Δευτέρα, 22 Μαΐου 2017

A prospective cohort study of insomnia and chronic kidney disease in Japanese workers

Abstract

Purpose

The role of insomnia in chronic kidney disease (CKD) is controversial. To date, there have been no prospective studies investigating insomnia, CKD and the effect of shift work. We assessed insomnia and CKD risk in a prospective, occupational cohort study.

Methods

A total of 3600 participants with normal kidney function were followed for an average of 4.4 years. Insomnia was assessed using the Athens Insomnia Scale (AIS). CKD was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 at the first health examination. Cox proportional hazard regression models were used to estimate hazard ratios with 95% confidence intervals of insomnia for CKD development.

Results

A total of 182 CKD cases were identified. After adjustment for potential confounders, we did not observe an association between insomnia (AIS score ≥6) and CKD. However, the AIS item of awakening during the night was associated with a significantly increased CKD risk (hazard ratio = 3.10, 95% confidence interval 1.68–5.30). In further analyses, having difficulty with sleep induction was associated with an increased CKD risk among shift workers (hazard ratio = 3.34, 95% confidence interval 1.22–8.31). This association was not present among non-shift workers.

Conclusions

Awakening during the night is associated with a moderately increased CKD risk.



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A Practical Method for Computation of Laplace Inverses by Post–Widder’s Formula

Abstract

In this note, a novel method for parametric inversion of Laplace transforms by means of the Post–Widder formula is developed. In brief, the coefficients of the MacLaurin series equivalent of the sequence, which converges to Post–Widder's formula at infinity, are calculated by means of the iterated Aitken transform. Subsequently, the asymptotic values of such coefficients are obtained using the diagonal Padé approximants in a computationally efficient manner. Our method revives the classical Post–Widder formula from the practical viewpoint.



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Immediate antibiotics for uncomplicated RTIs do not reduce risk of admission and death, study finds

Offering a delayed rather than an immediate prescription for antibiotics to adults with lower respiratory tract infections is associated with a lower likelihood of a subsequent GP consultation and no...
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Necrotic cutaneous vasculitic skin lesions: a case of atypical Henoch-Schönlein purpura in a child with heterozygosity for factor V Leiden

Description

A Caucasian boy aged 5 years presented with acute onset of a non-tender, palpable purpuric rash to his lower limbs, preceded by a mild upper respiratory tract infection. Clinical findings were consistent with Henoch-Schönlein purpura (HSP) and he was discharged with community follow-up to monitor his lesions, blood pressure and urinalysis.

However, he clinically deteriorated over the following week with two further admissions due to evolving purpuric skin lesions (figure 1) and development of severe joint pain requiring opioid analgesia. There was no clinical evidence of renal or intestinal involvement.

Figure 1

Initial presentation of the purpuric Henoch Schonlein purpura rash.

Over a subsequent 6-week period, his purpuric lesions progressed to full thickness skin necrosis (figure 2). This was confirmed by a plastic surgery assessment and he was referred for a tertiary rheumatology review. He underwent a series...



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Surgery in late melanoma adrenal metastasis

Metastatic melanoma to adrenal gland are very infrequent, being generally associated with additional evidence of systemic disease and, consequently, with short-term survival. However, the prognosis and the therapeutic management vary depending on some important oncological features. Long-term survival rates have been described after complete resection of metastatic disease. Here, we report the case of a woman aged 41 years diagnosed with a cutaneous melanoma on the right side of her paravertebral region, level III of Clark, in 2002, who underwent surgical excision of the tumour with negative margins and a negative sentinel node. She posteriorly developed pulmonary metastasis in 2006 and 2009, both resected with curative intention and in 2013, she was diagnosed with an adrenal metastasis. Therefore, she was submitted to an uneventful right laparoscopic adrenalectomy. The pathology report described metastasis of a cutaneous melanoma, negative for BRAF mutation. The patient is actually disease-free after 30 months of follow-up.



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Unusual course of a haematoma of the thigh

Description

A Caucasian woman aged 56 years presented to emergency room (ER) department with leucorrhoea and fever since 48 hours. She was a smoker, had no diabetes history, no prosthetic material and denied use of injected drugs.

A month before, the patient had a closed inguinal trauma due to fall from height with a muscle strain of the anterior right thigh. Despite rest and analgesics, she went to ER several times because of progressive local pain and swelling. After 3 weeks, a local ultrasound scan showed a 3 cm size haematoma associated with probable rupture of obturator internus and rectus femoris muscles. On the following days, she developed fetid leucorrhoea associated with movements and compression of the anterior thigh. On physical examination and analyses, she had sepsis criteria and the abdomen/pelvic CT scan (figure1A, B) and MRI (figure1C, D) showed an abscess of 105x25mm size, complicated with...



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Bottom of an iceberg: undiagnosed aortic aneurysm masquerading as vocal cord palsy

Description

A previously healthy woman aged 60 years was referred to a tertiary referral cancer centre with change of voice for 1 week suspecting neoplastic aetiology on account of her tobacco chewing habit of more than 20 years. No history of voice abuse, fever or cough was there preceding the onset of the change of voice. She did not have any previous history of hospitalisation or diagnosed comorbidities. On clinical examination, her pulse rate was 82 bpm; blood pressure was 130/90 mm Hg and respiratory rate was 12/min.

Video laryngoscopy examination revealed left vocal cord palsy with no obvious lesion. A whole-body F18 FDG PET–CT scan revealed the presence of 6.6x4.8x6.7 cm lobulated sacullar aneurysm arising from the aortic arch between the origins of the left common carotid and subclavian arteries (figures 1 and 2). The likely mycotic aneurysm caused significant surrounding metabolically active inflammatory changes (figure 3). The...



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Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): L. Marcellin, P. Santulli, S. Chouzenoux, O. Cerles, C. Nicco, B. Dousset, M. Pallardy, S. Kerdine-Römer, PA. Just, C. Chapron, F. Batteux
The redox-sensitive nuclear factor erythroid-derived 2-like 2 (NRF2) controls endogenous antioxidant enzymes’ transcription and protects against oxidative damage which is triggered by inflammation and known to favor progression of endometriosis. Glutamate Cysteine Ligase (GCL), a target gene of NRF2, is the first enzyme in the synthesis cascade of glutathione, an important endogenous antioxidant. Sixty-one patients, with thorough surgical examination of the abdominopelvic cavity, were recruited for the study: 31 with histologically-proven endometriosis and 30 disease-free women taken as controls. Expressions of NRF2 and GCL were investigated by quantitative RT-PCR and immunohistochemistry in eutopic and ectopic endometria from endometriosis-affected women and in endometrium of disease-free women. Ex vivo stromal and epithelial cells were extracted and purified from endometrial and endometriotic biopsies to explore expression of NRF2 and GCL in both stromal and epithelial compartments by western blot. Finally, in order to strengthen the role of NRF2 in endometriosis pathogenesis, we evaluated the drop of NRF2 expression in a mouse model of endometriosis using NRF2 knockout (NRF2-/-) mice. The mRNA levels of NRF2 and GCL were significantly lower in ectopic endometria of endometriosis-affected women compared to eutopic endometria of disease-free women. The immunohistochemical analysis confirmed the decreased expression of both NRF2 and GCL in ectopic endometriotic tissues compared to eutopic endometria of endometriosis-affected and disease-free women. Immunoblotting revealed a significant decreased of NRF2 and GCL expression in epithelial and stroma cells from ectopic lesions of endometriosis-affected women compared to eutopic endometria from controls. Using a murine model of endometriosis, NRF2-/- implants were more fibrotic compared to wild-type with an increased weight and volume. These findings indicate that expression of the transcription factor NRF2 and its effector GCL are both profoundly deregulated in endometriotic lesions towards increased growth and fibrogenetic processes.

Graphical abstract

image


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The many faces of compartmentalized PKA signalosomes

Publication date: September 2017
Source:Cellular Signalling, Volume 37
Author(s): Omar Torres-Quesada, Johanna E. Mayrhofer, Eduard Stefan
Cellular signal transmission requires the dynamic formation of spatiotemporally controlled molecular interactions. At the cell surface information is received by receptor complexes and relayed through intracellular signaling platforms which organize the actions of functionally interacting signaling enzymes and substrates. The list of hormone or neurotransmitter pathways that utilize the ubiquitous cAMP-sensing protein kinase A (PKA) system is expansive. This requires that the specificity, duration, and intensity of PKA responses are spatially and temporally restricted. Hereby, scaffolding proteins take the center stage for ensuring proper signal transmission. They unite second messenger sensors, activators, effectors, and kinase substrates within cellular micro-domains to precisely control and route signal propagation. A-kinase anchoring proteins (AKAPs) organize such subcellular signalosomes by tethering the PKA holoenzyme to distinct cell compartments. AKAPs differ in their modular organization showing pathway specific arrangements of interaction motifs or domains. This enables the cell- and compartment- guided assembly of signalosomes with unique enzyme composition and function. The AKAP-mediated clustering of cAMP and other second messenger sensing and interacting signaling components along with functional successive enzymes facilitates the rapid and precise dissemination of incoming signals. This review article delineates examples for different means of PKA regulation and for snapshots of compartmentalized PKA signalosomes.



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Beyond implementation research for improving maternal, newborn and child health globally [Letters]



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Fair pricing or pricing for profit? [News]



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Relation of total sugars, fructose and sucrose with incident type 2 diabetes: a systematic review and meta-analysis of prospective cohort studies [Research]

BACKGROUND:

Sugar-sweetened beverages are associated with type 2 diabetes. To assess whether this association holds for the fructose-containing sugars they contain, we conducted a systematic review and meta-analysis of prospective cohort studies.

METHODS:

We searched MEDLINE, Embase, CINAHL and the Cochrane Library (through June 2016). We included prospective cohort studies that assessed the relation of fructose-containing sugars with incident type 2 diabetes. Two independent reviewers extracted relevant data and assessed risk of bias. We pooled risk ratios (RRs) using random effects meta-analyses. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

RESULTS:

Fiffeen prospective cohort studies (251 261 unique participants, 16 416 cases) met the eligibility criteria, comparing the highest intake (median 137, 35.2 and 78 g/d) with the lowest intake (median 65, 9.7 and 25.8 g/d) of total sugars, fructose and sucrose, respectively. Although there was no association of total sugars (RR 0.91, 95% confidence interval [CI] 0.76–1.09) or fructose (RR 1.04, 95% CI 0.84–1.29) with type 2 diabetes, sucrose was associated with a decreased risk of type 2 diabetes (RR 0.89, 95% CI 0.80–0.98). Our confidence in the estimates was limited by evidence of serious inconsistency between studies for total sugars and fructose, and serious imprecision in the pooled estimates for all 3 sugar categories.

INTERPRETATION:

Current evidence does not allow us to conclude that fructose-containing sugars independent of food form are associated with increased risk of type 2 diabetes. Further research is likely to affect our estimates.

Trial registration:

ClinicalTrials.gov, no. NCT01608620



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Quick and easy methods for "clean-catch" urine samples [Letters]



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Necrotizing fasciitis after scalpel injury sustained during postmortem examination [Practice]



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Developmental surveillance of young children in clinical settings: Time to step out or step up? [Commentary]



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Sodium-glucose cotransporter 2 inhibitors for treating diabetes mellitus [Practice]



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Response to: "Beyond implementation research for improving maternal, newborn and child health globally" [Letters]



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Kerion [Practice]



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Is AI a threat or benefit to health workers? [News]



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Toxic shock syndrome, tampons and laboratory standard-setting [Humanities]



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Renowned researchers inducted into hall of fame [News]



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Tonsillitis

Tonsillitis: Inflammation of one or both tonsils, typically as a result of infection by a virus or 'bacteria.



MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Traumatic phacocele: a rare but unique scenario

Description

The term phacocele is derived from a Greek word, where ‘phaco’ denotes lens and ‘kele’ meaning herniation. It is an unusual and very rare clinical condition.1

A 48-year-old male patient presented with sudden-onset diminution of vision, redness, pain in his left eye following blunt trauma 2 days ago. There was no significant ocular or systemic history. Visual acuity was perception of light positive with projection of rays accurate in left eye and 20/20 in right eye. On slit-lamp examination of the affected eye, there was a solid globular mass in the subconjunctival space located in the superonasal quadrant measuring 8x9 mm with smooth surface and rounded margins. There was an area of suspected scleral dehiscence, temporal to the mass lesion with uveal show (figure 1A). There was diffuse corneal oedema with descemet's folds. Anterior chamber detail was not clearly visible because of hyphaema (figure 1B). Intraocular pressure was 4 mm Hg....



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Angioscopy-guided selective aspiration thrombectomy for acute pulmonary thromboembolism

An 83-year-old woman with a history of pulmonary thromboembolism 10 years ago was referred for dyspnea. Anticoagulation therapy was terminated by her family doctor 3 years previously. On admission, D-dimer level was 16.6 µg/mL and arterial blood gas showed 88.1% on room air. Pulmonary arteriography (PAG) revealed some filling defects, mainly in the right interlobar artery (figure 1A). Non-obstructive angioscopy (NOA)1 showed two kinds of thrombi in the pulmonary arteries. At the translucent area, a massive, red, smooth thrombus was seen (figure 1B, video 1). Between the massive thrombus, floating, mobile, white-red, puff-like thrombi were demonstrated (figure 1C, video 2). As the thrombi entered the catheter spontaneously, aspiration was performed using a 20 mL syringe. Thrombi in the guiding catheter were collected by removing the guiding catheter. For the first trial, red thrombi were effectively aspirated (figure...



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Laryngocoele formation after ingestion of fish bone

Description

A 72-year-old man presented to the clinic with a 3-week history of anterior left neck pain. He described constant discomfort since eating fish a few weeks prior. He recalled pain at the time of eating, and felt he had ingested a fish bone.

There was no dysphagia, dyspnoea or haemoptysis on presentation. He had a medical history of type II diabetes mellitus, with no previous Ear, Nose and Throat issues.

Examination of the neck and oropharynx was normal. There were no palpable nodes or masses. Flexible nasendoscopy demonstrated a normal larynx. A lateral X-ray of the neck was arranged and showed no foreign body.

He was treated with simple analgesia and antacid, with a plan to review in 1 week.

He was reviewed and again examination and nasendoscopy were normal. CT scan revealed a traumatic laryngocoele at the left piriform sinus (figures 1 and 2).

...



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Severe medication-induced peripheral neuropathy treated with topical doxepin cream in a paediatric patient with leukaemia

A 17-year-old female with recently relapsed acute lymphoblastic leukaemia and a treatment course complicated by rhinocerebral mucormycosis infection developed severe peripheral neuropathy during the treatment for mucormycosis infection. This was felt to be a medication side effect. Her peripheral neuropathy was refractory to many well-established treatments, but ultimately responded dramatically and consistently to a novel therapy, topical doxepin cream (5%). This case report is the first published report of the application of topical doxepin cream for treatment of peripheral neuropathy in a paediatric patient.



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Systemic inflammatory response syndrome (SIRS) and a left bundle branch block (LBBB) due to nitrofurantoin

We present a case of a 74-year-old woman, who was on nitrofurantoin treatment for urinary tract infection (UTI), with fever and chills 7 hours after taking nitrofurantoin. She was hospitalised and evaluated for worsening UTI and sepsis. Initially, it appeared to be secondary to post-UTI sepsis because of possible resistant infection or conditions like pulmonary embolism or acute hepatitis. The patient also developed systemic inflammatory response syndrome, left bundle branch block (LBBB), thrombocytopaenia and transaminitis. Considering the side effects of nitrofurantoin, it was stopped. The patient showed improvement and recovered completely with symptomatic and supportive treatment. During follow-up visits with her primary care physician, thrombocytopaenia, transaminitisandLBBB were found to have been resolved.



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Actinomycosis presenting as an anterior abdominal mass after laparoscopic cholecystectomy

Abdominal actinomycosis is a rare disease caused by different anaerobic Actinomyces species. We report the case of a 55-year-old woman who presented with a painless, slow growing, left upper abdominal mass that developed after a laparoscopic cholecystectomy. A CT scan and MRI of the abdomen revealed a desmoid tumour of the left rectus abdominis muscle.

Surgical excision was performed with an uneventful postoperative course. The histological analysis of the specimen was inconsistent with a desmoid tumour and revealed an infection of Actinomyces israelii in the anterior abdominal wall that was confirmed with a microbiology culture. The surgical treatment was followed by a course of penicillin antibiotic therapy for 6 months. This treatment resulted in full recovery with no further complications. Although it is rare, the patient’s history of laparoscopic cholecystectomy was identified as the likely source of infection.



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Addition of rituximab to CHOP-like chemotherapy in first line treatment of primary mediastinal B-cell lymphoma

The addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) -like therapy has improved survival in primary mediastinal B-cell lymphoma (PMBCL) patients. However, these res...

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Power of PgR expression as a prognostic factor for ER-positive/HER2-negative breast cancer patients at intermediate risk classified by the Ki67 labeling index

The Ki67 labeling index (LI) is regarded as a significant prognostic marker in ER-positive/HER2-negative breast cancer patients. The expression of PgR has recently been identified as another prognostic marker....

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Schlafstörungen bei Lungenkrankheiten

Zusammenfassung

Lungenkrankheiten können den normalen, gesunden Schlaf in vielfältiger Weise beeinträchtigen. Einschränkungen der Lungenfunktion bewirken eine Störung des Gasaustausches, die sich in Form von schlafbezogenen Hypoxämien und Hypoventilationen äußern können. Der Schlaf kann bei den betroffenen Patienten aber auch durch andere Faktoren gestört werden, wie z. B. durch nächtlichen Husten oder Dyspnoe. Schließlich gibt es bei mehreren Lungenkrankheiten komplexe und z. T. wechselseitige Beziehungen zur Schlafapnoe. Die Schlafstörungen bei Lungenkrankheiten äußern sich klinisch u. a. in schlechter Schlafqualität, Tagesmüdigkeit und -schläfrigkeit sowie reduzierter Lebensqualität. Die apparative Diagnostik umfasst Pulsoxymetrie, Kapnometrie und Poly(somno)graphie. Therapeutisch stehen neben der Behandlung der pulmonalen Grunderkrankung die O2-Gabe, die nichtinvasive Ventilationstherapie sowie die CPAP-Therapie („continuous positive airway pressure") im Vordergrund.



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Acrylfentanyl: Another new psychoactive drug with fatal consequences

The last decades witnessed the appearance of a series of new psychoactive substances (NPS) on the drug scene [1]. These new compounds have proven to be a serious challenge for legislators and health operators; indeed, by marketing them as items not for human consumption (such as ladybug attractant, plant food, bath salts)[2], the producers of such compounds effectively manage to circumvent the law, and to market “legal highs”[3]. Despite governments all over the world constantly update the lists of scheduled substances, new chemical structures keep hitting the market on an almost monthly basis, both in USA and in Europe[4].

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DNA decontamination of fingerprint brushes

Fingerprints and DNA are both valuable sources of forensic evidence. Today, the ability to generate DNA profiles from touched objects [1–4], resulting from the increased sensitivity of DNA typing methodologies, has enabled the routine collection of DNA from fingerprints. In cases where conventional fingerprint analysis is uninformative due to smeared or partial prints, DNA analysis provides an alternative means for obtaining probative evidence about the offender. In some laboratories, the collection of DNA from evidentiary items occurs prior to latent print processing, while in others collection occurs following exposure to various optical, physical and chemical fingerprint enhancement methods [5–7].

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The influence of impact direction and axial loading on the bone fracture pattern

Knowledge on long bone failure mechanisms and fracture patterns may assist anthropologists and physicians in legal (forensic) medicine, i.e., in identifying the trauma that caused an injury. Traffic accidents, for example, is of major importance since road traffic injuries are the leading cause of death worldwide among young people aged 10–24 years, with nearly 400,000 people under the age of 25 dying in the world’s roads [39]. Analysis of bone fractures may assist in reconstructing the location of pedestrians relative to the vehicle and their position (standing or recumbent), moving phase (standing or moving), the impact direction, the type of collision (front, corner, sideswipe), and the type and speed of the vehicle.

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NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells

NADPH oxidases (NOX) are reactive oxygen species- (ROS-) generating enzymes regulating numerous redox-dependent signaling pathways. NOX are important regulators of cell differentiation, growth, and proliferation and of mechanisms, important for a wide range of processes from embryonic development, through tissue regeneration to the development and spread of cancer. In this review, we discuss the roles of NOX and NOX-derived ROS in the functioning of stem cells and cancer stem cells and in selected aspects of cancer cell physiology. Understanding the functions and complex activities of NOX is important for the application of stem cells in tissue engineering, regenerative medicine, and development of new therapies toward invasive forms of cancers.

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Plastic Surgery Inclusion in the Undergraduate Medical Curriculum: Perception, Challenges, and Career Choice—A Comparative Study

Objective. The undergraduate medical curriculum has been overcrowded with core learning outcomes with no formal exposure to plastic surgery. The aim of this study was to compare medical students from two educational settings for the basic understanding, preferred learning method, and factors influencing a career choice in plastic surgery. Design and Setting. A prospective cohort study based on a web-based anonymous questionnaire sent to final year medical students at Birmingham University (United Kingdom), McGill University (Canada), and a control group (non-medical staff). The questions were about plastic surgery: (1) source of information and basic understanding; (2) undergraduate curriculum inclusion and preferred learning methods; (3) factors influencing a career choice. A similar questionnaire was sent to non-medical staff (control group). The data was analysed based on categorical outcomes (Chi-square χ2) and level of significance . Results. Questionnaire was analysed for 243 students (Birmingham, , 52%) (McGill , 54%). Birmingham students (14%) considered the word “plastic” synonymous with “cosmetic” more than McGill students (4%, ). Teaching was the main source of knowledge for McGill students (39%, ) while Birmingham students and control group chose the media (70%, ). McGill students (67%) more than Birmingham (49%, ) considered curriculum inclusion. The preferred learning method was lectures for McGill students (61%, ) but an optional module for Birmingham (61%). A similar proportion (18%) from both student groups considered a career in plastic surgery. Conclusions. Medical students recognised the need for plastic surgery inclusion in the undergraduate curriculum. There was a difference for plastic surgery source of information, operations, and preferred method of learning for students. The study highlighted the urgent need to reform plastic surgery undergraduate teaching in collaboration with national educational bodies worldwide.

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Highly Sensitive Colorimetric Assay for Determining Fe3+ Based on Gold Nanoparticles Conjugated with Glycol Chitosan

A highly sensitive and simple colorimetric assay for the detection of Fe3+ ions was developed using gold nanoparticles (AuNPs) conjugated with glycol chitosan (GC). The Fe3+ ion coordinates with the oxygen atoms of GC in a hexadentate manner (O-Fe3+-O), decreasing the interparticle distance and inducing aggregation. Time-of-flight secondary ion mass spectrometry showed that the bound Fe3+ was coordinated to the oxygen atoms of the ethylene glycol in GC, which resulted in a significant color change from light red to dark midnight blue due to aggregation. Using this GC-AuNP probe, the quantitative determination of Fe3+ in biological, environmental, and pharmaceutical samples could be achieved by the naked eye and spectrophotometric methods. Sensitive response and pronounced color change of the GC-AuNPs in the presence of Fe3+ were optimized at pH 6, 70°C, and 300 mM NaCl concentration. The absorption intensity ratio (A700/A510) linearly correlated to the Fe3+ concentration in the linear range of 0–180 μM. The limits of detection were 11.3, 29.2, and 46.0 nM for tap water, pond water, and iron supplement tablets, respectively. Owing to its facile and sensitive nature, this assay method for Fe3+ ions can be applied to the analysis of drinking water and pharmaceutical samples.

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Unusual Case of Extraction of Maxillary Lateral Incisors and Mandibular Central Incisors

Introduction. This article’s purpose is to report a case where maxillary lateral incisors and mandibular central incisors are extracted and a canine substitution was performed as the best therapeutic option in order to obtain symmetry in a malocclusion with an upper lateral incisor with poor prognostic, solve moderate crowding, get enough space for the permanent dentition, and provide stability to the results. Case Report. An 11-year-old boy with straight profile with acute-to-normal nasolabial angle and protruded lips, mixed dentition, lower and upper severe crowding, and a bilateral molar angle Class I. The left maxillary lateral incisor failed endodontic treatment secondary to an intrusive traumatic lesion in the primary and permanent dentition. The treatment of choice was the extraction of both upper lateral incisors and both central lower incisors. The patient finished with molar and canine angle Class I and coincident midlines and was functionally stable; both lateral and protrusive jaw movements were effectively made by the first premolars and central incisors and canines without improper contacts of the rest of the teeth. Overbite of one-third and correct overjet were also achieved, and the esthetic outcome was satisfactory due to the composed material restorations of both the central and lateral incisors, as well as recontouring of the first maxillary premolars.

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Effectiveness of a Commercial Lactic Acid Bacteria Intervention Applied to Inhibit Shiga Toxin-Producing Escherichia coli on Refrigerated Vacuum-Aged Beef

Because of their antagonistic activity towards pathogenic and spoilage bacteria, some members of the lactic acid bacteria (LAB) have been evaluated for use as food biopreservatives. The objectives of this study were to assess the antimicrobial utility of a commercial LAB intervention against O157 and non-O157 Shiga-toxigenic E. coli (STEC) on intact beef strip loins during refrigerated vacuum aging and determine intervention efficacy as a function of mode of intervention application. Prerigor strip loins were inoculated with a cocktail ( log10 CFU/ml) of rifampicin-resistant (100.0 μg/ml; ) O157 and non-O157 STEC. Inoculated loins were chilled to ≤4°C and treated with  log10 CFU/ml LAB intervention using either a pressurized tank air sprayer (conventional application) or air-assisted electrostatic sprayer (ESS). Surviving STEC were enumerated on tryptic soy agar supplemented with 100.0 μg/ml rifampicin (TSAR) to determine STEC inhibition as a function of intervention application method (conventional, ESS) and refrigerated aging period (14, 28 days). Intervention application reduced STEC by 0.4 log10 CFU/cm2 (), although application method did not impact STEC reductions (). Data indicate that the LAB biopreservative may assist beef safety protection when utilized within a multi-intervention beef harvest, fabrication, and aging process.

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The Changes in Rats with Sciatic Nerve Crush Injury Supplemented with Evening Primrose Oil: Behavioural, Morphologic, and Morphometric Analysis

Nerve crush injuries are commonly used models for axonotmesis to examine peripheral nerve regeneration. As evening primrose oil (EPO) is rich in omega-6 essential fatty acid component and gamma-linolenic acid, studies have shown the potential role of EPO in myelination. Seventy-two healthy adult Sprague-Dawley rats were classified into three groups: normal group, control group, and experimental group. The result indicates that there was significant difference in toe-spreading reflex between the normal and the control groups (, ) and the normal and the EPO groups (, ) and significant difference between EPO and the control groups (, ). Regeneration of axons and myelin in nerve fibre in the EPO-treated group developed better and faster than in the control group. In the control group, the shape of the axon was irregular with a thinner myelin sheath. In the experimental group, the shape of the axons, the thickness of the myelin sheath, and the diameter of the axons were almost the same as in the normal group. In conclusion, EPO supplementation may be beneficial as a therapeutic option for disturbances of nerve interaction.

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Histopathological and Reproductive Evaluation in Male Rats Fed Jatropha curcas Seed Cake with or without Alkaline Hydrolysis and Subjected to Heat Treatment

Jatropha curcas cake, a by-product of biodiesel production, is rich in protein and has potential to be used in livestock feed; however, the presence of antinutritional factors and phorbol esters limits its use. Thus, this study investigated toxicological and reproductive effects in male Wistar rats after subchronic exposure to J. curcas cake subjected to detoxification procedures. Rats were divided into seven groups () and treated for 60 days. The control group received commercial feed, while experimental groups received a diet containing 5% J. curcas cake nonhydrolyzed or hydrolyzed with 5 M NaOH. The cakes were unwashed or washed with ethanol or water and were autoclaved at 121°C for 30 minutes. Alkaline hydrolysis combined with ethanol washing decreased the phorbol ester concentration in the cake by 98%. Histopathological findings included diffuse degeneration of the liver and edema around the pulmonary vessels in the nonhydrolyzed groups. In addition, nontreated females mated with males of nonhydrolyzed unwashed group showed a decreased number of live fetuses and an increased placental weight. There were no signs of toxicity in rats given hydrolyzed cakes washed and unwashed, indicating that alkaline hydrolysis associated with heat treatment is an efficient method for detoxification of the J. curcas cake.

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Autism spectrum disorder-associated genes and the development of dentate granule cells

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe clinical symptoms such as the deficiency of the social communication, repetitive and stereotyped behaviors, and restricted interests. Although complex genetic and environmental factors are thought to contribute to the development of ASD, the precise etiologies are largely unknown. Neuroanatomical observations have been made of developmental abnormalities in different brain regions, including dentate gyrus of hippocampus, which is widely accepted as the center for learning and memory. However, little is known about what roles ASD-associated genes play in the development of hippocampal dentate granule cells. In this article, we summarized functions and pathophysiological significance of 6 representative ASD-associated genes, SEMA5A, PTEN, NLGN, EN-2, FMR1, and MECP2, by focusing on the development of dentate gyrus. We then introduced a recently developed gene transfer method directed to neonatal dentate granule cells. This new method will be useful for elucidating physiological as well as pathophysiological significance of ASD-associated genes in the development of hippocampal formation.



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Structure-based prediction of Wnt binding affinities for Frizzled-type cysteine-rich domain [Protein Structure and Folding]

Wnt signaling pathways are of significant interest in development and oncogenesis. The first step in these pathways typically involves the binding of a Wnt protein to the cysteine-rich domain (CRD) of a Frizzled receptor; Wnt-Frizzled interactions can be antagonized by secreted Frizzled-related proteins (sFRPs), which also contain a Frizzled-like CRD. The large number of Wnts, Frizzleds and sFRPs, as well as the hydrophobic nature of Wnt, pose challenges to laboratory-based investigations of interactions involving Wnt. Here, utilizing structural knowledge of a representative Wnt-Frizzled CRD interaction, as well as experimentally-determined binding affinities for a selection of Wnt-Frizzled CRD interactions, we generate homology models of Wnt-Frizzled CRD interactions and develop a quantitative structure-activity relationship for predicting their binding affinities. The derived model incorporates a small selection of terms derived from scoring functions used in protein-protein docking, as well as an energetic term considering the contribution made by the lipid of Wnt to the Wnt-Frizzled binding affinity. Validation with an external test set suggests that the model can accurately predict binding affinity for 75% of cases, and that the error associated with the predictions is comparable to the experimental error. The model was applied to predict the binding affinities of the full range of mouse and human Wnt-Frizzled and Wnt-sFRP interactions, indicating trends in Wnt binding affinity for Frizzled and sFRP CRDs. The comprehensive predictions made in this study provide the basis for laboratory-based studies of previously unexplored Wnt-Frizzled and Wnt-sFRP interactions, which in turn, may reveal further Wnt signaling pathways.

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Lysophosphatidylinositol-induced activation of the cation channel TRPV2 triggers glucagon-like peptide-1 secretion in enteroendocrine L cells [Cell Biology]

The lysophosphatidylinositol (LPI) has crucial roles in multiple physiological processes, including insulin exocytosis from pancreatic islets. However, the role of LPI in secretion of glucagon like peptide-1 (GLP-1), a hormone that enhances glucose-induced insulin secretion, is unclear. Here, we used the murine enteroendocrine L cell line GLUTag and primary murine small intestinal cells to elucidate the mechanism of LPI-induced GLP-1 secretion. Exogenous LPI addition increased intracellular Ca2+ concentrations ([Ca2+]i) in GLUTag cells and induced GLP-1 secretion from both GLUTag and acutely prepared primary intestinal cells. The [Ca2+]i increase was suppressed by an antagonist for G protein-coupled receptor 55 (GPR55) and by silencing of GPR55 expression, indicating involvement of Gq and G12/13 signaling pathways in the LPI-induced increased [Ca2+]i levels and GLP-1 secretion. However, GPR55 agonists did not mimic many of effects of LPI. We also found that phospholipase C inhibitor and Rho-associated kinase inhibitor suppressed the [Ca2+]i increase and that LPI increased the number of focal adhesions, indicating actin reorganization. Of note, blockage or silencing of transient receptor potential cation channel subfamily V member 2 (TRPV2) channels suppressed both the LPI-induced [Ca2+]i increase and GLP-1 secretion. Furthermore, LPI accelerated TRPV2 translocation to the plasma membrane, which was significantly suppressed by a GPR55 antagonist. These findings suggest that TRPV2 activation via actin reorganization induced by Gq and G12/13 signaling is involved in LPI-stimulated GLP-1 secretion in enteroendocrine L cells. Since GPR55 agonists largely failed to mimic the effects of LPI, its actions on L cells are at least partially independent of GPR55 activation.

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Changes in the Dynamics of the Cardiac Troponin C Molecule Explain the Effects of Ca2+-Sensitizing Mutations [Computational Biology]

Cardiac troponin C (cTnC) is the regulatory protein that initiates cardiac contraction in response to Ca2+. TnC binding Ca2+ initiates a cascade of protein-protein interactions that begins with the opening of the N-terminal domain of cTnC, followed by cTnC binding the Troponin I switch peptide (TnISW). We have evaluated, through isothermal titration calorimetry (ITC) and MD simulation, the effect of several clinically relevant mutations (A8V, L29Q, A31S, L48Q, Q50R and C84Y) on the Ca2+ affinity, structural dynamics, and calculated interaction strengths between cTnC and each of Ca2+ and TnISW. Surprisingly the Ca2+ affinity measured by ITC was only significantly affected by half of these mutations, with the exceptions of the L48Q, Q50R and C84Y mutants, which had an affinity 10-fold, 3-fold and 3-fold higher than wild-type, respectively. This suggests that Ca2+ affinity of N-TnC in isolation is insufficient to explain the pathogenicity of these mutations. Molecular Dynamics (MD) simulation was used to evaluate the effects of these mutations on Ca2+ binding, structural dynamics, and TnI interaction independently. Many of the mutations had a pronounced effect on the balance between the open and closed conformations of the TnC molecule, which provides an indirect mechanism for their pathogenic properties. Our data demonstrate that the structural dynamics of the cTnC molecule are key in determining myofilament Ca2+ sensitivity. Our data further suggest that modulation of the structural dynamics is the underlying molecular mechanism for many disease mutations that are far from the regulatory Ca2+ binding site of cTnC.

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Fibrinogen domain of FREP1 is a broad spectrum malaria transmission-blocking vaccine antigen [Immunology]

FREP1 in mosquito midguts facilitates P. falciparum parasite transmission. Fibrinogen-like (FBG) domain of FREP1 is highly conserved (>90% identical) among Anopheles species from different continents, suggesting that anti-FBG antibodies may block malaria transmission to all anopheline mosquitoes. Using standard membrane-feeding assays, anti-FREP1 polyclonal antibodies significantly blocked transmission of P. berghei and P. vivax to An. gambiae and An. dirus respectively. Furthermore, in vivo studies of mice immunized with FBG achieved >75% blocking efficacy of P. berghei to An. gambiae, without triggering immunopathology. Anti-FBG serum also reduced >81% P. falciparum infection to An. gambiae. Finally, we showed that FBG interacted with Plasmodium gametocytes and ookinetes, revealing the molecular mechanism of its antibody transmission-blocking activity. Collectively, our data support that FREP1-mediated Plasmodium transmission to mosquitoes is a conserved pathway, and targeting FBG domain of FREP1 will limit the transmission of multiple Plasmodium species to multiple Anopheles species.

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Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper-ion entry site [Protein Structure and Folding]

Metallo-chaperones are a diverse family of trafficking molecules that provide metal ions to protein targets for use as cofactors. The copper chaperone for Sod1 (Ccs1) activates immature copper-zinc superoxide dismutase (Sod1) by delivering copper and facilitating the oxidation of the Sod1 intramolecular disulfide bond. Here, we present structural, spectroscopic, and cell-based data supporting a novel copper-induced mechanism for Sod1 activation. Ccs1 binding exposes an electropositive cavity and proposed "entry site" for copper ion delivery on immature Sod1. Copper-mediated sulfenylation leads to a sulfenic acid intermediate that eventually resolves to form the Sod1 disulfide bond with concomitant release of copper into the Sod1 active site. Sod1 is the predominant disulfide bond requiring enzyme in the cytoplasm and this copper-induced mechanism of disulfide bond formation obviates the need for a thiol/disulfide oxidoreductase in that compartment.

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Heme-thiolate sulfenylation of human cytochrome P450 4A11 functions as a redox switch for catalytic inhibition [Metabolism]

Cytochrome P450 (P450, CYP) 4A11 is a human fatty acid ω-hydroxylase that catalyzes the oxidation of arachidonic acid to the eicosanoid 20- hydroxyeicosatetraenoic acid (20-HETE), which plays important roles in regulating blood pressure regulation. Variants of P450 4A11 have been associated with high blood pressure and resistance to anti-hypertensive drugs, and 20-HETE has both pro- and antihypertensive properties relating to increased vasoconstriction and natriuresis, respectively. These physiological activities are likely influenced by the redox environment, but the mechanisms are unclear. Here, we found that reducing agents (e.g., dithiothreitol and tris(carboxyethyl)phosphine) strongly enhanced the catalytic activity of P450 4A11, but not of 10 other human P450s tested. Conversely, added H2O2 attenuated P450 4A11 catalytic activity. Catalytic roles of five of the potentially eight implicated Cys residues of P450 4A11 were eliminated by site-directed mutagenesis. Using an isotope-coded dimedone/iododimedone labeling strategy and mass spectrometry of peptides, we demonstrated that the heme-thiolate cysteine (Cys- 457) is selectively sulfenylated in a H2O2 concentration-dependent manner. This sulfenylation could be reversed by reducing agents, including dithiothreitol and dithionite. Of note, we observed heme ligand cysteine sulfenylation of P450 4A11 ex vivo in kidneys and livers derived from CYP4A11 transgenic mice. We also detected sulfenylation of murine P450s 4a12 and 4b1 heme peptides in kidneys. To our knowledge, reversible oxidation of the heme thiolate has not previously been observed in P450s, to our knowledge, and may have relevance for 20-HETE-mediated functions.

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The ATP-dependent Chromatin Remodeling Enzymes CHD6, CHD7, and CHD8 Exhibit Distinct Nucleosome Binding and Remodeling Activities [Enzymology]

Proper chromatin regulation is central to genome function and maintenance. The group III CHD family of ATP-dependent chromatin remodeling enzymes--comprising CHD6, CHD7, CHD8, and CHD9--has well-documented roles in transcription regulation impacting both organism development and disease etiology. These four enzymes are similar in their constituent domains, yet these enzymes fill surprisingly non-redundant roles in the cell, with deficiencies in individual enzymes leading to dissimilar disease states such as CHARGE syndrome or autism spectrum disorders. The mechanisms explaining their divergent, non-overlapping functions are unclear. In this study, we performed an in-depth biochemical analysis of purified CHD6, CHD7, and CHD8, and discovered distinct differences in chromatin remodeling specificities and activities among them. We report that CHD6 and CHD7 both bind with high affinity to short linker DNA, while CHD8 requires longer DNA for binding. As a result, CHD8 slides nucleosomes into positions with more flanking linker DNA than does CHD7. Moreover, we found that while CHD7 and CHD8 slide nucleosomes, CHD6 disrupts nucleosomes in a distinct non-sliding manner. The different activities of these enzymes likely lead to differences in chromatin structure, and thereby transcriptional control, at the enhancer and promoter loci where these enzymes bind. Overall, our work provides a mechanistic basis for both the non-redundant roles, and the diverse mutant disease states, of these enzymes in vivo.

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Serum amyloid A: an ozone-induced circulating factor with potentially important functions in the lung-brain axis [Research]

Accumulating evidence suggests that O3 exposure may contribute to CNS dysfunction. Here, we posit that inflammatory and acute-phase proteins in the circulation increase after O3 exposure and systemically convey signals of O3 exposure to the CNS. To model acute O3 exposure, female Balb/c mice were exposed to 3 ppm O3 or forced air for 2 h and were studied after 6 or 24 h. Of 23 cytokines and chemokines, only KC/CXCL1 was increased in blood 6 h after O3 exposure. The acute-phase protein serum amyloid A (A-SAA) was significantly increased by 24 h, whereas C-reactive protein was unchanged. A-SAA in blood correlated with total leukocytes, Ms, and neutrophils in bronchoalveolar lavage from O3-exposed mice. A-SAA mRNA and protein were increased in the liver. We found that both isoforms of A-SAA completely crossed the intact blood-brain barrier, although the rate of SAA2.1 influx was approximately 5 times faster than that of SAA1.1. Finally, A-SAA protein, but not mRNA, was increased in the CNS 24 h post-O3 exposure. Our findings suggest that A-SAA is functionally linked to pulmonary inflammation in our O3 exposure model and that A-SAA could be an important systemic signal of O3 exposure to the CNS.—Erickson, M. A., Jude, J., Zhao, H., Rhea, E. M., Salameh, T. S., Jester, W., Pu, S., Harrowitz, J., Nguyen, N., Banks, W. A., Panettieri Jr., R. A., Jordan-Sciutto, K. L. Serum amyloid A: an ozone-induced circulating factor with potentially important functions in the lung-brain axis.



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Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling [Research]

Tendon stem/progenitor cells (TSCs) have been found in different anatomic locations and showed a promising regenerative potential. We identified a role of TSCs in the regulation of inflammation during healing of acute tendon injuries. Delivery of connective tissue growth factor (CTGF) into full-transected rat patellar tendons significantly increased the number of CD146+ TSCs, leading to enhanced healing. In parallel, CTGF delivery significantly reduced the number of iNOS+ M1 Ms and increased the expression of anti-inflammatory IL-10 at 2 d after surgery, with over 85% CD146+ TSCs expressing IL-10. By 1 wk, the elevated IL-10 expression remained, and IL-6 expression was significantly attenuated in CTGF-delivered tendon healing. Matrix metalloproteinase (MMP)-3 expression in CTGF-delivered tendon was organized along with the reorienting collagen fibers by 1 wk after surgery, in comparison with the control group showing the abundant MMP-3 expression localized at healing junction. Tissue inhibitor of metalloprotease (TIMP)-3 was expressed in CD146+ TSCs at 1 wk with CTGF, in contrast to control with no TIMP-3 expression. In vitro, IL-10 expression was detected only when tendon cells were stimulated with IL-1β, and CTGF and significantly higher in CD146+ TSCs than CD146 tendon cells. Similarly, TIMP-3 expression was detected only when treated with CTGF or CTGF and IL-1β that is significantly higher in CD146+ TSCs compared to CD146 tendon cells. Signaling study with specific inhibitors and Western blot analysis demonstrated that CTGF-induced expression of IL-10 and TIMP-3 in CD146+ TSCs are regulated by JNK/signal transducer and activator of transcription 3 signaling. Taken together, these findings suggest anti-inflammatory roles of CTGF-stimulated TSCs that are likely associated with improved tendon healing.—Tarafder, S., Chen, E., Jun, Y., Kao, K., Sim, K. H., Back, J., Lee, F. Y., Lee, C. H. Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling.



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Prostaglandin E receptor subtype 4 regulates lipid droplet size and mitochondrial activity in murine subcutaneous white adipose tissue [Research]

The purpose of this study was to investigate whether genetic ablation of prostaglandin E receptor subtype 4 (EP4) affects white adipose tissue (WAT) remodeling mediated by β3-adrenergic stimulation. The selective β3-adrenergic agonist, CL316243 (1 mg/kg/d, i.p.) caused a greater increase in metabolic rate in EP4-knockout mice. CL316243 fragmented the unilocular lipid droplet into multilocular lipid vacuoles and increased mitochondrial biogenesis and its activity. These changes were amplified in mice with EP4 deficiency and were selectively seen in subcutaneous WAT. The expression of fat-specific protein (FSP)-27, a protein that promotes fusion of triglycerides and formation of unilocular lipid droplets were diminished, whereas the expression of phosphorylated AMPK, the upstream regulator of FSP27, was enhanced in EP4-deficient mice. The present study showed that EP4 acts as a negative regulator of WAT remodeling, it tightly coordinates rates of triglyceride storage in lipid droplets and mitochondrial respiratory function in subcutaneous white adipocytes through the phosphorylated AMPK-FSP27 signaling axis. Thus, deletion of EP4 increases mitochondrial biogenesis and oxidative capacity in WAT, and fat mass loss ensues in mice.—Ying, F., Cai, Y., Cai, Y., Wang, Y., Tang, E. H. C. Prostaglandin E receptor subtype 4 regulates lipid droplet size and mitochondrial activity in murine subcutaneous white adipose tissue.



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Physiologic regulation of heart rate and blood pressure involves connexin 36-containing gap junctions [Research]

Chronically elevated sympathetic nervous activity underlies many cardiovascular diseases. Elucidating the mechanisms contributing to sympathetic nervous system output may reveal new avenues of treatment. The contribution of the gap junctional protein connexin 36 (Cx36) to the regulation of sympathetic activity and thus blood pressure and heart rate was determined using a mouse with specific genetic deletion of Cx36. Ablation of the Cx36 protein was confirmed in sympathetic preganglionic neurons of Cx36 knockout (KO) mice. Telemetric analysis from conscious Cx36 KO mice revealed higher variance in heart rate and blood pressure during rest and activity compared to wild-type (WT) mice, and smaller responses to chemoreceptor activation when anesthetized. In the working heart–brain stem preparation of the Cx36 KO mouse, respiratory-coupled sympathetic nerve discharge was attenuated and responses to chemoreceptor stimulation and noxious stimulation were blunted compared to WT mice. Using whole cell patch recordings, sympathetic preganglionic neurons in spinal cord slices of Cx36 KO mice displayed lower levels of spikelet activity compared to WT mice, indicating reduced gap junction coupling between neurons. Cx36 deletion therefore disrupts normal regulation of sympathetic outflow with effects on cardiovascular parameters.—Lall, V. K., Bruce, G., Voytenko, L., Drinkhill, M., Wellershaus, K., Willecke, K., Deuchars, J., Deuchars, S. A. Physiologic regulation of heart rate and blood pressure involves connexin 36–conaining gap junctions.



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Akt signaling is sustained by a CD44 splice isoform-mediated positive feedback loop

Tumor cells nearly invariably evolve sustained PI3K/Akt signaling as an effective means to circumvent apoptosis and maintain survival. However, for those tumor cells that do not acquire PI3K/Akt mutations to achieve this end the underlying mechanisms have remained obscure. Here we describe the discovery of a splice isoform-dependent positive feedback loop that is essential to sustain PI3K/Akt signaling in breast cancer. Splice isoform CD44s promoted expression of the hyaluronan synthase HAS2 by activating the Akt signaling cascade. The HAS2 product hyaluronan (HA) further stimulated CD44s-mediated Akt signaling, creating a feed-forward signaling circuit that promoted tumor cell survival. Mechanistically, we identified FOXO1 as a bona fide transcriptional repressor of HAS2. Akt-mediated phosphorylation of FOXO1 relieved its suppression of HAS2 transcription, with FOXO1 phosphorylation status maintained by operation of the positive feedback loop. In clinical specimens of breast cancer, we established that the expression of CD44s and HAS2 were positively correlated. Our results establish a positive feedback mechanism that sustains PI3K/Akt signaling in tumor cells, further illuminating the nearly universal role of this pathway in cancer cell survival.

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VHL inactivation in precancerous kidney cells induces an inflammatory response via ER stress-activated IRE1{alpha} signaling

Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss-of-function in the development of ccRCC via inflammation remains poorly understood. VHL mutant cells exhibit metabolic abnormalities that can cause chronic endoplasmic reticulum (ER) stress and unfolded protein response (UPR). We hypothesize that unresolved ER stress induces the inflammatory responses observed in ccRCC. ER stress markers including BiP and XBP1s were significantly increased in cultured and primary VHL loss-of-function kidney cells. In epithelial cells, the kinase activity of IRE1α was required for the induction of NFκB and JNK and for the recruitment of macrophages. IRE1α kinase activity was also important for the development of fibrotic phenotype in conditional Vhlh knockout mice. Our results offer insights into the therapeutic potential against ccRCC development by relieving metabolic stress. Such cancer prevention strategy may be critical for high-risk cohorts such as the familial VHL disease patients.

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Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy

Inherent intermediate-to-low affinity T cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering re-instated Th1 function in tumor-infiltrating lymphocytes (TILs) that had been functionally disabled in the human renal cell carcinoma (RCC) environment without unleashing undesired Th2 cytokines or IL-10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFN-γ compared to T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T cell function makes it an attractive tool for ATT.

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Manifestation of Geometric and Electronic Shell Structures of Metal Clusters in Intercluster Reactions

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01912
ancac3?d=yIl2AUoC8zA


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Manipulating Ion Migration for Highly Stable Light-Emitting Diodes with Single-Crystalline Organometal Halide Perovskite Microplatelets

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b02629
ancac3?d=yIl2AUoC8zA


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Airway stenting in a child with spondyloepiphyseal dysplasia congenita: 13-year survival

We describe the case of a boy with spondyloepiphyseal dysplasia congenita. At birth, he experienced severe respiratory distress necessitating tracheotomy. Endoscopy done because mechanical ventilation failed to resolve desaturations disclosed severe tracheo-bronchomalacia. A Polyflex silicone stent was placed in the trachea (replaced by Y-Dumon stent) and 2 Palmaz metallic stents in the mainstem bronchi (overlapped with 2 Jomed stents 5 years later). Airway stenting guaranteed a suitable respiratory status and allowed a child who was expected to die at birth, to reach 13.5 years old in good conditions.

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Uncovering the pathogenesis of microtia using bioinformatics approach

Bioinformatics is widely used in the field of cancer research, but in the research of pathogenesis of congenital malformations the situation is different. The aim of this study was to explore the underlying mechanism using bioinformatics approach.

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Functional outcome of patients with prolonged hypoglycemic encephalopathy

Little is known about the causes, clinical course and long-term outcome of comatose patients with prolonged hypoglycemic encephalopathy.

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Nasal high flow in management of children with status asthmaticus: a retrospective observational study

Asthma is the most common obstructive airway disease in children and adults. Nasal high flow (NHF) is a recent device that is now used as a primary support for respiratory distress. Several studies have report...

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The Use of Antibiotic Beads to Salvage the Infected Breast Implant

When an implant becomes infected, implant salvage is often performed where the implant is removed, capsulectomy is performed, and a new implant is inserted. The patient is discharged with a PICC line and 6-8 weeks of IV antibiotics. This method has variable success and subjects the patient to long-term systemic antibiotics. In the 1960s, the use of antibiotic-impregnated beads for the treatment of chronic osteomyelitis was described. These beads deliver antibiotic directly to the site of the infection, thereby eliminating the complications of systemic IV antibiotics.

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Does negative pressure wound therapy influence subjacent bacterial growth? A systematic review

Negative pressure wound therapy is a ubiquitous wound management resource. The influence of NPWT on the bacterial bioburden of the subjacent wound remains unclear. We sought to examine the evidence.

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An Analysis of the Operative Experience of Plastic Surgery Trainees in the United Kingdom Using eLogbook

We performed a comprehensive analysis of the operative experience of UK Plastic Surgery Trainees using the web-based eLogbook.

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Studying the blood pressures of antegrade and retrograde internal mammary vessels: Do they really work as recipient vessels?

The proximal ends of the internal mammary (IM) vessels are now the most common recipient vessels for breast reconstruction. On the other hand, bilateral deep inferior epigastric artery perforator (DIEP) flaps are often needed according to the territory and the volume needed for reconstruction. The usefulness of retrograde IM vessels as second recipients has recently been reported, but there are very few quantitative studies on the hydrodynamics of the retrograde IM vessels. Since the flow is dependent on the pressure differential, the blood pressures of the antegrade IM artery (AIMA), antegrade IM vein (AIMV), retrograde IM artery (RIMA), retrograde IM vein (RIMV), and the recirculated intraflap vein (FV) were investigated to solve this question and confirm the reliability and usefulness of retrograde IM vessels.

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Commentary: Cubital tunnel syndrome caused by intraneural or extraneural ganglion cysts-case report and review of the literature

Chang et al. describe 16 patients with extraneural ganglion cysts and 3 with intraneural ganglion cysts among their cohort of 184 consecutive patients with cubital tunnel syndrome. The authors do an admirable job of recognizing a connection to the elbow joint in each case. Despite the juxta-articular location of these cysts, many of these in the literature are still thought not to arise from the elbow joint. The finding that all patients with ganglion cysts had osteoarthritis of the elbow is reminiscent of the findings reported for peroneal extraneural and intraneural cysts arising from a degenerative superior tibiofibular joint (STFJ).

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Composite breast reconstruction: implant-based breast reconstruction with adjunctive lipofilling

Options for breast reconstructions enclose autologous tissue transfers or implants. Fat grafting is gaining more interest in this specific field of breast surgery. This study concentrates on the technique and aesthetic results of breast reconstruction with fat grafts combined with implants, in women who have undergone total mastectomy.

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Analysis of surgical results and of residual postoperative deformities in preaxial polydactyly of the hand

Polydactyly is the most common congenital anomaly of the hand. It may occur as a separate event or as part of a syndrome, with preaxial polydactyly of the hand (or thumb duplication) being the most common among Caucasians. The present study analyzed the surgical results and the residual postoperative deformities of patients with thumb duplication.

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Hemodynamic changes caused by acupuncture in healthy volunteers: a prospective, single-arm exploratory clinical study

Radial pressure pulse wave (RPPW) examination has been a key diagnostic component of traditional Chinese medicine. The objective of this study was to investigate the changes in RPPW along with various hemodyna...

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Antiviral activity of phenanthrenes from the medicinal plant Bletilla striata against influenza A virus

Influenza represents a serious public health concern. The emergence of resistance to anti-influenza drugs underlines the need to develop new drugs. This study aimed to evaluate the anti-influenza viral activit...

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Clinical outcomes in children with Henoch–Schönlein purpura nephritis without crescents

Abstract

Background

Henoch–Schönlein purpura is the most common vasculitis in children. Its long-term prognosis depends on renal involvement. The management of Henoch–Schönlein purpura nephritis (HSPN) remains controversial. This study reports the prognosis of children with HSPN presenting with class 2 International Study of Kidney Disease in Children (ISKDC) nephritis.

Methods

All children with HSPN class 2 diagnosed between 1995 and 2015 in four pediatric nephrology centers were included, and clinical and biological data were collected from the medical files. The primary endpoint was proteinuria remission defined as a proteinuria <200 mg/L.

Results

Ninety-two children were included in the study with a median follow-up of 36 (6–120) months; 28% had nephrotic syndrome, 31% proteinuria >3 g/L, 52% proteinuria between 1 and 3 g/L, and 18% proteinuria <1 g/L. Forty-seven percent of patients received orally treatment with steroids alone, 37% received methylprednisolone pulses followed by steroids orally, 18% received no steroids. Although 85% reached remission during follow-up, 12% did not maintain complete remission over time so that only 75% remained in complete remission by the end of the follow-up. Univariate analysis found a higher likelihood of remission in patients with higher proteinuria at disease onset (p = 0.009). This trend was not found in the multivariate analysis after adjusting for treatments, as patients with higher proteinuria were most often treated with steroids.

Conclusion

Our study shows that one fourth of patients with HSPN class 2 remain proteinuric and thus carry the risk of developing chronic kidney disease over the long term. This finding, together with the better outcome of patients treated with steroids, is in favor of using high-dose steroids orally or IV in these patients.



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EU nations set to wipe out forests and not account for emissions

gettyimages-601069158-800x533.jpg

The drive for biofuels that international treaties wrongly consider to be emissions-free is driving plans to boost tree harvests in Europe, forgetting about associated emissions

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Circulating tumor DNA profiling reveals clonal evolution and real-time disease progression in advanced hepatocellular carcinoma

Abstract

Circulating tumor DNA (ctDNA) provides a potential non-invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real-time track the therapeutic responses in the longitudinal monitoring. This article is protected by copyright. All rights reserved.



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Hepcidin levels and gastric cancer risk in the EPIC-EurGast Study

Abstract

Hepcidin is the main regulator of iron homeostasis and dysregulation of proteins involved in iron metabolism has been associated with tumorogenesis. However, to date, no epidemiological study has researched the association between hepcidin levels and gastric cancer risk. To further investigate the relationship between hepcidin levels and gastric cancer risk, we conducted a nested case-control study (EURGAST) within the multicentric European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow-up. We measured serum levels of hepcidin-25, iron, ferritin, transferrin and C-reactive protein. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by hepcidin levels were estimated from multivariable conditional logistic regression models. Mediation effect of the ferritin levels on the hepcidin-gastric cancer pathway was also evaluated.

After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and hepcidin levels (OR 5ng/l = 0.96, 95% CI = 0.93-0.99). No differences were found by tumor localization or histological type. In mediation analysis, we found that the direct effect of hepcidin only represents a non-significant 38% (95% CI: -69%, 91%). In summary, these data suggest that the inverse association of hepcidin levels and gastric cancer risk was mostly accounted by ferritin levels. Further investigation including repeated measures of hepcidin is needed to clarify their role in gastric carcinogenesis. This article is protected by copyright. All rights reserved.



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Rapid molecular sexing of three-spined sticklebacks, Gasterosteus aculeatus L., based on large Y-chromosomal insertions

Abstract

There is a need for rapid and reliable molecular sexing of three-spined sticklebacks, Gasterosteus aculeatus, the supermodel species for evolutionary biology. A DNA region at the 5′ end of the sex-linked microsatellite Gac4202 was sequenced for the X chromosome of six females and the Y chromosome of five males from three populations. The Y chromosome contained two large insertions, which did not recombine with the phenotype of sex in a cross of 322 individuals. Genetic variation (SNPs and indels) within the insertions was smaller than on flanking DNA sequences. Three molecular PCR-based sex tests were developed, in which the first, the second or both insertions were covered. In five European populations (from DE, CH, NL, GB) of three-spined sticklebacks, tests with both insertions combined showed two clearly separated bands on agarose minigels in males and one band in females. The tests with the separate insertions gave similar results. Thus, the new molecular sexing method gave rapid and reliable results for sexing three-spined sticklebacks and is an improvement and/or alternative to existing methods.



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A systematic review and meta-analysis of long-term studies (five or more years) assessing maxillary sinus floor augmentation

Publication date: Available online 22 May 2017
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): T. Starch-Jensen, H. Aludden, M. Hallman, C. Dahlin, A.-E. Christensen, A. Mordenfeld
The objective was to test the hypothesis of no difference in long-term (≥5 years) implant treatment outcomes after maxillary sinus floor augmentation (MSFA) with autogenous bone graft compared to a mixture of autogenous bone graft and bone substitutes or bone substitutes alone. A MEDLINE (PubMed), Embase, and Cochrane Library search in combination with a hand-search of relevant journals was conducted. Human studies published in English between January 1, 1990 and October 1, 2016 were included. Nine studies fulfilled the inclusion criteria. The survival of suprastructures has never been compared within the same study. The 5-year implant survival after MSFA with autogenous bone graft was 97%, compared to 95% for Bio-Oss; the reduction in vertical height of the augmented sinus was equivalent with the two treatment modalities. Non-comparative studies demonstrated high survival rates for suprastructures and implants regardless of the grafting material used. Meta-analysis revealed an overall estimated patient-based implant survival of 95% (confidence interval 0.92–0.96). High implant stability quotient values, high patient satisfaction, and limited peri-implant marginal bone loss were revealed in non-comparative studies. No long-term randomized controlled trial comparing the different treatment modalities was identified. Hence, the conclusions drawn from the results of this systematic review should be interpreted with caution.



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The accuracy of three-dimensional prediction of soft tissue changes following the surgical correction of facial asymmetry: An innovative concept

Publication date: Available online 22 May 2017
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): T. Mundluru, A. Almukhtar, X. Ju, A. Ayoub
The accuracy of three-dimensional (3D) predictions of soft tissue changes in the surgical correction of facial asymmetry was evaluated in this study. Preoperative (T1) and 6–12-month postoperative (T2) cone beam computed tomography scans of 13 patients were studied. All patients underwent surgical correction of facial asymmetry as part of a multidisciplinary treatment protocol. The magnitude of the surgical movement was measured; virtual surgery was performed on the preoperative scans using Maxilim software. The predicted soft tissue changes were compared to the actual postoperative appearance (T2). Mean (signed) distances and mean (absolute) distances between the predicted and actual 3D surface meshes for each region were calculated. The one-sample t-test was applied to test the alternative hypothesis that the mean absolute distances had a value of <2.0mm. A novel directional analysis was applied to analyse the accuracy of the prediction of soft tissue changes. The results showed that the distances between the predicted and actual postoperative soft tissue changes were less than 2.0mm in all regions. The predicted facial morphology was narrower than the actual surgical changes in the cheek regions. 3D soft tissue prediction using Maxilim software in patients undergoing the correction of facial asymmetry is clinically acceptable.



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Raised blood platelet levels 'strong predictor' of cancer

Having a high blood platelet count is a strong predictor of cancer and should be urgently investigated to save lives, according to a large-scale study. Around two per cent of people over 40 -- up to half a million people in the UK -- have a raised blood...

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EU nations set to wipe out forests and not account for emissions

The drive for biofuels that international treaties wrongly consider to be emissions-free is driving plans to boost tree harvests in Europe, forgetting about associated emissions

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Mechanisms of Tanshinone II a inhibits malignant melanoma development through blocking autophagy signal transduction in A375 cell

Malignant melanoma (MM) is one of the high degree of malignancy and early prone to blood and lymph node metastasis. There is not cured for MM. Tan II A has been reported to reduce cancer cell proliferation. Bu...

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Use of the QIAGEN GeneReader NGS system for detection of KRAS mutations, validated by the QIAGEN Therascreen PCR kit and alternative NGS platform

The detection of somatic mutations in primary tumors is critical for the understanding of cancer evolution and targeting therapy. Multiple technologies have been developed to enable the detection of such mutat...

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Erratum to: Clinical impact of postoperative loss in psoas major muscle and nutrition index after radical cystectomy for patients with urothelial carcinoma of the bladder



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Identification of endonuclease domain-containing 1 as a novel tumor suppressor in prostate cancer

Endonuclease domain containing 1 (ENDOD1) is implicated in tumorigenesis and aggressiveness of multiple tumors. In this study, we aimed to investigate the role of ENDOD1 in prostate cancer (PCa).

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Haemoglobin level increase as an efficacy biomarker during axitinib treatment for metastatic renal cell carcinoma: a retrospective study

Axitinib is used after failure of first line treatment for metastatic renal cell carcinoma (mRCC). A known side effect is the increase of haemoglobin level (HbL) during treatment with a suspected correlation w...

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Creation of a Short-Range Ordered Two-Dimensional Electron Gas Channel in Al2O3/In2O3 Interfaces

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01964
ancac3?d=yIl2AUoC8zA


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CO2 Delivery To Accelerate Incisional Wound Healing Following Single Irradiation of Near-Infrared Lamp on the Coordinated Colloids

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01442
ancac3?d=yIl2AUoC8zA


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Interdiffusion Reaction-Assisted Hybridization of Two-Dimensional Metal–Organic Frameworks and Ti3C2Tx Nanosheets for Electrocatalytic Oxygen Evolution

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01409
ancac3?d=yIl2AUoC8zA


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Three-Dimensional Hetero-Integration of Faceted GaN on Si Pillars for Efficient Light Energy Conversion Devices

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01967
ancac3?d=yIl2AUoC8zA


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A management tool for reducing the potential risk of windthrow for coastal Casuarina equisetifolia L. stands on Hainan Island, China

Abstract

Coastal forests are normally established to mitigate coastal natural disasters instead of artificial barriers because of their low cost, ecological friendliness and economic benefits. The stand stability of coastal forests is of great importance to protect against coastal natural disasters. In the present study, we produced a stand density management diagram (SDMD) that can quantitatively guide the management of stand density to reduce the potential risk of windthrow in the coastal Casuarina equisetifolia L. plantations in southern China. The SDMD was developed using a relative spacing index (RS), average slenderness coefficient (SC) and a system of two equations as the basic components. The RS was used to characterize the growing stock, and the average SC was included to assess stand stability. Finally, we illustrated the application of the SDMD in formulating thinning schedules to secure stand stability. For comparison purposes, management options both with and without considering stand stability were produced and discussed. The study indicated that the SDMD produced here can provide detailed quantitative guidance of regulating stand density to secure stand stability for C. equisetifolia plantations. Additionally, this SDMD can be used to develop thinning schedules for a wide range of site qualities and management objectives for C. equisetifolia plantations.



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The various aspects of genetic and epigenetic toxicology: testing methods and clinical applications

Genotoxicity refers to the ability of harmful substances to damage genetic information in cells. Being exposed to chemical and biological agents can result in genomic instabilities and/or epigenetic alteration...

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Association Between Inflammatory Skin Disease and Cardiovascular and Cerebrovascular Co-Morbidities in US Adults: Analysis of Nationwide Inpatient Sample Data

Abstract

Background

Psoriasis, atopic dermatitis or eczema (AD-E), pemphigus, bullous pemphigoid (BP), and hidradenitis are chronic inflammatory skin disorders associated with systemic immune activation, considerable symptom burden, stigma, functional disturbances, and mental health symptoms. All of these might increase cardiovascular risk.

Objective

The objective of this study was to determine whether these inflammatory skin diseases are associated with increased cardiovascular/cerebrovascular risk and/or disease.

Methods

We analyzed data from the 2002–2012 National Inpatient Sample, including a representative 20% sample of all US hospitalizations (n = 72,108,077 adults).

Results

In multivariate logistic regression models with propensity score matching, patients hospitalized with versus without a diagnosis the inflammatory skin diseases examined had higher odds of obesity (odds ratio [95% confidence interval] for pemphigus: 1.16 [1.05–1.29]; BP 1.14 [1.06–1.23]; AD-E: 1.82 [1.79–1.86]; psoriasis: 2.36 [2.32–2.41]; hidradenitis: 2.79 [2.59–3.01]). Inflammatory skin disease was also associated with significantly higher odds of different cardiovascular risk factors, including hypertension (pemphigus: 1.39 [1.31–1.48]; BP 1.96 [1.88–2.05]; AD-E: 1.19 [1.17–1.21]; psoriasis: 1.61 [1.59–1.64]), and diabetes mellitus with complications (pemphigus: 1.34 [1.18–1.52]; BP: 2.06 [1.90–2.24]; AD-E: 1.13 [1.10–1.17]; psoriasis: 1.39 [1.35–1.44]), as well as vascular, cardiovascular, and cerebrovascular disease, including peripheral vascular disease (pemphigus: 1.14 [1.00–1.30]; BP: 1.83 [1.69–1.98]; AD-E: 1.18 [1.14–1.22]; psoriasis: 1.32 [1.28–1.35]), peripheral and visceral atherosclerosis (BP: 1.67 [1.53–1.81]; AD-E: 1.16 [1.12–1.20]; psoriasis: 1.27 [1.24–1.30]), pulmonary circulation disorders (pemphigus: 1.67 [1.39–2.01]; BP: 2.17 [1.92–2.45]; AD-E: 1.39 [1.33–1.45]; psoriasis: 1.37 [1.31–1.43]), congestive heart failure (pemphigus: 1.75 [1.60–1.90]; BP: 2.82 [2.68–2.98]; AD-E: 1.10 [1.07–1.13]; psoriasis: 1.05 [1.02–1.07]), history of transient ischemic attack (pemphigus: 1.36 [1.14–1.62]; BP: 2.03 [1.83–2.26]; AD-E: 1.19 [1.15–1.23]; psoriasis: 1.31 [1.26–1.36]), and cerebrovascular disease. In stratified analyses, multiple inflammatory skin diseases were associated with significantly higher rates of obesity, hypertension, and/or diabetes in patients aged <50 years and females.

Conclusions

Psoriasis, pemphigus, BP, AD-E, and hidradenitis were all associated with increased cardiovascular and cerebrovascular risk, especially at younger age.



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The in vivo Th17 and Treg immune responses to Aggregatibacter actinomycetemcomitans

Summary

The periodontal pathogen Aggregatibacter actinomycetemcomitans is known to elicit systemic immune response in infected host, and occasionally causes non-oral infections. Detailed information on its immunopathological responses and the involvement of bacterial virulence factors remains to be elucidated. The aim of this study was to assess the systemic immune response to A. actinomycetemcomitans oral infection. We used an animal model that simulates systemic dissemination of the bacteria by injecting live wild type (WT) D7S-1 and double knockout mutant of leukotoxin and cytolethal distending toxin (ΔltxΔcdt) A. actinomycetemcomitans strains in rat oral mucosa. Draining lymph nodes were examined for Treg and Th17 subsets and their associated mediators. An increase in the proportion of Th17 cells and decrease in Treg cells over the experimental period of 3 weeks were similarly observed for rats challenged with WT and ΔltxΔcdt. Significant up and down-regulation of proinflammatory cytokines in the Th17 gene pathway was noted, as well as several qualitative differences between WT and ΔltxΔcdt. Furthermore, we observed differential fold regulation in key genes associated with a proinflammatory response in ΔltxΔcdt-inoculated rats relative to D7S-1 group. This suggests that although the knockout of these two virulence factors (ΔltxΔcdt) may suppress certain proinflammatory genes, it causes similar over-expression of other genes compared to D7S-1, indicating a common factor that still remains in the pathogenicity of A. actinomycetemcomins.

This article is protected by copyright. All rights reserved.



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Automated algorithm for counting microbleeds in patients with familial cerebral cavernous malformations

Abstract

Purpose

Familial cerebral cavernous malformation (CCM) patients present with multiple lesions that can grow both in number and size over time and are reliably detected on susceptibility-weighted imaging (SWI). Manual counting of lesions is arduous and subject to high variability. We aimed to develop an automated algorithm for counting CCM microbleeds (lesions <5 mm in diameter) on SWI images.

Methods

Fifty-seven familial CCM type-1 patients were included in this institutional review board-approved study. Baseline SWI (n = 57) and follow-up SWI (n = 17) were performed on a 3T Siemens MR scanner with lesions counted manually by the study neuroradiologist. We modified an algorithm for detecting radiation-induced microbleeds on SWI images in brain tumor patients, using a training set of 22 manually delineated CCM microbleeds from two random scans. Manual and automated counts were compared using linear regression with robust standard errors, intra-class correlation (ICC), and paired t tests. A validation analysis comparing the automated counting algorithm and a consensus read from two neuroradiologists was used to calculate sensitivity, the proportion of microbleeds correctly identified by the automated algorithm.

Results

Automated and manual microbleed counts were in strong agreement in both baseline (ICC = 0.95, p < 0.001) and longitudinal (ICC = 0.88, p < 0.001) analyses, with no significant difference between average counts (baseline p = 0.11, longitudinal p = 0.29). In the validation analysis, the algorithm correctly identified 662 of 1325 microbleeds (sensitivity=50%), again with strong agreement between approaches (ICC = 0.77, p < 0.001).

Conclusion

The automated algorithm is a consistent method for counting microbleeds in familial CCM patients that can facilitate lesion quantification and tracking.



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Power of pedigree likelihood analysis in extended pedigrees to classify rare variants of uncertain significance in cancer risk genes

Abstract

Rare and private variants of uncertain significance (VUS) are routinely identified in clinical panel, exome, and genome sequencing. We investigated the power of single family co-segregation analysis to aid classification of VUS. We simulated thousands of pedigrees using demographics in China and the United States, segregating benign and pathogenic variants. Genotypes and phenotypes were simulated using penetrance models for Lynch syndrome and breast/ovarian cancer. We calculated LOD scores adjusted for proband ascertainment (LODadj), to determine power to yield quantitative evidence for, or against, pathogenicity of the VUS. Power to classify VUS was higher for Chinese than United States pedigrees. The number of affected individuals explained the most variation in LODadj (21–38%). The distance to the furthest affected relative (FAR) from the proband explained 1–7% of the variation for the benign VUS and Lynch associated cancers. Minimum age of onset (MAO) explained 5–13% of the variation in families with pathogenic breast/ovarian cancer variants. Random removal of 50% of the phenotype/genotype data reduced power and the variation in LODadj was best explained by FAR followed by the number of affected individuals and MAO when the founder was only two generations from the proband. Power to classify benign variants was ~2x power to classify pathogenic variants. Affecteds-only analysis resulted in virtually no power to correctly classify benign variants and reduced power to classify pathogenic variants. These results can be used to guide recruitment efforts to classify rare and private VUS.



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Thickness Resonance Acoustic Microscopy for Nanomechanical Subsurface Imaging

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b02170
ancac3?d=yIl2AUoC8zA


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Impact of legumes and plant proteins consumption on cognitive performances in the elderly

Numerous studies have investigated the role of the dietary factors in the prevention of cognitive decline but the short-term effects of foods choice on cognitive performances in the elderly are poorly explored...

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Erratum to: Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease



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Mouse sperm sent into space produces healthy IVF babies

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The first experiment to test how space travel could affect mammals’ reproduction shows that pregnancy can smooth over DNA damage from cosmic radiation

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Arthroscopic Treatment of Osseous Instability of the Shoulder

Abstract

Background

Bony deficiency of the anteroinferior glenoid rim as a result of a dislocation can lead to recurrent glenohumeral instability. These lesions, traditionally treated by open techniques, are increasingly being treated arthroscopically as our understanding of the pathophysiology and anatomy of the glenohumeral joint becomes clearer. Different techniques for arthroscopic management have been described and continue to evolve. While the success of the repair is surgeon dependent, the recent advances in arthroscopic shoulder surgery have contributed to the growing acceptance of arthroscopic reconstruction of glenoid bone defects to restore stability.

Questions/Purposes

The purpose of this study was to describe arthroscopic surgical management options for patients with glenohumeral osseous lesions and instability.

Methods

A comprehensive search of PubMed, Cochrane, and Medline was conducted to identify eligible studies. The reference lists of identified articles were then screened. Both technique articles and long-term outcome studies evaluating arthroscopic management of glenohumeral lesions were included.

Results

Studies included for final analysis ranged from Level II to V evidence. Technique articles include suture anchor fixation of associated glenoid rim fractures, arthroscopic reduction and percutaneous fixation of greater tuberosity fractures, arthroscopic filling ("remplissage") of the humeral Hill-Sachs lesion, and an all-arthroscopic Latarjet procedure. The overall redislocation rate varied but was consistently <10% with a low complication rate.

Conclusion

Management of glenohumeral instability can be challenging but more recent advances in arthroscopic techniques have provided improved means of treating this diagnosis. This manuscript provides a comprehensive review of the arthroscopic treatment of osseous instability of the shoulder. It provides an in depth look at the various treatment options and describes techniques for each.



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Cortical cytoskeleton dynamics regulates plasma membrane calcium ATPase isoform-2 (PMCA2) activity

Publication date: August 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 8
Author(s): Marianela G. Dalghi, Mariela Ferreira-Gomes, Nicolás Montalbetti, Alexandre Simonin, Emanuel E. Strehler, Matthias A. Hediger, Juan Pablo Rossi
We have previously shown that purified actin can directly bind to human plasma membrane Ca2+ ATPase 4b (hPMCA4b) and exert a dual modulation on its Ca2+-ATPase activity: F-actin inhibits PMCA while short actin oligomers may contribute to PMCA activation. These studies had to be performed with purified proteins given the nature of the biophysical and biochemical approaches used. To assess whether a functional interaction between the PMCAs and the cortical cytoskeleton is of physiological relevance, we characterized this phenomenon in the context of a living cell by monitoring in real-time the changes in the cytosolic calcium levels ([Ca2+]CYT). In this study, we tested the influence of drugs that change the actin and microtubule polymerization state on the activity and membrane expression of the PMCA transiently expressed in human embryonic kidney (HEK293) cells, which allowed us to observe and quantify these relationships in a live cell, for the first time. We found that disrupting the actin cytoskeleton with cytochalasin D significantly increased PMCA-mediated Ca2+ extrusion (~50–100%) whereas pre-treatment with the F-actin stabilizing agent jasplakinolide caused its full inhibition. When the microtubule network was disrupted by pretreatment of the cells with colchicine, we observed a significant decrease in PMCA activity (~40–60% inhibition) in agreement with the previously reported role of acetylated tubulin on the calcium pump. In none of these cases was there a difference in the level of expression of the pump at the cell surface, thus suggesting that the specific activity of the pump was the regulated parameter. Our results indicate that PMCA activity is profoundly affected by the polymerization state of the cortical cytoskeleton in living cells.

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