Peri-operative factors predisposing to pharyngocutaneous fistula after total laryngectomy: analysis of a large multi-institutional patient cohort

Pharyngocutaneous fistula (PCF) is a problematic complication following total laryngectomy. Disagreement remains regarding predisposing factors. This study examines perioperative factors predicting PCF followi...

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Global Head and Neck Cancer Diagnostics Market to grow at a CAGR of nearly 11.52% by 2021 - Medgadget (blog)

Medgadget (blog)

Global Head and Neck Cancer Diagnostics Market to grow at a CAGR of nearly 11.52% by 2021 Medgadget (blog) The Global Head and Neck Cancer Diagnostics Market is predicted to grow at a significant rate, at a CAGR of nearly 11.52% during the forecast period. Head and Neck cancer is among the 10 most common types of cancers worldwide. These forms of cancer ... and more »

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Pertussis outbreak investigation of Mekdela district, South Wollo zone, Amhara region, North-West Ethiopia

Pertussis is a highly contagious respiratory illness caused by Bordetella pertussis. It is one of the most common vaccine-preventable bacterial infections that affects all susceptible individuals, regardless of a...

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Peri-operative factors predisposing to pharyngocutaneous fistula after total laryngectomy: analysis of a large multi-institutional patient cohort

Pharyngocutaneous fistula (PCF) is a problematic complication following total laryngectomy. Disagreement remains regarding predisposing factors. This study examines perioperative factors predicting PCF followi...

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The CLOSER trial: a multi-center study on the clinical safety and effectiveness of closerTM VSS, a novel resorbable transfemoral vascular access sealing system

Abstract

Objectives

To evaluate the safety and effectiveness of the Closer Vascular Sealing System (VSS) against prespecified performance goals (PGs) in sealing femoral arterial access following 5–7 Fr procedures.

Background

Inconsistent safety profiles, costs and learning curves of earlier generation vascular closure devices have limited their widespread use following transfemoral procedures.

Methods

In this prospective single-arm, multi-center trial, we compared the clinical outcomes in patients undergoing 5–7 Fr transfemoral diagnostic or interventional procedures and access sites managed with Closer VSS against pre-specified PGs. The primary endpoints were time to hemostasis (TTH) and 30-day access site closure-related major complications; secondary endpoints included time to ambulation (TTA), time to discharge eligibility (TTDE), time to discharge (TTD), 30-day access site minor complications, procedure and device success.

Results

A total of 220 subjects (49.5% interventional) were enrolled. The mean TTH was 1.78 ± 7.81 min in the intention to treat and 0.98 ± 3.71 min in the per protocol cohort. Median TTH was 0 min with immediate hemostasis achieved in 80.5% of subjects, mean TTA was 2.50 ± 1.05 hr, and mean TTDE was 2.83 ± 1.54 hr. Thirty-day follow-up was completed on 219 subjects. There were no access site closure-related major complications, minor complication rate was 0.0% for diagnostic and 2.75% for interventional procedures.

Conclusions

In patients undergoing 5–7 Fr transfemoral diagnostic and interventional procedures, the CLOSER Trial met both its primary effectiveness and safety PGs. Immediate hemostasis was achieved in the majority of patients without major complication.

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Efficacy and rebound rates in propranolol-treated subglottic hemangioma: A literature review

Objective

Propranolol has recently become the treatment of choice for management of subglottic and airway hemangiomas. This literature review aimed to determine the success rate of propranolol for managing these lesions as well as the rate of rebound growth following propranolol treatment cessation.

Study Design

Literature search involving MEDLINE and Scopus to identify English-language articles.

Methods

Studies were identified using hemangioma, subglottic or airway, and propranolol for search terms. Studies were eligible for inclusion if they reported the treatment used, individual deidentified patient data, and contained patients without medical or surgical treatment prior to propranolol therapy

Results

Initial review included 107 abstracts. Twenty-four articles including case reports and case series met inclusion criteria and were included in the qualitative analysis. Forty-nine patients were included. Twenty-eight (57%) were treated with propranolol alone, and 20 (41%) were treated with a combination of propranolol and a corticosteroid. Thirty-seven (76%) of patients were treated with a dose of 2 mg/kg/d of propranolol. The initial treatment was successful in 43 (88%) of patients. Rebound growth occurred in four (9%) patients. Overall, six (12%) patients underwent surgical resection.

Conclusions

Propranolol is efficacious for treating subglottic hemangiomas. Rebound growth does occur in a small subset of patients during the propranolol wean. Close observation for children during weaning of propranolol therapy for subglottic hemangioma is essential. Adjunctive management strategies need to be used in patients with rebound growth. Laryngoscope, 2017

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Constructing a patient-specific computer model of the upper airway in sleep apnea patients

Objective

The use of computer simulation to develop a high-fidelity model has been proposed as a novel and cost-effective alternative to help guide therapeutic intervention in sleep apnea surgery. We describe a computer model based on patient-specific anatomy of obstructive sleep apnea (OSA) subjects wherein the percentage and sites of upper airway collapse are compared to findings on drug-induced sleep endoscopy (DISE).

Study Design

Basic science computer model generation.

Methods

Three-dimensional finite element techniques were undertaken for model development in a pilot study of four OSA patients. Magnetic resonance imaging was used to capture patient anatomy and software employed to outline critical anatomical structures. A finite-element mesh was applied to the volume enclosed by each structure. Linear and hyperelastic soft-tissue properties for various subsites (tonsils, uvula, soft palate, and tongue base) were derived using an inverse finite-element technique from surgical specimens. Each model underwent computer simulation to determine the degree of displacement on various structures within the upper airway, and these findings were compared to DISE exams performed on the four study patients.

Results

Computer simulation predictions for percentage of airway collapse and site of maximal collapse show agreement with observed results seen on endoscopic visualization.

Conclusion

Modeling the upper airway in OSA patients is feasible and holds promise in aiding patient-specific surgical treatment.

Level of Evidence

NA. Laryngoscope, 2017

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Minimal shedding of the glycocalyx layer during abdominal hysterectomy

Surgery with and without hypervolaemia may cause shedding (breakdown) of the endothelial glycocalyx layer, but the severity of this problem is unclear.

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Recovery and prediction of postoperative muscle power – is it still a problem?

In the postoperative period, immediate recovery of muscular power is essential for patient safety, but this can be affected by anaesthetic drugs, opioids and neuromuscular blocking agents (NMBA). In this cohor...

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Impact of intrathecal morphine analgesia on the incidence of pulmonary complications after cardiac surgery: a single center propensity-matched cohort study

Acute pain and systemic opioids may both negatively impact respiratory function after cardiac surgery. This study analyzes the local practice of using intrathecal morphine analgesia (ITMA) with minimal parente...

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Identification, heterologous expression and characterization of a dye-decolorizing peroxidase of Pleurotus sapidus

The coding sequence of a peroxidase from the secretome of Pleurotus sapidus was cloned from a cDNA library. Bioinformatic analyses revealed an open reading frame of 1551 bp corresponding to a primary translation ...

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Survey of methanotrophic diversity in various ecosystems by degenerate methane monooxygenase gene primers

Methane is the second most important greenhouse gas contributing to about 20% of global warming. Its mitigation is conducted by methane oxidizing bacteria that act as a biofilter using methane as their energy ...

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Development of a circulation direct sampling and monitoring system for O2 and CO2 concentrations in the gas–liquid phases of shake-flask systems during microbial cell culture

Monitoring the environmental factors during shake-flask culture of microorganisms can help to optimise the initial steps of bioprocess development. Herein, we developed a circulation direct monitoring and samp...

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PPE27 in Mycobacterium smegmatis Enhances Mycobacterial Survival and Manipulates Cytokine Secretion in Mouse Macrophages

Journal of Interferon & Cytokine Research , Vol. 0, No. 0.


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Doctors called the symptoms of cancer, about which little who knows - www.MICEtimes.asia (press release)

www.MICEtimes.asia (press release)

Doctors called the symptoms of cancer, about which little who knows www.MICEtimes.asia (press release) Throat cancer or larynx, lung, can occur even in non-smokers. Therese Bartholomew Bevers specialist Andersonville cancer center believes that: "in most cases, cough not associated with cancer, however, frequent and severe coughing can be a symptom of ...

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Body image in head and neck cancer patients treated with radiotherapy: the impact of surgical procedures

In this study, we aimed to investigate the impact of surgical procedures on the body image of head and neck cancer patients treated with radiotherapy and with or without radical surgery.

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DEMQOL and DEMQOL-Proxy: a Rasch analysis

DEMQOL and DEMQOL-Proxy are widely used patient reported outcome measures (PROMs) of health related quality of life in people with dementia (PWD). Growing interest in routine use of PROMs in health care calls ...

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Technical tip for direct closure of donor site of anterolateral thigh rectangular flaps wider than 9 cm used for pharyngo-esophageal reconstruction

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Cytoreductive nephrectomy for metastatic renal cell carcinoma: inequities in access exist despite improved survival

Abstract

The use of cytoreductive nephrectomy (CRN) in the targeted therapy era is still debated. We aimed to determine factors associated with reduced use of CRN and determine the effect of CRN on overall survival in patients with metastatic renal cell carcinoma (RCC). All advanced RCC diagnosed between 2001 and 2009 in New South Wales, Australia, were identified from the Central Cancer Registry. Records of treatment and death were electronically linked. Follow-up was to the end of 2011. Multivariable logistic regression analysis was used to determine factors associated with the receipt of CRN. Cox proportional hazards model was used to determine factors associated with survival. A total of 1062 patients were identified with metastatic RCC of whom 289 (27%) received CRN. There was no difference in the use of CRN over the time period of the study. Females (OR 0.68 (95% CI: 0.48–0.96)), unmarried individuals (OR 0.68 (95% CI: 0.48–0.96)), treatment in a nonteaching hospital (OR 0.26 (95% CI: 0.18–0.36)) and individuals without private insurance (OR 0.29 (95% CI: 0.20–0.41)) all had reduced likelihood of receiving CRN. On multivariable analysis, not receiving CRN resulted in a 90% increase in death (HR 1.90 (95% CI: 1.61–2.25)). In addition, increasing age (P < 0.001), increasing Charlson comorbidity status (P = 0.002) and female gender also had a significant independent association with death. Despite a strong association with improved survival, individuals who are elderly, female, have treatment in a nonteaching facility or have no private insurance have a reduced likelihood of receiving CRN.

Cytoreductive nephrectomy is commonly used in conjunction with systemic therapy to treat advanced renal cell carcinoma. Despite a strong association with improved survival, individuals who are elderly, female, have treatment in a nonteaching facility or do not have private insurance have a reduced likelihood of receiving this surgery.

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Cancer Research UK launches trial to test new drug in patients with advanced cancer - Cancer Research UK

Cancer Research UK

Cancer Research UK launches trial to test new drug in patients with advanced cancer Cancer Research UK This early phase trial will test the safety and tolerability of the drug and establish the recommended dose for patients with a variety of cancers including advanced bowel, lung, ovarian, urothelial, pancreatic, breast, head and neck, and oesophageal ...

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Blood urea nitrogen to serum creatinine ratio as a prognostic factor in diarrhea-associated hemolytic uremic syndrome: a validation study

Abstract

Identifying those children with complicated forms of diarrhea-associated hemolytic uremic syndrome (D+HUS) on admission can optimize their management. Recently, the blood urea nitrogen to serum creatinine ratio (BCR) at admission has been proposed as a novel and accurate predictor of complicated clinical outcome in D+HUS; therefore, we performed this retrospective study aimed to validate such observation in a larger series of patients. A complicated course was defined as developing one or more of the following: severe neurological or bowel injury, pancreatitis, cardiac or pulmonary involvement, hemodynamic instability, hemorrhage, and death. Data from 161 children were reviewed, 50 of them with a complicated disease including five deaths. Those with worse evolution presented a lower admission BCR than those with good outcome (22.5 vs. 30.8; p = 0.005). BCR at admission showed a limited ability to identify children at risk of a complicated course, with an AUC of 0.63 (95% CI 0.58–0.71) and an optimal cutoff point of ≤ 26.7, which achieves a sensitivity of 70% (95% CI 55.2–81.7) and a specificity of 56.7% (95% CI 47–66).

Conclusion: In this validation study, the BCR at admission provided a limited value to predict severe forms of D+HUS.

What is Known: • BCR at admission has been proposed as an accurate predictor of complicated clinical course in children with D+HUS.

What is New: • In a larger series of children with D+HUS, we were unable to confirm the usefulness of the admission BCR to early identify those at risk of complicated forms of the disease. • Further research is warranted to improve the optimal detection of these high-risk patients.

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Role of illumination intensity in microcystin development using Microcystis aeruginosa as the model algae

Abstract

Microcystis aeruginosa (M. aeruginosa) is one of the most common genera of cyanobacteria in algal blooms. In the present work, the impact of the illumination intensity on the growth of M. aeruginosa has been studied and a grinding method for the extraction of intracellular microcystins (MCs) was developed. The variations of algal density, pH, total phosphorus (TP), and total nitrogen (TN) have been investigated during MCs' culturing period. Results showed that the extraction efficiency of MC-YR by the grinding method was 275% higher than the sonication method, and the extraction efficiencies of MC-RR and MC-LR by the grinding method were similar to the sonication method. The optimal illumination intensity for M. aeruginosa was found to be 19–38 μmol m⁻² s⁻¹ with suitable pH range of 7.5–10.5. Active release of extracellular MCs was not significantly observed when illumination intensities were ≤ 38 μmol m⁻² s⁻¹. Furthermore, the intracellular MC yields under different illumination intensities were found to be a relatively stable level. However, excess illumination intensity (≥ 47 μmol m⁻² s⁻¹) led to the lysis of algal cell and increased the concentrations of extracellular MCs, with MC-RR as the dominant compound. The calculated intracellular/extracellular MCs ratios for MC-RR, MC-LR, and MC-YR were 2.38 (N = 100, SD = 2.44), 2.68 (N = 64, SD = 3.48), and 1.25 (N = 30, SD = 1.64), respectively. Strong illumination intensity and cell lysis were found to be the two major factors influencing the release of extracellular MCs.

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Biophysics explains how immune cells kill bacteria - Science Daily

Science Daily

Biophysics explains how immune cells kill bacteria Science Daily Yuma Ito, an Assistant Professor in the lab, shows that MST analysis is superior to standard analysis methods by revealing details on the temporal and spatial variation of the movement. "Standard methods analyze the mean square displacement of the ... and more »

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A systematic review of performance-enhancing pharmacologicals and biotechnologies in the Army

Introduction

In 2015, the Australian Army commissioned a systematic review to assess the evidence on effectiveness and safety of pharmacological and biotechnological products for cognitive enhancement specifically in Army personnel.

Methods

Searches for studies examining biotechnological and pharmacological products in Army populations were conducted in December 2015. Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO were searched without date or language restrictions. WHO's International Clinical Trials Registry Platform and ClinicalTrials.gov were searched to identify ongoing trials. Studies meeting inclusion criteria were evaluated for risk of bias using Cochrane's Risk of Bias tool. Due to heterogeneity of findings, meta-analysis could not be conducted. Findings were synthesised narratively and by vote-counting method.

Results

Sixteen pharmacological enhancement products were evaluated in 22 randomised controlled trials (RCTs), involving 1284 personnel. Only three of the studies were published since 2010. The interventions evaluated were varied, including supplements (eg, carbohydrate), stimulants (eg, caffeine) and hormones (eg, melatonin). Generally, caffeine provided an improvement in performance compared with placebo on 5/7 reported cognitive outcomes, followed by levothyroxine (four cognitive outcomes) and prazosin (three cognitive outcomes). Performance results were mixed (finding an improvement and no effect in comparison to placebo) for caffeine and melatonin on two outcomes. No evidence was found pertaining to biotechnological products. Studies rarely reported safety outcomes (eg, adverse events and addiction).

Conclusion

Findings from this review need to be interpreted with considerable caution. Future studies should include outcomes such as acute and long-term adverse events, and should evaluate cognitive performance using cognitive tests that are specific to the Army population.

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Retrospective analysis of four-year injury data from the Infantry Training Centre, Catterick

Introduction

Musculoskeletal injury (MSKI) represents a considerable threat to the effectiveness and productivity of military organisations globally. The impact on the medical chain, occupational disposal with associated loss of working days and associated financial burden have far-reaching consequence. The moral and legal responsibility to reduce avoidable injuries through risk assessment and prevention strategies is fundamental to governance and a key component of best practice.

Methods

A retrospective observational analysis was performed of 4101 MSKIs presenting from a total inflow of 10 498 British Army Infantry recruits recorded over four consecutive training years between 2012 and 2016. Injury incidence, site, type and week of training were recorded and analysed.

Results

The total incidence of all MSKI was observed as 39.1%. Overuse injuries were the most common subclassification of injury type (24.5%), followed by trauma (8.8%) and then stress fractures (5.7%). Causes of medical discharge over a four-year cumulative incidence were from overuse injuries (59.3%), stress fractures (21.5%) and trauma (19.2%). 45.5% of all MSKIs presented within the first eight weeks of training.

Conclusions

MSKI data highlighted the requirement for a comprehensive service evaluation of the Combat Infantryman's Course and subsequent justification for the introduction of an injury prevention intervention — Project OMEGA.

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Differential Response Pattern of Oropharyngeal Pressure by Bolus and Dry Swallows

Abstract

The aim of this study was to determine if bolus and dry swallow showed similar pressure changes in the oropharynx using our newly developed device. A unique character of it includes that baropressure can be measured with the sensor being placed in the balloon and can assess the swallowing mechanics in terms of pressure changes in the oropharynx with less influences of direct contacts of boluses and oropharyngeal structures during swallow indirectly. Fifteen healthy subjects swallowed saliva (dry), 15 ml of water, 45 ml of water, and 15 ml of two different types of food in terms of viscosity (potage soup-type and mayonnaise-type foods). Suprahyoid muscle activity was recorded simultaneously. Three parameters, area under the curve (AUC), peak amplitude, and duration of pressure, were analyzed from each swallow. Almost all of the bolus swallowing events had biphasic baropressure responses consisting of an early phase and late phase (99%), whereas 90% of the saliva swallowing events had a single phase. AUC, peak, and duration displayed greater effects during the late phase than during the early phase. Baropressure of the early phase, but not of the late phase, significantly increased with increasing volume; however, small but significant viscosity effects on pressure were seen during both phases. Peak pressure of the late phase was preceded by maximum muscle activity, whereas that of the early phase was seen when muscle activity displayed a peak response. These findings indicated that our device with the ability to measure baropressure has the potential to provide additional parameter to assess the swallow physiology, and biphasic baropressure responses in the early and late phases could reflect functional aspects of the swallowing reflexes.

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Predictive Value of the New Zealand Secretion Scale (NZSS) for Pneumonia

Abstract

Accumulated pharyngo-laryngeal secretions have been associated with aspiration and pneumonia. While traditional secretion scales evaluate location and amount, the eight-point New Zealand Secretion Scale (NZSS) uniquely encompasses a responsiveness subcomponent. This prospective observational study investigated the predictive value of NZSS for aspiration and pneumonia. Consecutive inpatients (N:180) referred for flexible endoscopic evaluation of swallowing (FEES) were recruited (neurological 49%, critical care 31%, structural 15%, other 5% etiologies). Mean age was 63 years (range 18–95 years, S.D. 18). A standardized protocol was completed on 264 FEES (180 first FEES, 84 repeat FEES). Penetration-aspiration scale (PAS) (ICC = .89) and NZSS (ICC = .91) were independently scored by two raters. Aspiration of food and/or fluids occurred in 36% of FEES; 24% silently. Median NZSS was 3 (range 0–7); with silent aspiration of secretions in 33% of FEES. There was a significant correlation between NZSS and PAS (R = .37, p < .001). Incidence of pneumonia during admission was 46% and was significantly associated with PAS (p < .001), NZSS (p < .001), age (p < .001), and tracheostomy (p < .001). Of those who developed pneumonia, 33% had both high PAS (>5) and high NZSS (>4). Eleven percent of those who developed pneumonia had an elevated NZSS (>4) in the absence of aspiration (PAS < 6). This large study reports the significant relationship between accumulated secretions, airway responsiveness, and pneumonia. This comprehensive scale is a useful tool when carrying out endoscopic evaluation and has the potential to predict pneumonia in patients irrespective of their aspiration status.

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Cross-Cultural Adaptation and Validation of the SWAL-QoL Questionnaire in Greek

Abstract

The purpose of this study was to translate and adapt the 44-item SWAL-QoL into Greek and examine its internal consistency, test–retest reliability, external construct validity, and discriminant validity in order to provide a validated dysphagia-specific QoL instrument in the Greek language. The instrument was translated into Greek using the back translation to ensure linguistic validity and was culturally adapted resulting in the SWAL-QoL-GR. Two groups of participants were included: a patient group of 86 adults (48 males; age range: 18–87 years) diagnosed with oropharyngeal dysphagia, and an age-matched healthy control group (39 adults; 19 males; age range: 18–84 years). The Greek 30-item version of the WHOQOL-BREF was used for assessment of construct validity. Overall, the questionnaire achieved good to excellent psychometric values. Internal consistency of all 10 subscales and the physical symptoms scale of the SWAL-QoL-GR assessed by Cronbach's α was good to excellent (0.811 < α < 0.940). Test–retest validity was found to be good to excellent as well. In addition, moderate to strong correlations were found between seven of the ten subscales of the SWAL-QoL-GR with limited items of the WHOQΟL-BREF (0.401 < ρ < 0.65), supporting good construct validity of the SWAL-QoL-GR. The SWAL-QoL-GR also correctly differentiated between patients with dysphagia and age-matched healthy controls (p < 0.001) on all 11 scales, further indicating excellent discriminant validity. Finally, no significant differences were found between the two sexes. This cultural adaptation and validation allows the use of this tool in Greece, further enhancing our clinical and scientific efforts to increase the evidence-based practice resources for dysphagia rehabilitation in Greece.

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Changes in Swallowing-Related Quality of Life After Endoscopic Treatment for Zenker’s Diverticulum Using the SWAL-QOL Questionnaire

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Transplantation of Amniotic Scaffold-Seeded Mesenchymal Stem Cells and/or Endothelial Progenitor Cells From Bone Marrow to Efficiently Repair 3-cm Circumferential Urethral Defect in Model Dogs

Tissue Engineering Part A , Vol. 0, No. 0.


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Bone Regeneration Mediated by a Bioactive and Biodegradable Extracellular Matrix-Like Hydrogel Based on Elastin-Like Recombinamers

Tissue Engineering Part A , Vol. 0, No. 0.


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Mimicking Cartilage Tissue Zonal Organization by Engineering Tissue-Scale Gradient Hydrogels as 3D Cell Niche

Tissue Engineering Part A , Vol. 0, No. 0.


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A Single Administration of Fish oil Inhibits the Acute Inflammatory Response in Rats

Publication date: Available online 22 August 2017
Source:Asian Pacific Journal of Tropical Medicine
Author(s): Laura Lícia Milani de Arruda, Franciele Queiroz Ames, Damila Rodrigues de Morais, Renata Grespan, Ana Paula Maziero Gil, Maria Angélica Raffaini Covas Pereira Silva, Jesuí Vergílio Visentainer, Roberto Kenji Nakamura Cuman, Ciomar Aparecida Bersani-Amado
ObjectiveTo investigate the antiinflammatory effects of a single administration of fish oil (FO) on the acute inflammatory response.MethodsThe paw edema and pleurisy models were used to evaluate the effects of FO dissolved in olive oil (FOP) orally administered in a single dose in rats. Nitric oxide (NO) concentrations in the pleural exudate were performed according to the Griess method and the cytokine concentrations were determined by Luminex Bead-based Multiplex Assay.ResultsFOP treatment (30 and 300 mg/kg) significantly reduced paw edema. FOP treatment at 18.75, 37.5, 75.0, 150.0, and 300 mg/kg decreased both the volume of pleural exudate and cellular migration into the pleural cavity and each of these doses presented the same effectiveness. Treatment with FOP (300 mg/kg) reduced NO, TNF-α, IL-1β, and IL-6 concentrations in the pleural exudate.ConclusionsThe present data provide evidence that FO has inhibitory effects on the acute inflammatory response when administered in a single dose in rats. This effect might be attributable to a direct inhibitory effect of FO on the production or release of inflammatory mediators that are involved in the pathological processes evaluated herein.



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At the confluence of ribosomally synthesized peptide modification and radical S-adenosylmethionine (SAM) enzymology [Protein Structure and Folding]

Radical SAM (RS) enzymology has emerged as a major biochemical strategy for the homolytic cleavage of unactivated C-H bonds. At the same time, the posttranslational modification of ribosomally encoded peptides is a rapidly expanding area of investigation, already shown to lead to a wide range of natural products that include a redox cofactor, antibiotics, quorum-sensing molecules, growth regulators, and mature proteins. In this mini-review, we discuss the cross-section of these two disciplines, highlighting the recently uncovered importance of protein-protein interactions, in particular, between the ribosomally-encoded peptide substrate and its chaperone, which functions either as a stand-alone protein or as an N-terminal domain to the Radical SAM enzyme in the peptide modification cascade. The need for further structural and functional work on this class of RS enzymes is emphasized, given the poorly understand roles performed by multiple, auxiliary iron-sulfur clusters and the paucity of protein X-ray structural data for RS enzymes.

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Increased heme synthesis in yeast induces a metabolic switch from fermentation to respiration even under conditions of glucose repression [Metabolism]

Regulation of mitochondrial biogenesis and respiration is a complex process that involves several signaling pathways and transcription factors, as well as communication between the nuclear and mitochondrial genomes. Under aerobic condition, the budding yeast Saccharomyces cerevisiae metabolizes glucose predominantly by glycolysis and fermentation. We have recently shown that altered chromatin structure in yeast induces respiration by a mechanism that requires transport and metabolism of pyruvate in mitochondria. However, how pyruvate controls the transcriptional responses underlying the metabolic switch from fermentation to respiration is unknown. Here, we report that this pyruvate effect involves heme. We found that heme induces transcription of HAP4, the transcriptional activation subunit of the Hap2/3/4/5p complex, required for growth on nonfermentable carbon sources, in a Hap1p- and Hap2/3/4/5p-dependent manner. Increasing cellular heme levels by inactivating ROX1, which encodes a repressor of many hypoxic genes, or by overexpressing HEM3 or HEM12 induced respiration and elevated ATP levels. Increased heme synthesis, even under conditions of glucose repression, activated Hap1p and the Hap2/3/4/5p complex and induced transcription of HAP4 and genes required for the tricarboxylic acid (TCA) cycle, electron transport chain (ETC) and oxidative phosphorylation (OXPHOS), leading to a switch from fermentation to respiration. Conversely, inhibiting metabolic flux into the TCA cycle reduced cellular heme levels and HAP4 transcription. Together, our results indicate that the glucose-mediated repression of respiration in budding yeast is at least partly due to the low cellular heme level.

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Discovery of a widespread prokaryotic 5-oxoprolinase that was hiding in plain sight [Microbiology]

5-Oxoproline (OP) is well known as an enzymatic intermediate in the eukaryotic γ-glutamyl cycle, but it is also an unavoidable damage product formed spontaneously from glutamine and other sources. Eukaryotes metabolize OP via an ATP-dependent 5-oxoprolinase; most prokaryotes lack homologs of this enzyme - and the γ-glutamyl cycle - but are predicted to have some way to dispose of OP if its spontaneous formation in vivo is significant. Comparative analysis of prokaryotic genomes showed that the gene encoding pyroglutamyl peptidase, which removes N-terminal OP residues, clusters in diverse genomes with genes specifying homologs of a fungal lactamase (renamed prokaryotic 5-oxoprolinase A, pxpA) and homologs of allophanate hydrolase subunits (renamed pxpB and pxpC). Inactivation of Bacillus subtilis pxpA, pxpB, or pxpC genes slowed growth, caused 5-OP accumulation in cells and medium, and prevented use of OP as a nitrogen source. Assays of cell lysates showed that ATP-dependent 5-oxoprolinase activity disappeared when pxpA, pxpB, or pxpC was inactivated. 5-Oxoprolinase activity could be reconstituted in vitro by mixing recombinant B. subtilis PxpA, PxpB, and PxpC proteins. In addition, overexpressing Escherichia coli pxpABC genes in E. coli increased 5-oxoprolinase activity in lysates ≥1,700-fold. This work shows that OP is a major universal metabolite damage product and that OP disposal systems are common in all domains of life. Furthermore, it illustrates how easily metabolite damage and damage-control systems can be overlooked, even for central metabolites in model organisms.

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Jill Zarin Shares a Positive Update on Husband Bobby's Health: 'What a Turnaround!' - PEOPLE.com

PEOPLE.com

Jill Zarin Shares a Positive Update on Husband Bobby's Health: 'What a Turnaround!' PEOPLE.com Bobby Zarin's health is getting better by the day since he was released from the hospital earlier this month. On Monday, Jill Zarin took to Instagram where she gave an uplifting update on her husband, who has been battling thyroid cancer. The couple ...

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“Lilypalooza,” Mont Clare, to benefit little girl with cancer - The Times Herald

"Lilypalooza," Mont Clare, to benefit little girl with cancer The Times Herald Lily Pagnotta, 6, poses for a photo with Warren Birch, left, and C.J. Santangelo, both of the A-Team, a nonprofit that will host "Lilypalooza" Sunday, Aug. 27, 2017 at St. Michael's picnic grounds, Mont Clare. Lily was diagnosed with Hodgkin's lymphoma ...

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Gene mutational pattern and expression level in 560 acute myeloid leukemia patients and their clinical relevance

Cytogenetic aberrations and gene mutations have long been regarded as independent prognostic markers in AML, both of which can lead to misexpression of some key genes related to hematopoiesis. It is believed t...

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Local allergic rhinitis is an independent rhinitis phenotype: The results of a 10-years follow-up study

Abstract

Background

The knowledge about the natural history of local allergic rhinitis (LAR) is limited. One unmeet question is to demonstrate whether LAR should be considered the first step in the development of allergic rhinitis (AR) or an independent phenotype. The aim of this study was to prospectively evaluate the natural history of a population with LAR, the potential conversion to AR with systemic atopy, and the development of asthma during 10 years.

Methods

This is the second phase of a 10 year follow-up study of a cohort of 176 patients with LAR of recent onset and 115 age- and sex-matched healthy controls prospectively evaluated from 2005 to 2016. Clinical-demographic questionnaire, spirometry, skin prick-test, and specific-IgE were evaluated yearly. Nasal allergen provocation tests (NAPT) with D. pteronyssinus, Alternaria alternata, Olea europaea, and grass pollen were performed at baseline, and after 5 and 10 years.

Results

After 10 years LAR patients experienced a significant and clinically relevant worsening of the rhinitis, with increase of emergency assistance, development of asthma, loss of allergen tolerance, and impairment of the quality of life. This worsening became significant after 5 years and progressed throughout 10 years.

A similar rate of development of AR with systemic atopy was detected in patients and controls (9.7% vs 7.8%, Log-rank p=0.623). In 5 patients conversion to systemic atopy occurred >10 years (3%).

Conclusions

LAR is a well-differentiated clinical entity with a low rate of development of systemic atopy, a natural evolution towards worsening and a risk factor for suffering asthma.

This article is protected by copyright. All rights reserved.

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Dr. Cagle to retire from CMH ENT & Allergy Clinic - Bolivar Herald-Free Press (subscription)

Dr. Cagle to retire from CMH ENT & Allergy Clinic Bolivar Herald-Free Press (subscription) Ericksen specializes in allergy management, as well as adult and pediatric ear, nose and throat issues, including sinus issues, sleep apnea and nasal obstruction, head and neck cancer, thyroid and parathyroid surgery, salivary gland surgery, facial ...

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Suicide on TV: minimising the risk to vulnerable viewers

On 31 March Netflix released its series 13 Reasons Why,1 portraying the fictional death of 17 year old Hannah Baker, who records her story on tapes before her suicide. Each of the 13 episodes...

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Construction of a Polyhedral DNA 12-Arm Junction for Self-Assembly of Wireframe DNA Lattices

ACS Nano

DOI: 10.1021/acsnano.7b03538

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Tumore alle ovaie: attenzione al borotalco - Blasting News

Blasting News

Tumore alle ovaie: attenzione al borotalco Blasting News Il caso della donna ammalatasi di tumore alle ovaie sta facendo molto parlare, non solo perché è stato riconosciuto il legame tra le sostanze contenute nel borotalco e la malattia, ma perché gli studi avevano già posto il problema oltre 10 anni fa. Era ... and more »

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Interleukin-8 in cancer pathogenesis, treatment and follow-up

Immune responses are characterized by the activation of leukocytes and migration of hematopoietic cells to secondary lymphoid organs or to the site of inflammation [1]. Under inflammatory conditions, the expression of specific chemokines, a class of soluble small proteins with potent chemotactic activity, is markedly up-regulated [2]. Chemokines constitute a large family of structurally related polypeptide signaling molecules characterized by their ability to promote the directed chemotaxis of leukocytes.

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Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Alerie Guzman De La Fuente, Simona Lange, Maria Elena Silva, Ginez A. Gonzalez, Herbert Tempfer, Peter van Wijngaarden, Chao Zhao, Ludovica Di Canio, Andrea Trost, Lara Bieler, Pia Zaunmair, Peter Rotheneichner, Anna O'Sullivan, Sebastien Couillard-Despres, Oihana Errea, Maarja A. Mäe, Johanna Andrae, Liqun He, Annika Keller, Luis F. Bátiz, Christer Betsholtz, Ludwig Aigner, Robin J.M. Franklin, Francisco J. Rivera
The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfb^ret/ret mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

Graphical abstract

Teaser

Following toxin-induced demyelination in PC-deficient mice and using a number of in vitro approaches, Guzman de la Fuente et al. show that CNS pericytes (PCs) respond to demyelination and, through Lama2 secretion, stimulate oligodendrocyte progenitor cell differentiation during remyelination. These findings extend PC function beyond vascular homeostasis toward regeneration.


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Dopamine Encodes Retrospective Temporal Information in a Context-Independent Manner

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Kaitlyn M. Fonzi, Merridee J. Lefner, Paul E.M. Phillips, Matthew J. Wanat
The dopamine system responds to reward-predictive cues to reflect a prospective estimation of reward value, although its role in encoding retrospective reward-related information is unclear. We report that cue-evoked dopamine release in the nucleus accumbens core encodes the time elapsed since the previous reward or rather the wait time. Specifically, a cue that always follows the preceding reward with a short wait time elicits a greater dopamine response relative to a distinct cue that always follows the preceding reward with a long wait time. Differences in the dopamine response between short wait and long wait cues were evident even when these cues were never experienced together within the same context. Conditioned responding updated accordingly with a change in cue-evoked dopamine release but was unrelated to a difference in the dopamine response between cues. Collectively, these findings illustrate that the cue-evoked dopamine response conveys a subjective estimation of the relative reward rate.

Graphical abstract

Teaser

Fonzi et al. demonstrate that cue-evoked dopamine release encodes retrospective time-related information. They find that the dopamine system can discern differences between cues that have never been experienced together in the same context.


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The Proprioceptive System Regulates Morphologic Restoration of Fractured Bones

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Ronen Blecher, Sharon Krief, Tal Galili, Eran Assaraf, Tomer Stern, Yoram Anekstein, Gabriel Agar, Elazar Zelzer
Successful fracture repair requires restoration of bone morphology and mechanical integrity. Recent evidence shows that fractured bones of neonatal mice undergo spontaneous realignment, dubbed "natural reduction." Here, we show that natural reduction is regulated by the proprioceptive system and improves with age. Comparison among mice of different ages revealed, surprisingly, that 3-month-old mice exhibited more rapid and effective natural reduction than newborns. Fractured bones of null mutants for transcription factor Runx3, lacking functional proprioceptors, failed to realign properly. Blocking Runx3 expression in the peripheral nervous system, but not in limb mesenchyme, recapitulated the null phenotype, as did inactivation of muscles flanking the fracture site. Egr3 knockout mice, which lack muscle spindles but not Golgi tendon organs, displayed a less severe phenotype, suggesting that both receptor types, as well as muscle contraction, are required for this regulatory mechanism. These findings uncover a physiological role for proprioception in non-autonomous regulation of skeletal integrity.

Graphical abstract

Teaser

Blecher et al. report that natural reduction, the process whereby fractured bones are realigned, fails in mutant mice lacking functional proprioceptive circuitry. Surprisingly, natural reduction was more rapid and effective in 3-month-old mice than in newborns. These findings suggest a physiological role for proprioception in non-autonomous regulation of skeletal integrity.


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Constitutive Immune Activity Promotes Tumorigenesis in Drosophila Intestinal Progenitor Cells

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Kristina Petkau, Meghan Ferguson, Silvia Guntermann, Edan Foley
Gut innate immune defenses control bacterial populations and protect the host interior from invasion. Although excess intestinal immune activity frequently promotes inflammatory illnesses, we know little about the consequences of chronic innate immune activity exclusively in endodermal gut cells of an otherwise normal animal. To address this question, we examined the consequences of persistent inflammatory signals in adult fly intestinal progenitor cells. We found that constitutive immune activity disrupts expression of homeostatic regulators such as Notch pathway components and induces hyperplasia throughout the gut. Consistent with these observations, we found that persistent immune signals interfere with progenitor cell differentiation and exacerbate the formation of Notch-dependent intestinal tumors. These findings uncover a link between constitutive immune activity and tumorigenesis in intestinal stem cells.

Graphical abstract

Teaser

Petkau et al. show that persistent immune activity in gut progenitor cells promotes tumorigenesis in adult flies.


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Mediator MED23 Links Pigmentation and DNA Repair through the Transcription Factor MITF

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Min Xia, Kun Chen, Xiao Yao, Yichi Xu, Jiaying Yao, Jun Yan, Zhen Shao, Gang Wang
DNA repair is related to many physiological and pathological processes, including pigmentation. Little is known about the role of the transcriptional cofactor Mediator complex in DNA repair and pigmentation. Here, we demonstrate that Mediator MED23 plays an important role in coupling UV-induced DNA repair to pigmentation. The loss of Med23 specifically impairs the pigmentation process in melanocyte-lineage cells and in zebrafish. Med23 deficiency leads to enhanced nucleotide excision repair (NER) and less DNA damage following UV radiation because of the enhanced expression and recruitment of NER factors to chromatin for genomic stability. Integrative analyses of melanoma cells reveal that MED23 controls the expression of a melanocyte master regulator, Mitf, by modulating its distal enhancer activity, leading to opposing effects on pigmentation and DNA repair. Collectively, the Mediator MED23/MITF axis connects DNA repair to pigmentation, thus providing molecular insights into the DNA damage response and skin-related diseases.

Graphical abstract

Teaser

Xia et al. find that MED23 controls Mitf expression by modulating its enhancer function, thus connecting DNA repair to pigmentation.


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Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Alba Torrents de la Peña, Jean-Philippe Julien, Steven W. de Taeye, Fernando Garces, Miklos Guttman, Gabriel Ozorowski, Laura K. Pritchard, Anna-Janina Behrens, Eden P. Go, Judith A. Burger, Edith E. Schermer, Kwinten Sliepen, Thomas J. Ketas, Pavel Pugach, Anila Yasmeen, Christopher A. Cottrell, Jonathan L. Torres, Charlotte D. Vavourakis, Marit J. van Gils, Celia LaBranche, David C. Montefiori, Heather Desaire, Max Crispin, Per Johan Klasse, Kelly K. Lee, John P. Moore, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders
The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs).

Graphical abstract

Teaser

Native-like HIV-1 envelope trimers are a platform for efforts to induce broadly neutralizing antibodies. Torrents de la Peña et al. design HIV-1 envelope trimers with enhanced stability and reduced flexibility. These modified trimers improve the induction of neutralizing antibodies and provide new opportunities toward elicitation of broadly neutralizing antibodies.


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PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Maria Gato-Cañas, Miren Zuazo, Hugo Arasanz, Maria Ibañez-Vea, Laura Lorenzo, Gonzalo Fernandez-Hinojal, Ruth Vera, Cristian Smerdou, Eva Martisova, Imanol Arozarena, Claudia Wellbrock, Diana Llopiz, Marta Ruiz, Pablo Sarobe, Karine Breckpot, Grazyna Kochan, David Escors
PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.

Graphical abstract

Teaser

Gato-Cañas et al. find that PDL1 protects cancer cells from interferon toxicity by counteracting interferon signaling through the activities of two non-classical conserved motifs. Human cancers acquire somatic mutations within these motifs that enhance PDL1 anti-interferon activities, favoring tumor progression.


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Triggering of NOD2 Receptor Converts Inflammatory Ly6Chigh into Ly6Clow Monocytes with Patrolling Properties

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Anne-Julie Lessard, Manon LeBel, Benoit Egarnes, Paul Préfontaine, Peter Thériault, Arnaud Droit, Alexandre Brunet, Serge Rivest, Jean Gosselin
The signals that regulate the fate of circulating monocytes remain unknown. In the present study, we demonstrate that triggering of the NOD2 receptor by muramyl dipeptide (MDP) converts inflammatory Ly6C^high monocytes into patrolling Ly6C^low monocytes. Administration of MDP to Nr4a1^−/− mice, which lack Ly6C^low monocytes, or to Ly6C^low-depleted mice led to the emergence of blood-patrolling monocytes with a profile similar to that of Ly6C^low monocytes, including high expression of CX3CR1 and LFA1. Using intravital microscopy in animal models of inflammatory diseases, we also found that converted Ly6C^high monocytes patrol the endothelium of blood vessels and that their presence contributes to a reduction in the inflammatory response following MDP injection. Our results demonstrate that NOD2 contributes to the regulation of blood monocytes and suggest that it could be therapeutically targeted to treat inflammatory diseases.

Graphical abstract

Teaser

The signals that regulate the conversion of inflammatory monocytes into patrolling subset(s) remain unknown. Here, Lessard et al. demonstrate that triggering NOD2 transforms inflammatory Ly6C^high monocytes into Ly6C^low monocytes that look and function like patrolling cells.


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Serotonergic Modulation of Sensory Representation in a Central Multisensory Circuit Is Pathway Specific

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Zheng-Quan Tang, Laurence O. Trussell
Many studies have explored how neuromodulators affect synaptic function, yet little is known about how they modify computations at the microcircuit level. In the dorsal cochlear nucleus (DCN), a region that integrates auditory and multisensory inputs from two distinct pathways, serotonin (5-HT) enhances excitability of principal cells, predicting a generalized reduction in sensory thresholds. Surprisingly, we found that when looked at from the circuit level, 5-HT enhances signaling only from the multisensory input, while decreasing input from auditory fibers. This effect is only partially explained by an action on auditory nerve terminals. Rather, 5-HT biases processing for one input pathway by simultaneously enhancing excitability in the principal cell and in a pathway-specific feed-forward inhibitory interneuron. Thus, by acting on multiple targets, 5-HT orchestrates a fundamental shift in representation of convergent auditory and multisensory pathways, enhancing the potency of non-auditory signals in a classical auditory pathway.

Graphical abstract

Teaser

Neuromodulators may alter sensory processing upon changes in behavioral state. Tang and Trussell demonstrate that the neuromodulator serotonin shifts the representation of convergent auditory and multisensory pathways at a microcircuit level, enhancing the potency of non-auditory signals in a classical auditory brain region.


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Composition and Control of a Deg/ENaC Channel during Presynaptic Homeostatic Plasticity

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Brian O. Orr, David Gorczyca, Meg A. Younger, Lily Y. Jan, Yuh-Nung Jan, Graeme W. Davis
The homeostatic control of presynaptic neurotransmitter release stabilizes information transfer at synaptic connections in the nervous system of organisms ranging from insect to human. Presynaptic homeostatic signaling centers upon the regulated membrane insertion of an amiloride-sensitive degenerin/epithelial sodium (Deg/ENaC) channel. Elucidating the subunit composition of this channel is an essential step toward defining the underlying mechanisms of presynaptic homeostatic plasticity (PHP). Here, we demonstrate that the ppk1 gene encodes an essential subunit of this Deg/ENaC channel, functioning in motoneurons for the rapid induction and maintenance of PHP. We provide genetic and biochemical evidence that PPK1 functions together with PPK11 and PPK16 as a presynaptic, hetero-trimeric Deg/ENaC channel. Finally, we highlight tight control of Deg/ENaC channel expression and activity, showing increased PPK1 protein expression during PHP and evidence for signaling mechanisms that fine tune the level of Deg/ENaC activity during PHP.

Graphical abstract

Teaser

Orr et al. define the subunit composition of an essential Deg/ENaC channel that controls the rapid induction and sustained expression of presynaptic homeostatic plasticity. The demonstration that PPK1 incorporates into DEG/ENaC channels with diverse physiological activities highlights the potential for tremendous DEG/ENaC channel diversity in Drosophila.


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Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Oliver H. Miller, Andreas Bruns, Imen Ben Ammar, Thomas Mueggler, Benjamin J. Hall
The NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant depression. Understanding how antagonism of NMDARs alters synapse and circuit function is pivotal to developing circuit-based therapies for depression. Using virally induced gene deletion, ex vivo optogenetic-assisted circuit analysis, and in vivo chemogenetics and fMRI, we assessed the role of NMDARs in the medial prefrontal cortex (mPFC) in controlling depression-related behavior in mice. We demonstrate that post-developmental genetic deletion of the NMDAR subunit GluN2B from pyramidal neurons in the mPFC enhances connectivity between the mPFC and limbic thalamus, but not the ventral hippocampus, and reduces depression-like behavior. Using intersectional chemogenetics, we show that activation of this thalamocortical circuit is sufficient to elicit a decrease in despair-like behavior. Our findings reveal that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus (MDT)→mPFC circuit that controls depression-like behavior.

Graphical abstract

Teaser

In these experiments, Miller et al. show that GluN2B-containing NMDARs are enriched at synapses between the medial dorsal thalamus and medial prefrontal cortex. They also show that post-developmental deletion of these receptors in the mPFC enhances synaptic connectivity and that direct activation of this circuit in vivo drives strong antidepressant-like behavior in mice.


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Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Hillary L. Woodworth, Hannah M. Batchelor, Bethany G. Beekly, Raluca Bugescu, Juliette A. Brown, Gizem Kurt, Patrick M. Fuller, Gina M. Leinninger
Dopamine (DA) neurons in the ventral tegmental area (VTA) are heterogeneous and differentially regulate ingestive and locomotor behaviors that affect energy balance. Identification of which VTA DA neurons mediate behaviors that limit weight gain has been hindered, however, by the lack of molecular markers to distinguish VTA DA populations. Here, we identified a specific subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) and preferentially comprise mesolimbic, but not mesocortical, DA neurons. Genetically targeted ablation of VTA NtsR1 neurons uncouples motivated feeding and physical activity, biasing behavior toward energy expenditure and protecting mice from age-related and diet-induced weight gain. VTA NtsR1 neurons thus represent a molecularly defined subset of DA neurons that are essential for the coordination of energy balance. Modulation of VTA NtsR1 neurons may therefore be useful to promote behaviors that prevent the development of obesity.

Graphical abstract

Teaser

Woodworth et al. identify a subset of VTA dopamine neurons that express neurotensin receptor-1. Ablation of these neurons leads to enhanced physical activity and energy expenditure that protect mice from diet-induced obesity, revealing an important role for VTA NtR1 neurons in the regulation of body weight.


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Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Mikkel Roland Holst, Maite Vidal-Quadras, Elin Larsson, Jie Song, Madlen Hubert, Jeanette Blomberg, Magnus Lundborg, Maréne Landström, Richard Lundmark
Cellular blebbing, caused by local alterations in cell-surface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrin-independent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension-mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

Graphical abstract

Teaser

Holst et al. show that clathrin-independent endocytosis facilitates the rearrangement of the cell surface in response to a decrease in cell volume. This regulation, mediated by the protein GRAF1, suppresses cellular blebbing and the invasiveness of cancer cells, clarifying why GRAF1 acts as a tumor suppressor.


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Asymmetric Centriole Numbers at Spindle Poles Cause Chromosome Missegregation in Cancer

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Marco R. Cosenza, Anna Cazzola, Annik Rossberg, Nicole L. Schieber, Gleb Konotop, Elena Bausch, Alla Slynko, Tim Holland-Letz, Marc S. Raab, Taronish Dubash, Hanno Glimm, Sven Poppelreuther, Christel Herold-Mende, Yannick Schwab, Alwin Krämer
Chromosomal instability is a hallmark of cancer and correlates with the presence of extra centrosomes, which originate from centriole overduplication. Overduplicated centrioles lead to the formation of centriole rosettes, which mature into supernumerary centrosomes in the subsequent cell cycle. While extra centrosomes promote chromosome missegregation by clustering into pseudo-bipolar spindles, the contribution of centriole rosettes to chromosome missegregation is unknown. We used multi-modal imaging of cells with conditional centriole overduplication to show that mitotic rosettes in bipolar spindles frequently harbor unequal centriole numbers, leading to biased chromosome capture that favors binding to the prominent pole. This results in chromosome missegregation and aneuploidy. Rosette mitoses lead to viable offspring and significantly contribute to progeny production. We further show that centrosome abnormalities in primary human malignancies frequently consist of centriole rosettes. As asymmetric centriole rosettes generate mitotic errors that can be propagated, rosette mitoses are sufficient to cause chromosome missegregation in cancer.

Graphical abstract

Teaser

Extra centrosomes are frequent in human cancers and cause chromosome missegregation via clustering into a pseudo-bipolar mitotic spindle array. Cosenza et al. now demonstrate that centriole rosettes, a transient stage of extra centrosome formation, drive chromosome missegregation in addition to centrosome clustering and are frequently found in primary tumors.


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SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Waaqo Daddacha, Allyson E. Koyen, Amanda J. Bastien, PamelaSara E. Head, Vishal R. Dhere, Geraldine N. Nabeta, Erin C. Connolly, Erica Werner, Matthew Z. Madden, Michele B. Daly, Elizabeth V. Minten, Donna R. Whelan, Ashley J. Schlafstein, Hui Zhang, Roopesh Anand, Christine Doronio, Allison E. Withers, Caitlin Shepard, Ranjini K. Sundaram, Xingming Deng, William S. Dynan, Ya Wang, Ranjit S. Bindra, Petr Cejka, Eli Rothenberg, Paul W. Doetsch, Baek Kim, David S. Yu
DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.

Graphical abstract

Teaser

SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection and is dysregulated in Aicardi-Goutières syndrome and cancer. Daddacha et al. define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.


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Omega-3 fatty acid levels in red blood cell membranes and physical decline over 3 years: longitudinal data from the MAPT study

Abstract

Studies have shown that omega-3 polyunsaturated fatty acids (PUFAs) are associated with brain, cardiovascular, and immune function, as well as physical performance and bone health in older adults. So far, few studies have investigated the associations between PUFA status and performance-based tests of physical function. The objective of this study was to investigate the associations between the omega-3 PUFA levels (eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)) in red blood cell (RBC) membranes and physical performance, in a sample of community-dwelling older adults. This is a longitudinal observational study using data from the Multidomain Alzheimer's Disease Trial (MAPT), a randomized, placebo-controlled trial. Four hundred participants from MAPT placebo group with available PUFA data were included. Omega-3 PUFA levels in RBC membranes were measured at baseline, and their percentage of total RBC membrane fatty acid content was calculated. We dichotomized the standardized omega-3 PUFA levels in RBC membranes as low (lowest quartile) vs. high (three upper quartiles). Gait speed (in m/s) and short physical performance battery (SPPB) score (range from 0 to 12, higher is better) were used to assess physical performance at baseline and after 6, 12, 24, and 36 months. Participants were 75.2 (± 4.3) years old and 68% were female. Bivariate analyses found that the characteristic of the participants in the lowest quartile of omega-3 PUFA levels (Q1) and those in the three upper quartiles (Q2–Q4) was not different at baseline; only those in Q1 were slightly older. In an unadjusted model, the difference in gait speed after 3 years of follow-up was significant (− 0.09 ± 0.03 m/s; p = 0.008) between participants in Q1 and those in Q2–Q4. In a model adjusted for age, gender, educational level, cognitive function, depressive status, body mass index, physical activity, grip strength, and their time interaction, this difference remained clinically relevant (− 0.07 ± 0.04 m/s; p = 0.075). No difference between the two groups was found for the SPPB score development over 3 years. Older adults with subjective memory complaints and in the lower quartile of omega-3 have a faster decline on gait speed compared to people in the three upper quartiles. Other longitudinal studies are needed to explore this association and to examine mechanisms.

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Human pluripotent stem cell-derived TSC2-haploinsufficient smooth muscle cells recapitulate features of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both Tuberous Sclerosis Complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSCs), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/- mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributed to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM which can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM.

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EMX2 gene expression predicts liver metastasis and survival in colorectal cancer

The Empty Spiracles Homeobox (EMX-) 2 gene has been associated with regulation of growth and differentiation in neuronal development. While recent studies provide evidence that EMX2 regulates tumorigenesis of ...

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BiClamp® vessel-sealing device for open hepatic resection of malignant and benign liver tumours: a single-institution experience

Intraoperative blood loss during hepatectomy worsens prognosis, and various tools have been used to improve perioperative safety and feasibility. We aimed to retrospectively evaluate the feasibility and safety...

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Active smoking and risk of breast cancer in a Danish nurse cohort study

No scientific consensus has been reached on whether active tobacco smoking causes breast cancer. We examine the association between active smoking and breast cancer risk in Denmark, which has some of the highe...

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Prognostic significance of the total number of harvested lymph nodes for lymph node-negative gastric cancer patients

The relationship between the number of harvested lymph nodes (HLNs) and prognosis of gastric cancer patients without an involvement of lymph nodes has not been well-evaluated. The objective of this study is to...

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Prognostic impact of a new score using neutrophil-to-lymphocyte ratios in the serum and malignant pleural effusion in lung cancer patients

Various studies have reported that the neutrophil-to-lymphocyte ratio in the serum (sNLR) may serve as a cost-effective and useful prognostic factor in patients with various cancer types. However, no study has...

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Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?

The branched chain amino acids (BCAAs) are leucine, valine and isoleucine. A multi-million dollar industry of nutritional supplements has grown around the concept that dietary supplements of BCAAs alone produc...

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Infective dermatitis associated with human T-lymphotropic virus type 1 infection in Adelaide, South Australia

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The correlation between periodontal health status and suspectibility to infections associated with craniomaxillofacial osteosynthesis plates

none.

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Peri-operative factors predisposing to pharyngocutaneous fistula after total laryngectomy: analysis of a large multi-institutional patient cohort

Abstract

Background

Pharyngocutaneous fistula (PCF) is a problematic complication following total laryngectomy. Disagreement remains regarding predisposing factors. This study examines perioperative factors predicting PCF following total laryngectomy using a large multicenter data registry.

Methods

Retrospective cohort analysis was performed using patients undergoing total laryngectomy in the ACS-NSQIP database for 2006–2014. Sub-analysis was performed based on reconstruction type. Outcome of interest was PCF development within 30 days.

Results

Multivariate analysis of 971 patients was performed. Three variables showed statistical significance in predicting PCF: wound classification of 3 and 4 vs. 1–2 (OR 6.42 P < 0.0004 and OR 8.87, P < 0.0042), pre-operative transfusion of > 4 units of packed red blood cells (OR 6.28, P = 0.043), and free flap versus no flap reconstruction (OR 2.81, P = 0.008).

Conclusions

This study identifies important risk factors for development of PCF following total laryngectomy in a large, multi-institutional cohort of patients, thereby identifying a subset of patients at increased risk.

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The Differential Contribution of the Innate Immune System to a Good Pathological Response in the Breast and Axillary Lymph Nodes Induced by Neoadjuvant Chemotherapy in Women with Large and Locally Advanced Breast Cancers

The tumour microenvironment consists of malignant cells, stroma, and immune cells. The role of adaptive immunity in inducing a pathological complete response (pCR) in breast cancer with neoadjuvant chemotherapy (NAC) is well studied. The contribution of innate immunity, however, is poorly documented. Breast tumours and axillary lymph nodes (ALNs) from 33 women with large and locally advanced breast cancers (LLABCs) undergoing NAC were immunohistochemically assessed for tumour-infiltrating macrophages (TIMs: M1 and M2), neutrophils (TINs), and dendritic cells (TIDCs) using labelled antibodies and semiquantitative methods. Patients' blood neutrophils (), DCs (mDC1 and pDC), and their costimulatory molecules () were also studied. Pathological results were classified as pCR, good (GPR) or poor (PRR). In breast and metastatic ALNs, high levels of CD163+ TIMs were significantly associated with a pCR. In blood, high levels of neutrophils were significantly associated with pCR in metastatic ALNs, whilst the % of mDC1 and pDC and expression of HLA-DR, mDC1 CD40, and CD83 were significantly reduced. NAC significantly reduced tumour DCs but increased blood DCs. PPRs to NAC had significantly reduced HLA-DR, CD40, and CD86 expression. Our study demonstrated novel findings documenting the differential but important contributions of innate immunity to pCRs in patients with LLABCs undergoing NAC.

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Effect of Weight Loss, Exercise, or Both on Undercarboxylated Osteocalcin and Insulin Secretion in Frail, Obese Older Adults

Background. Obesity exacerbates age-related decline in glucometabolic control. Undercarboxylated osteocalcin (UcOC) regulates pancreatic insulin secretion. The long-term effect of lifestyle interventions on UcOC and insulin secretion has not been investigated. Methods. One hundred seven frail, obese older adults were randomized into the control (), diet (), exercise (), and diet-exercise () groups for 1 year. Main outcomes included changes in UcOC and disposition index (DI). Results. UcOC increased in the diet group (36 ± 11.6%) but not in the other groups ( between groups). Although similar increases in DI occurred in the diet-exercise and diet groups at 6 months, DI increased more in the diet-exercise group (92.4 ± 11.4%) than in the diet group (61.9 ± 15.3%) at 12 months (). UcOC and body composition changes predicted DI variation in the diet group only (), while adipocytokines and physical function changes contributed to DI variation in both the diet ( and 0.107) and diet-exercise ( and 0.243) groups ( for all). Conclusions. Diet, but not exercise or both, increases UcOC, whereas both diet and diet-exercise increase DI. UcOC accounts for DI variation only during active weight loss, while adipocytokines and physical function contribute to diet-exercise-induced DI variation, highlighting different mechanisms for lifestyle-induced improvements in insulin secretion. This trial was registered with ClinicalTrials.gov number NCT00146107.

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Modulatory Mechanism of Polyphenols and Nrf2 Signaling Pathway in LPS Challenged Pregnancy Disorders

Early embryonic loss and adverse birth outcomes are the major reproductive disorders that affect both human and animals. The LPS induces inflammation by interacting with robust cellular mechanism which was considered as a plethora of numerous reproductive disorders such as fetal resorption, preterm birth, teratogenicity, intrauterine growth restriction, abortion, neural tube defects, fetal demise, and skeletal development retardation. LPS-triggered overproduction of free radicals leads to oxidative stress which mediates inflammation via stimulation of NF-κB and PPARγ transcription factors. Flavonoids, which exist in copious amounts in nature, possess a wide array of functions; their supplementation during pregnancy activates Nrf2 signaling pathway which encounters pregnancy disorders. It was further presumed that the development of strong antioxidant uterine environment during gestation can alleviate diseases which appear at adult stages. The purpose of this review is to focus on modulatory properties of flavonoids on oxidative stress-mediated pregnancy insult and abnormal outcomes and role of Nrf2 activation in pregnancy disorders. These findings would be helpful for providing new insights in ameliorating oxidative stress-induced pregnancy disorders.

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Time-Varying Hydraulic Gradient Model of Paste-Like Tailings in Long-Distance Pipeline Transportation

Paste-like tailings slurry (PTLS) is always simplified as a Bingham plastic fluid, leading to excessive computational errors in the calculation of the hydraulic gradient. In the case of paste-like tailings in long-distance pipeline transportation, to explore a high-precision and reliable hydraulic gradient formula, the rheological behavior of paste-like tailings slurry was analyzed, a time-varying hydraulic gradient model was constructed, and a series of laboratory shear tests were conducted. The results indicate that the PTLS shows noticeable shear-thinning characteristics in constant shear tests; the calculated hydraulic gradient declined by about 56%, from 4.44 MPa·km−1 to 1.95 MPa·km−1 within 253 s, and remained constant for the next four hours during the pipeline transportation. Comparing with the balance hydraulic gradient obtained in a semi-industrial loop test, the computational errors of those calculated by using the time-varying hydraulic gradient model, Jinchuan formula, and Shanxi formula are 15%, 78%, and 130%, respectively. Therefore, our model is a feasible and high-precision solution for the calculation of the hydraulic gradient of paste-like tailings in long-distance pipeline transportation.

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Physical Properties Investigation of Reduced Graphene Oxide Thin Films Prepared by Material Inkjet Printing

The article is focused on the study of the optical properties of inkjet-printed graphene oxide (GO) layers by spectroscopic ellipsometry. Due to its unique optical and electrical properties, GO can be used as, for example, a transparent and flexible electrode material in organic and printed electronics. Spectroscopic ellipsometry was used to characterize the optical response of the GO layer and its reduced form (rGO, obtainable, for example, by reduction of prepared layers by either annealing, UV radiation, or chemical reduction) in the visible range. The thicknesses of the layers were determined by a mechanical profilometer and used as an input parameter for optical modeling. Ellipsometric spectra were analyzed according to the dispersion model and the influence of the reduction of GO on optical constants is discussed. Thus, detailed analysis of the ellipsometric data provides a unique tool for qualitative and also quantitative description of the optical properties of GO thin films for electronic applications.

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IL-25 Could Be Involved in the Development of Allergic Rhinitis Sensitized to House Dust Mite

Background and Purpose. When house dust mite (HDM), a common allergen, comes into the mucosal membrane, it may stimulate innate immunity. However, the precise role of interleukin- (IL-) 25 in the development of HDM-induced nasal allergic inflammation is still unclear. Therefore, we investigated the role of IL-25 in allergic rhinitis (AR) patients sensitized to HDM. Methods. To confirm the production of IL-25 in human nasal epithelial cells (HNECs), we stimulated HNECs. IL-25 expression in the nasal mucosa from control, non-AR (NAR) patients, and HDM-sensitized AR patients was assessed using immunohistochemistry, and quantitative reverse transcription PCR. Correlations between IL-25 and other inflammatory markers were explored. Results. An in vitro study showed significantly elevated concentrations of IL-25 in the HNEC samples with highest doses of HDM. Nasal tissues from AR patients sensitized to HDM showed significantly higher IL-25 expression, compared to those from the control or NAR patients. Moreover, the expression of IL-25 in nasal tissues from AR patients sensitized to HDM was positively associated with Th2 markers, such as ECP and GATA3. Conclusions. IL-25 expression increased with high-dose HDM stimulation and was related to Th2 markers. Therefore, IL-25 neutralization might offer a new strategy for treating patients with HDM-sensitized AR.

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Morphism of -Polar Fuzzy Graph

The main purpose of this paper is to introduce the notion of -polar -morphism on -polar fuzzy graphs. The action of -polar -morphism on -polar fuzzy graphs is studied. Some elegant theorems on weak and coweak isomorphism are obtained. Also, some properties of highly irregular, edge regular, and totally edge regular -polar fuzzy graphs are studied.

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Silicone Substrate with Collagen and Carbon Nanotubes Exposed to Pulsed Current for MSC Osteodifferentiation

Autologous human adipose tissue-derived mesenchymal stem cells (MSCs) have the potential for clinical translation through their induction into osteoblasts for regeneration. Bone healing can be driven by biophysical stimulation using electricity for activating quiescent adult stem cells. It is hypothesized that application of electric current will enhance their osteogenic differentiation, and addition of conductive carbon nanotubes (CNTs) to the cell substrate will provide increased efficiency in current transmission. Cultured MSCs were seeded and grown onto fabricated silicone-based composites containing collagen and CNT fibers. Chemical inducers, namely, glycerol phosphate, dexamethasone, and vitamin C, were then added to the medium, and pulsatile submilliampere electrical currents (about half mA for 5 cycles at 4 mHz, twice a week) were applied for two weeks. Calcium deposition indicative of MSC differentiation and osteoblastic activity was quantified through Alizarin Red S and spectroscopy. It was found that pulsed current significantly increased osteodifferentiation on silicone-collagen films without CNTs. Under no external current, the presence of 10% (m/m) CNTs led to a significant and almost triple upregulation of calcium deposition. Both CNTs and current parameters did not appear to be synergistic. These conditions of enhanced osteoblastic activities may further be explored ultimately towards future therapeutic use of MSCs.

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Physicochemical Characterization of Polysaccharides with Macrophage Immunomodulatory Activities Isolated from Red Ginseng (Panax ginseng C. A. Meyer)

In this study, four polysaccharide fractions designated as RGP1, RGP2, RGP3, and RGP4 were isolated from red ginseng by DEAE-52 cellulose chromatography, and their macrophage immunomodulatory activities were investigated. The results revealed that the proliferation, NO production, and neutral red phagocytosis of RAW 264.7 macrophage cells in groups treated with RGP1 and RGP2 in vitro were increased significantly compared to RGP3 and RGP4. In addition, the level of TNF-α in RAW 264.7 cells was significantly increased in RGP1 and RGP2 groups. All the results consistently indicated that polysaccharide fractions RGP1 and RGP2 had strong macrophage immunomodulatory activities. Furthermore, RGP1 and RGP2 were purified by Sephadex G-100 column and RGP2 was further fractionated into a homogeneous fraction RGP2-1, with the molecular weight of 2.16 × 104 Da. The analysis of monosaccharide composition revealed that RGP1 was composed of arabinose, glucose, and galactose with a relative molecular ratio of 0.02 : 0.88 : 0.10. RGP2-1 was composed of rhamnose, arabinose, glucose, and galactose with a relative molecular ratio of 0.02 : 0.10 : 0.77 : 0.11. These results provided evidences that the neutral polysaccharide fractions RGP1 and RGP2 possessed significant immunomodulatory activity and could be explored as a promising natural immunomodulating agent applied in functional foods or medicines.

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Clinical Outcomes for Minimally Invasive Primary and Secondary Orbital Reconstruction using an Advanced Synergistic Combination of Navigation and Endoscopy

Sequelae of inadequate orbital reconstruction include enophthalmos, hypoglobus, and diplopia. Accuracy of orbital reconstruction is largely subjective and especially difficult to achieve due to anatomic distortion in secondary or late reconstruction and in extensive injury. We combined computer navigation and endoscopy to perform accurate, aesthetic, and safe minimal-access primary and secondary orbital reconstruction.

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Sentinel lymph node biopsy for thin melanomas under the American Joint Committee on Cancer 8th edition cancer staging system

The American Joint Committee on Cancer (AJCC) will implement the 8th edition of their cancer staging system on the 1st January 2018, with changes to the way in which thin melanomas are classified. Our understanding of these criteria contrasts with previous correspondence in this journal.1 Tumours with a Breslow thickness <0.8mm will be classified as T1a if they do not exhibit ulceration, and as T1b if they do exhibit ulceration. All tumours measuring 0.8-1.0mm thick will be reclassified as T1b regardless of ulceration.

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Preventing the Complications of Tissue Expansion Using Fat Grafting Under Expanded Skin

We read with great interest the brief clinical report entitled "Preventing the complications of tissue expansion using fat grafting under expanded skin" by Jiang et al.1 The authors demonstrate for the first time a technique improving the texture of expanded skin and preventing expansion failure by lipofilling into the ischemic region of the expanded flap. We would like to congratulate the authors for their primary work to make the skin expansion can be smoothly completed. Improving expansion efficiency and decreasing complications of expansion are always the subjects that we have thought a great deal about and worked intensively on.

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Motor Nerve to the Masseter: A Pediatric Anatomic Study and the “3:1 Rule”

The motor nerve to the masseter (masseteric nerve) provides a robust local neural source for facial reanimation and nerve transfer. Its intraoperative identification is well-described in adults. The purpose of this study was to determine the location of the motor nerve to the masseter in the pediatric population using surgical landmarks.

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Non-living microvascular training models: Face validity of liquid latex and the challenge of structural vs. “physiological” patency assessment

Microvascular anastomosis training increasingly uses assessment tools to objectively evaluate the surgeons' performance and to track progression in this challenging learning curve. The first steps in microvascular skills acquisition are accomplished via a variety of training models in a safe simulation training environment1, with an increasing use of non-living biological models over living animal models, in line with the ethical considerations of replacement, reduction and refinement.

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Gender Perception After Raising Vowel Fundamental and Formant Frequencies: Considerations for Oral Resonance Research

Voice feminization therapy for male-to-female transgender women typically targets increasing fundamental frequency (F0). Increasing vowel formant frequencies (FFs) has also been proposed. To better understand formant conditions that shift listeners' perception of gender from male to "not-male," individual and combined vowel FFs were incrementally raised, whereas F0 was held constant at a gender-ambiguous level.

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