenocortical cells treated with bFGF showed a significant greater level of bFGF mRNA. In addition, HUVECs secrete bFGF in a density-dependent manner. In conclusion, the data suggest that endothelial cells regulate β-catenin activity in adrenocortical cells also via secretion of basic fibroblast growth factor.

Graphical abstract

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Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Koshiro Nishimoto, Minae Koga, Tsugio Seki, Kenji Oki, Elise P. Gomez-Sanchez, Celso E. Gomez-Sanchez, Mitsuhide Naruse, Tomokazu Sakaguchi, Shinya Morita, Takeo Kosaka, Mototsugu Oya, Tadashi Ogishima, Masanori Yasuda, Makoto Suematsu, Yasuaki Kabe, Masao Omura, Tetsuo Nishikawa, Kuniaki Mukai
Our group previously purified human and rat aldosterone synthase (CYP11B2 and Cyp11b2, respectively) from their adrenals and verified that it is distinct from steroid 11β-hydroxylase (CYP11B1 or Cyp11b1), the cortisol- or corticosterone-synthesizing enzyme. We now describe their distributions immunohistochemically with specific antibodies. In rats, there is layered functional zonation with the Cyp11b2-positive zona glomerulosa (ZG), Cyp11b1-positive zona fasciculata (ZF), and Cyp11b2/Cyp11b1-negative undifferentiated zone between the ZG and ZF. In human infants and children (<12 years old), the functional zonation is similar to that in rats. In adults, the adrenal cortex remodels and subcapsular aldosterone-producing cell clusters (APCCs) replace the continuous ZG layer. We recently reported possible APCC-to-APA transitional lesions (pAATLs) in 2 cases of unilateral multiple adrenocortical micro-nodules. In this review, we present 4 additional cases of primary aldosteronism, from which the extracted adrenals contain pAATLs, with results of next generation sequencing for these lesions. Immunohistochemistry for CYP11B2 and CYP11B1 has become an important tool for the diagnosis of and research on adrenocortical pathological conditions and suggests that APCCs may be the origin of aldosterone-producing adenoma.



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Analysis of ARMC5 expression in human tissues

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Annabel Berthon, Fabio Faucz, Jerome Bertherat, Constantine A. Stratakis
Mutations in ARMC5 gene have been recently identified as the main cause of Primary Macronodular Adrenocortical Hyperplasia (PMAH). PMAH patients have an ARMC5 germline mutation and, in addition, somatic tissue-specific mutations. This is consistent with the two-hit hypothesis of tumorigenesis and suggests that ARMC5 may be a tumor suppressor gene. As its function is still unclear, we analyzed the expression of the four ARMC5 isoforms in 46 normal human tissues. This showed that at least one ARMC5 isoform is ubiquitously expressed throughout the body; however, only 7 tissues expressed all isoforms, including the adrenal gland and the brain. Interestingly, the highest expression for ARMC5 in the brain is in the pituitary gland. The isoform ARMC5-003 was present in most endocrine tissues including the pituitary, adrenal glands and the pancreas. In this report, we present new data about the ARMC5 expression pattern in human tissues; its wide expression in brain, pituitary gland and other tissues suggest that mutations may be responsible for additional pathologies, beyond what is already known in PMAH and meningiomas.



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Seventeenth Conference on the Adrenal Cortex (Adrenal 2016) Boston, MA, March 28–31, 2016

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Bernard P. Schimmer, Raymond J. Rodgers




http://ift.tt/2iWAsTJ

Adrenal cortical and chromaffin stem cells: Is there a common progeny related to stress adaptation?

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Charlotte Steenblock, Maria F. Rubin de Celis, Andreas Androutsellis-Theotokis, Mariko Sue, Luis F. Delgadillo Silva, Graeme Eisenhofer, Cynthia L. Andoniadou, Stefan R. Bornstein
The adrenal gland is a highly plastic organ with the capacity to adapt the body homeostasis to different physiological needs. The existence of stem-like cells in the adrenal cortex has been revealed in many studies. Recently, we identified and characterized in mice a pool of glia-like multipotent Nestin-expressing progenitor cells, which contributes to the plasticity of the adrenal medulla. In addition, we found that these Nestin progenitors are actively involved in the stress response by giving rise to chromaffin cells. Interestingly, we also observed a Nestin-GFP-positive cell population located under the adrenal capsule and scattered through the cortex. In this article, we discuss the possibility of a common progenitor giving rise to subpopulations of cells both in the adrenal cortex and medulla, the isolation and characterization of this progenitor as well as its clinical potential in transplantation therapies and in pathophysiology.



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Introduction to the 2016 Keith L. Parker Memorial Lecturer: Douglas M. Stocco, Ph.D.

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Walter L. Miller
Douglas M. (Doug) Stocco is Professor Emeritus at Texas Tech University Health Sciences Center in Lubbock, TX, and is internationally renowned for his work characterizing the steroidogenic acute regulatory protein, StAR. Stocco's laboratory isolated and cloned StAR from mouse Leydig MA-10 cells, collaborated on the demonstration that StAR mutations cause congenital lipoid adrenal hyperplasia, and delineated much of what is known about the intracellular pathways that regulate its production. This work resolved a decades-long quest to identify the mechanism underlying the acute regulation of steroidogenesis.



http://ift.tt/2iXPUB4

The ER-mitochondria couple: In life and death from steroidogenesis to tumorigenesis

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Mabrouka Doghman-Bouguerra, Enzo Lalli
Steroidogenesis is a multistep process where interorganelle communications between the endoplasmic reticulum and mitochondria are critical. These intimate interactions physically occur through the Mitochondria-Associated ER membranes called MAMs. MAMs play important roles in mitochondrial morphology and in many cellular functions ranging from lipid metabolism, to calcium signaling and apoptosis together with a critical effect on steroidogenesis. Moreover, our recent characterization of new MAM resident proteins in adrenocortical cells extends the function of MAM in the mechanism of resistance of cancer cells to apoptotic stimuli and offers new perspectives in targeted therapeutic approaches for adrenocortical tumorigenesis.



http://ift.tt/2iWDwz2

A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Douglas M. Stocco, Amy H. Zhao, Lan N. Tu, Kanako Morohaku, Vimal Selvaraj
The synthesis of steroid hormones occurs in specific cells and tissues in the body in response to trophic hormones and other signals. In order to synthesize steroids de novo, cholesterol, the precursor of all steroid hormones, must be mobilized from cellular stores to the inner mitochondrial membrane (IMM) to be converted into the first steroid formed, pregnenolone. This delivery of cholesterol to the IMM is the rate-limiting step in this process, and has long been known to require the rapid synthesis of a new protein(s) in response to stimulation. Although several possibilities for this protein have arisen over the past few decades, most of the recent attention to fill this role has centered on the candidacies of the proteins the Translocator Protein (TSPO) and the Steroidogenic Acute Regulatory Protein (StAR). In this review, the process of regulating steroidogenesis is briefly described, the characteristics of the candidate proteins and the data supporting their candidacies summarized, and some recent findings that propose a serious challenge for the role of TSPO in this process are discussed.



http://ift.tt/2iXJnX2

SNAREs and cholesterol movement for steroidogenesis

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Fredric B. Kraemer, Wen-Jun Shen, Salman Azhar
Steroidogenesis is a complex process through which cholesterol traffics to mitochondria and is converted via a series of enzymatic steps to steroid hormones. Although the rate-limiting step in this process is the movement of cholesterol from the outer to the inner mitochondrial membrane via the actions of StAR, a continuous supply of cholesterol must be delivered to the outer mitochondrial membrane during active steroidogenesis and this is derived from multiple sources, including lipoprotein uptake, endogenous cholesterol synthesis and release from stores within cytoplasmic lipid droplets. A number of mechanisms have been suggested to contribute to cholesterol trafficking to mitochondria; however, there is no definitive consensus and this is particularly so in regards to trafficking from cytoplasmic lipid droplets. In this paper we review experiments in which we have surveyed the expression of SNARE proteins in steroidogenic tissue and cells and examined the role of SNAREs in mediating cholesterol movement from lipid droplets to the mitochondria based on multiple studies that identified SNAREs as components of cytoplasmic lipid droplets. We established and characterized an in vitro mitochondria reconstitution assay system that enabled us to examine the impact of adding recombinant SNARE proteins specifically on the movement of cholesterol from model lipid droplets to the outer mitochondrial membrane. Using this reconstitution assay system in combination with siRNA knockdown experiments in rat primary granulosa cells or in steroidogenic cell lines, we showed that several SNARE proteins are important components in the trafficking of cholesterol from lipid droplets to the mitochondria for steroidogenesis.



http://ift.tt/2iWu8eY

A single cell level measurement of StAR expression and activity in adrenal cells

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Jinwoo Lee, Takeshi Yamazaki, Hui Dong, Colin Jefcoate
The Steroidogenic acute regulatory protein (StAR) directs mitochondrial cholesterol uptake through a C-terminal cholesterol binding domain (CBD) and a 62 amino acid N-terminal regulatory domain (NTD) that contains an import sequence and conserved sites for inner membrane metalloproteases. Deletion of the NTD prevents mitochondrial import while maintaining steroidogenesis but with compromised cholesterol homeostasis. The rapid StAR-mediated cholesterol transfer in adrenal cells depends on concerted mRNA translation, p37 StAR phosphorylation and controlled NTD cleavage. The NTD controls this process with two cAMP-inducible modulators of, respectively, transcription and translation SIK1 and TIS11b/Znf36l1. High-resolution fluorescence in situ hybridization (HR-FISH) of StAR RNA resolves slow RNA splicing at the gene loci in cAMP-induced Y-1 cells and transfer of individual 3.5 kB mRNA molecules to mitochondria. StAR transcription depends on the CREB coactivator CRTC2 and PKA inhibition of the highly inducible suppressor kinase SIK1 and a basal counterpart SIK2. PKA-inducible TIS11b/Znf36l1 binds specifically to highly conserved elements in exon 7 thereby suppressing formation of mRNA and subsequent translation. Co-expression of SIK1, Znf36l1 with 3.5 kB StAR mRNA may limit responses to pulsatile signaling by ACTH while regulating the transition to more prolonged stress.



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Receptor tyrosine kinase inhibition by regorafenib/sorafenib inhibits growth and invasion of meningioma cells

Publication date: March 2017
Source:European Journal of Cancer, Volume 73
Author(s): Marcus Tuchen, Annette Wilisch-Neumann, Evelyn A. Daniel, Lisa Baldauf, Doreen Pachow, Johannes Scholz, Frank Angenstein, Oliver Stork, Elmar Kirches, Christian Mawrin
Systemic chemotherapeutic treatment for unresectable and/or aggressive meningiomas is still unsatisfying. PDGF receptor (PDGFR)-mediated activation of mitogenic signalling has been shown to be active in meningiomas. Therefore, we evaluate in vitro and in vivo the effects of inhibiting PDGFR using the clinically well-characterised tyrosine kinase inhibitors sorafenib or regorafenib in meningioma models. IOMM-Lee meningioma cells were used to assess cytotoxic effects, inhibition of proliferation, induction of apoptosis, as well as inhibition of migration and motility by sorafenib and regorafenib. Using an orthotopic mouse xenograft model, growth inhibition as monitored by magnetic resonance imaging, and overall survival of sorafenib- or regorafenib-treated mice compared with control animals was determined. Treatment of malignant IOMM-Lee cells resulted in significantly reduced cell survival and induction of apoptosis following regorafenib and sorafenib treatment. Western blots showed that both drugs target phosphorylation of p44/42 ERK via downregulation of the PDGFR. Both drugs additionally showed significant inhibition of cell motility and invasion. In vivo, mice with orthotopic meningioma xenografts showed a reduced volume (n.s.) of signal enhancement in MRI (mainly tumour) following sorafenib and regorafenib treatment. This was translated in a significantly increased overall survival time (p ≤ 0.05) for regorafenib-treated mice. Analyses of in vivo-grown tumours demonstrated again reduced PDGFR expression and expression/phosphorylation of p44/42. Sorafenib and regorafenib show antitumour activity in vitro and in vivo by targeting PDGFR and p44/42 ERK signalling.



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Acquisition of Basic Microsurgery Skills Using Home Based Simulation Training – A Randomised Control Study

Acquisition of the fine motor skills required in microsurgery can be challenging in the current training system. As a result, there is an increased demand for novel training and assessment methods to optimise learning outside the clinical setting. We present a randomised control trial of three microsurgical training models – laboratory tabletop training microscope (Laboratory Microscope, LM), low-cost jewellers microscope (Home Microscope, HM) and iPad trainer (Home Tablet, HT).

http://ift.tt/2iXC0P1

An analysis of the ideal muscle weight of gracilis muscle transplants for facial reanimation surgery with regard to the donor nerve and outcome

Free functional muscle transfers represent the "criterion standard" for smile reconstruction in facial paralysis. The gracilis muscle is a common donor muscle, however no data exist regarding volume of muscle tissue that is necessary for symmetric commissure excursion.

http://ift.tt/2iWBVJG

Benign hand tumors are indicated for surgery, according to patient-rated outcome measures

This study assessed the treatment outcomes of upper extremity benign tumours using the patient-rated outcome measure Hand20 questionnaire.

http://ift.tt/2iXtYG1

Surgical treatment of disabling conditions caused by anogenital lichen sclerosus in women: an account of surgical procedures and results, including patient satisfaction, benefits and improvements in aspects of health-related quality of life

Anogenital lichen sclerosus (LS), a chronic dermatitis causing scarring and introital stenosis, may prevent sexual intercourse and reduce health-related quality of life (QoL). Surgery can restore the anatomy, allowing patients to resume their sexual lives. This study investigates outcomes in women treated with local skin flaps.

http://ift.tt/2iWxQ8g

Impact of the method and success of pharyngeal reconstruction on the outcome of treating laryngeal and hypopharyngeal cancers with pharyngolaryngectomy: a national analysis

Surgical treatment of cancers which arise from or invade the hypopharynx presents major reconstructive challenges. Reconstructive failure exposes the airway and neck vessels to digestive contents.

http://ift.tt/2iXGlC5

Cephalometric Changes Associated With Spring-Assisted Cranioplasty For Scaphocephaly – Analysis Of The Changes In The First Three-Months

Spring-assisted cranioplasty (SAC) has become an accepted treatment for patients with sagittal craniosynostosis, however, early effects of springs on skull dimensions have never been assessed with objective measurements in the literature. This study evaluated changes in skull dimensions and intracranial volume (ICV) during the first three months of SAC for sagittal synostosis.

http://ift.tt/2iWsJoD