Case Report: Aquatic Therapy and End-Stage Dementia

A 54-year old female, retired due to progressive cognitive decline, was diagnosed with early-onset Alzheimer's dementia. Conventional medication therapy for dementia had proven futile. Initial evaluation revealed a non-verbal female seated in a wheelchair, dependent on 2-person assist for all transfers and activities of daily living (ADLs.) She had been either non-responsive or actively resistive for both ADLs and transfers in the 6 months prior to assessment. Following a total of 17 one hour therapy sessions over 19 weeks in a warm water therapy pool, she achieved ability to tread water for 15 minutes, transfers improved to moderate to-maximum assist from seated, ambulation improved to 1000' with minimum-to-moderate assist of 2 persons.

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Mild Traumatic Brain Injury in a High School Football Player with Familial Hemiplegic Migraine: A Case Report

Mild traumatic brain injury is a major concern in young athletes, with an estimated 1.6 to 3.8 million reported concussions in the US annually. Familial hemiplegic migraine is a rare autosomal-dominant condition characterized by sporadic episodes of transient unilateral motor weakness which may begin at any age. We present a case of a 17-year-old male with a history of familial hemiplegic migraine who suffered prolonged symptoms following a mild traumatic brain injury during sports participation.

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Atherosclerotic Disease and its Relationship to Lumbar Degenerative Disc Disease, Facet Arthritis and Stenosis with Computed Tomography Angiography

The intervertebral disc is the largest avascular structure in the body. It relies on passive diffusion from arteries at the periphery of the disc for nutrition. Prior studies have suggested a correlation between vascular disease and lumbar degenerative disc disease (DDD) but the association with facet arthritis and stenosis has not been evaluated.

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Role of Negative Vector Orbit in Orbital Blow-Out Fractures.

Background: Negative vector orbit is defined as the most anterior globe portion protrudes past the malar eminence. The aim of the study was to evaluate the relationship between negative vector orbit and blow-out fracture location analyzing the distance between the anterior corneal surface and orbital bone with facial soft tissue in medial and orbital floor blow out fractures using orbital computed tomography (CT). Methods: Seventy-seven patients diagnosed with blow-out fractures involving the medial or orbital floor were included. Distances from the anterior cornea to lower lid fat, inferior orbital wall, inferior orbital rim, and anterior cheek mass were measured using orbital CT scans. The proportion of negative vector orbit and measured distanced were compared between medial wall fracture and orbital floor fracture. Medical records including age, sex, concomitant ophthalmic diagnosis, and nature of injury were retrospectively reviewed. Results: Forty-three eyes from 43 patients diagnosed with medial wall fracture and 34 eyes from 34 patients diagnosed with orbital floor fracture were included. There was no significant difference in the distance from the anterior cornea to lower lid fat (P = 0.574), inferior orbital wall (P = 0.494), or orbital rim (P = 0.685). The distance from anterior cornea to anterior cheek mass was significantly different in medial wall fracture (-0.19 +/- 3.49 mm) compared with orbital floor fracture (-1.69 +/- 3.70 mm), P = 0.05. Negative vector orbit was significantly higher in orbital floor fracture patients (24 among 34 patients, 70.6%) compared with those with medial wall fractures (19 among 43 patients, 44.2%) (P = 0.04). Conclusions: Patients presenting with a negative vector orbit relationship when the most anterior portion of globe protruded past the anterior cheek mass and malar eminence were more likely to develop orbital floor fracture than medial wall fracture. (C) 2017 by Mutaz B. Habal, MD.

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The Americleft Project: A Modification of Asher-McDade Method for Rating Nasolabial Esthetics in Patients With Unilateral Cleft Lip and Palate Using Q-sort.

The purpose of this study was to investigate ways to improve rater reliability and satisfaction in nasolabial esthetic evaluations of patients with complete unilateral cleft lip and palate (UCLP), by modifying the Asher-McDade method with use of Q-sort methodology. Blinded ratings of cropped photographs of one hundred forty-nine 5- to 7-year-old consecutively treated patients with complete UCLP from 4 different centers were used in a rating of frontal and profile nasolabial esthetic outcomes by 6 judges involved in the Americleft Project's intercenter outcome comparisons. Four judges rated in previous studies using the original Asher-McDade approach. For the Q-sort modification, rather than projection of images, each judge had cards with frontal and profile photographs of each patient and rated them on a scale of 1 to 5 for vermillion border, nasolabial frontal, and profile, using the Q-sort method with placement of cards into categories 1 to 5. Inter- and intrarater reliabilities were calculated using the Weighted Kappa (95% confidence interval). For 4 raters, the reliabilities were compared with those in previous studies. There was no significant improvement in inter-rater reliabilities using the new method. Intrarater reliability consistently improved. All raters preferred the Q-sort method with rating cards rather than a PowerPoint of photos, which improved internal consistency in rating compared to previous studies using the original Asher-McDade method. All raters preferred this method because of the ability to continuously compare photos and adjust relative ratings between patients. (C) 2017 by Mutaz B. Habal, MD.

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Cleft Lip and Palate Repair: Our Experience.

Introduction: Cleft lip and palate is the most frequent congenital craniofacial deformity. In this article, the authors describe their experience with cleft lip and palate repair. Methods: Data regarding patients presenting with primary diagnosis of cleft lip and/or palate, between 2009 and 2015, were reviewed. Details including demographics, type of cleft, presence of known risk factors, surgical details, and follow-up visits were collected. Documented complications were reported. Caregivers' satisfaction was assessed with a survey. The survey used to assess satisfaction with cleft-related features was based on the cleft evaluation profile (CEP). In addition, 4 assessors used visual analog scale (VAS) to assess the aesthetic satisfaction. Results: Seven hundred fifty-two patients with primary diagnosis of cleft lip and/or palate underwent surgical correction at "S. Chiara" Hospital, 432 (57.45%) male and 320 (42.55%) female. The most common cleft types in our study were incomplete cleft palate (152 patients) and left unilateral complete cleft lip and palate (152 patients). Associated syndromes were found in 46 patients (6.12%). Cleft lip was repaired using a modified Tennison-Randall technique when the defect was unilateral, whereas a modified Mulliken technique was used for bilateral cleft lip. Cleft palate was repaired using the Bardach technique or Von Langenbeck technique at 5 to 6 months of age. Cleft lip and palate was repaired in several surgical steps. In total, complications were reported in 81 of 752 patients (14.16%). Average fathers' satisfaction score assessed using CEP was 4.5 (lip), 4.8 (nose), 4.7 (teeth), 4.8 (bite), 4.2 (breathing), 4.6 (profile). Average mothers' satisfaction score assessed using CEP was 4.3 (lip), 4.6 (nose), 4.4 (teeth), 4.5 (bite), 4.1 (breathing), 4.4 (profile). Average level of aesthetic satisfaction, assessed using VAS, was 8.7 (fathers), 8.1 (mothers), 7.9 (lay person), and 8.0 (senior cleft surgeon). Conclusion: The multidisciplinary management of children with oral cleft determinated good results, in terms of satisfaction and aesthetic appearance. From our experience, periosteoplasty and lip-adhesion are key surgical techniques. (C) 2017 by Mutaz B. Habal, MD.

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Does Fat Grafting Influence Postoperative Edema in Orthognathic Surgery?.

Purpose: Autologous fat grafting is a useful adjunctive procedure to orthognathic surgery and may also confer anti-inflammatory properties. The purpose of this study is to answer the clinical question: among patients undergoing orthognathic operations, what are the effects of fat grafting on facial edema (magnitude, duration, and rate of decrease)? Methods: A retrospective cohort study was performed. Three-dimensional photos (Canfield, Fairfield, NJ) from preoperative and a series of postprocedure time-points were analyzed. The data set was divided into a fat-grafted cohort and a non-fat-grafted cohort and later analyzed using paired and unpaired t tests and linear regressions to determine significant correlations. Results: One hundred sixteen pre- and postoperative three-dimensional photo data sets were included. The sample included 29 subjects. The facial volume was analyzed both overall and comparing each subgroup (orthognathic vs. orthognathic + fat grafting group). Postoperative facial volume increase averaged 23.7% for the entire cohort (FG and nFG). By week 12, the swelling decreased about 62% from baseline. In all patients, there was a statistically significant decrease in facial volume with time. In the fat-grafted group, despite adding volume, the facial volume was equal to the non-fat-grafted group at week 1, yet the rate of decrease was faster through week 12. Conclusion: The majority of postoperative facial edema decreases by 12 weeks following orthognathic surgery. In this cohort of patients, despite the addition of volume, concurrent fat grafting lessened postoperative edema, and led to a greater magnitude and speed of resolution. (C) 2017 by Mutaz B. Habal, MD.

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Mandibular Surgical Navigation: An Innovative Guiding Method.

Mandibular osteotomies are usually required to treat craniomaxillofacial disorders. Losses of mandibular continuity result in esthetic and functional deficiency. During the past 30 years, the spread of the computer-assisted surgery techniques, rapid prototyping, and surgical navigation technique has improved the reliability and the outcomes of mandibular resections and reconstructions, by providing realtime feedback to surgeon. Recent studies reported the feasibility and the precision of surgical navigation applied to mandibular surgical resection and reconstruction with fibula flap but none of them describes a method to navigate the jaw allowing its full motility during the operation. To our knowledge, this is the first-time description of such a kind of method to navigate the jaw positioning the dynamic reference frame directly on the mandibular branch to maintain the full mobility of the mandible. The method described in our series has allowed an accurate surgical navigation of the jaw without the need of intermaxillary fixation. This technique could greatly facilitate resection and reconstructive surgical procedures of the jaw while ensuring precision and accuracy. The encouraging results obtained in the present report suggest to further investigate the possibilities of this technique to better define the method and its indications. (C) 2017 by Mutaz B. Habal, MD.

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A Novel Dissector and Needle Holder Within One Tool.

No abstract available

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Partial Scalp and Auricula Avulsion in a Child.

No abstract available

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Tear Trough Deformity: Study of Filling Procedures for Its Correction.

The aim of this work is to discuss the anatomy of the tear trough region with relative danger areas, and to describe 2 different options to correct this deformity. The tear trough is a concave deformity of the orbital fat that is noticeable as a result of inherited anatomic differences and aging. However, the periorbital region is a complex area with its own septa and ligaments, fat compartments, muscles, vascularization, and lymphatic drainage and presents anatomic characteristics that must be taken into account in order to achieve good results and avoid complications. The use of hyaluronic acid gel or autologous fat for soft tissue correction is a good option. A total of 96 patients with periorbital hollowing were divided into 2 groups; each group received a different treatment, from December of 2013 to December of 2015, with hyaluronic- or lipo-filling. (C) 2017 by Mutaz B. Habal, MD.

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Stagnant Water Is Bound to Corrupt.

No abstract available

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Interobserver Consistency of Drug-Induced Sleep Endoscopy in Diagnosing Obstructive Sleep Apnea Using a VOTE Classification System.

Objectives: To explore the interobserver consistency of drug-induced sleep endoscopy (DISE) for patients with obstructive sleep apnea syndrome (OSAS) and review the current literature. Methods: In total, 55 patients with an apnea-hypopnea index >5, as determined by on overnight sleep study, were included in this study, 45 males and 10 females, with an average age of 46.87 +/- 10.06 years old (range, 19-71). For all OSAS patients, DISE was performed by the same surgeon, which was recorded digitally. The video recordings of DISE were evaluated independently by 3 experienced surgeons who were asked to note his or her decisions as the pattern, site, and degree of upper airway collapse using a VOTE (velum, oropharynx lateral wall, tongue base, and the epiglottis) classification system. Results: Interobserver consistency in the diagnosis of velum-related obstruction in anteroposterior, lateral, and concentric configurations ranged from poor to good. Only significant interobserver consistency among observers A and B was obtained in the diagnosis of oropharynx-related obstruction in the lateral configuration (concordance 60.0%, kappa: 0.365, P 0.20, all P values

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A Three-Dimensional Study of Midfacial Changes Following Le Fort II Distraction With Zygomatic Repositioning in Syndromic Patients.

Le Fort II distraction with zygomatic repositioning introduced the ability to restore central midfacial height and convexity independent of changes in orbital morphology. This study analyzes midfacial and orbital morphology before and after Le Fort II distraction with zygomatic repositioning. All patients who underwent Le Fort II Distraction with zygomatic repositioning between 2013 and 2015 were included. Two- and 3-dimensional measurements were made using 3dMD Vultus software to assess canthal tilt, nasolabial angle, ratio of midfacial to lower facial height, and absolute change in nasal length. Presence of an open bite and Angle classification were assessed before and after surgery. Four patients underwent segmental midface advancement using Le Fort II distraction with zygomatic repositioning. Associated diagnoses included Apert syndrome, Goldenhar syndrome, and achondroplasia. Changes in facial dimensions included: 3.19[degrees] improvement in canthal tilt (range -4.7[degrees] to 8.4[degrees]), 9[degrees] change in nasolabial angle (range -1.0[degrees] to 19[degrees]), and 0.69 cm increase in absolute nasal length (range 0.2-0.94 cm). Mean ratio of midfacial to lower facial height was 0.79 preoperatively and 0.89 postoperatively. Preoperatively, all patients demonstrated Angle class III with 3 of 4 patients demonstrating anterior open bite. All achieved closure of open bite and demonstrated class I or II occlusion. No complications were observed. Le Fort II distraction with zygomatic repositioning resulted in normalization of midfacial soft tissue landmarks. This form of advancement demonstrates the ability to selectively improve midfacial height and canthal tilt while restoring normal occlusion. (C) 2017 by Mutaz B. Habal, MD.

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Tissue Engineering Strategies for Auricular Reconstruction.

Simulating natural characteristics and aesthetics in reconstructed ears has provided a complex 3-dimensional puzzle for those treating patients with microtia. Costochondral grafts remain the gold standard for autologous reconstruction. However, other options such as Medpor and prosthetics are indicated depending on patient circumstances and personal choice. Research into tissue engineering offers an alternative method to a traditional surgical approach that may reduce donor-site morbidity. However, tissue engineering for microtia reconstruction brings new challenges such as cell sourcing, promotion of chondrogenesis, scaffold vascularization, and prevention of scaffold contraction. Advancements in 3D printing, nanofiber utilization, stem cell technologies, and decellularization techniques have played significant roles in overcoming these challenges. These recent advancements and reports of a successful clinical-scale study in an immunocompetent animal suggest a promising outlook for future clinical application of tissue engineering for auricular reconstruction. (C) 2017 by Mutaz B. Habal, MD.

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Cross-cueing cannot explain unified control in split-brain patients

Sir,

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WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells

Abstract

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

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Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation

Sir,

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Secondary Loss of Response to Infliximab in Pediatric Crohn's Disease: Does it Matter How and When We Start?.

Objectives: A significant proportion of children with Crohn's disease develop a secondary loss of response (LOR) to infliximab. Our aim was to study the impact of initial treatment strategies on secondary LOR. Methods: We reviewed the medical records of children with Crohn's disease who received scheduled maintenance infliximab therapy for at least 12 months. We compared children who developed LOR with those who did not; with regards to their clinical and laboratory parameters, disease phenotype and treatment strategy before developing LOR. Results: 73 children (Median age at diagnosis- 11 (2-16) years, 41 boys) who had received a median duration of 33 (13-110) months of infliximab therapy were included in the final analysis. LOR was seen in 25(34.2%). Demographic variables, disease phenotype (age, disease location and behavior), inflammatory parameters and PCDAI at induction with infliximab, was similar between both groups. Children with LOR had a significantly greater number of flares of the disease when compared to those who did not have LOR [4 (1 - 8) vs. 2(1-5) p = 0.03]. The choice of the concomitant immunomodulator - Methotrexate [11/29(37.9%)] vs. Azathioprine [11/36(30.5%)] (p = 0.6) did not affect LOR rates. The median time-lag between diagnosis and induction with infliximab was significantly longer in children with LOR as compared to those who did not have a LOR[28 (4-90) months vs. 12.5(1-121) months, p = 0.004]. Conclusion: Early use of infliximab in pediatric Crohn's disease is associated with a decrease in secondary LOR. The type of concomitant immunomodulator used does not make a difference to LOR rates. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Polyethylene Glycol 3350 With Electrolytes vs Polyethylene Glycol 4000 for Constipation: A Randomized, Controlled Trial.

Objectives: The long-term efficacy and safety of polyethylene glycol (PEG) in constipated children are unknown, and a head-to-head comparison of the different PEG formulations is lacking. We aimed to investigate non-inferiority of PEG3350 with electrolytes (PEG3350+E) compared to PEG4000 without electrolytes (PEG4000). Methods: In this double-blind trial, children aged 0.5 - 16 years with constipation, defined as a defecation frequency of =3 per week with

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Nutritional State and Feeding Behaviors of Children With Eosinophilic Esophagitis and Gastroesophageal Reflux Disease.

Objective: Because both gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) are associated with malnutrition and feeding dysfunction, this study compares growth, nutrition and feeding behaviors in children with GERD and EoE. Methods: Subjects aged 1-7 with GERD or EoE were enrolled in a prospective study. Assessments included length/height, weight, 3-day food diary, serum biomarkers of nutrition, and the Behavioral Pediatric Feeding Assessment Scale (BPFAS). Results: Mean weight-for-length z-scores in GERD and EoE children were -0.93 and -1.14 (p = NS) and mean body mass index z-scores were 0.29 and -0.13 (p = NS). Vitamin D intake was below the daily recommended intake (DRI) in GERD subjects. EoE subjects' intake was below DRI of Vitamin D and calcium. GERD and EoE groups both had normal intake of calories, carbohydrates, proteins, fats, and iron and normal serum ferritin (25 vs. 34 ng/mL), prealbumin (21 vs. 20 mg/dL), PTH (42 vs. 37 pg/mL), and Vitamin D (both 30 ng/mL). BPFAS problem and frequency scores were similar in GERD and EoE subjects but were higher than those of a historical cohort of healthy controls (Hedges'g of 0.95 and 1.1 respectively). EoE subjects on food allergen restriction diets had significantly less feeding dysfunction than those on regular diets. Conclusion: Since a selected group of children with uncomplicated GERD or EoE were without nutritional deficiencies but had maladaptive feeding, providing anticipatory guidance to minimize mealtime challenges, monitoring for improvement, or referring to a feeding therapist may be beneficial. A trial of food allergen restriction may provide additional benefit for those with EoE. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Enteroaggregative E. coli Subclinical Infection and co-Infections and Impaired Child Growth in the MAL-ED Cohort Study.

Objective: We evaluated the impact of subclinical enteroaggregative Escherichia coli (EAEC) infection alone and in combination with other pathogens in the first six months of life on child growth. Methods: Non-diarrheal samples from 1,684 children across eight Multisite Birth Cohort Study, Malnutrition and Enteric Diseases (MAL-ED) sites in Asia, Africa, and Latin America were tested monthly; over 90% of children were followed-up twice weekly for the first six months of life. Results: Children with subclinical EAEC infection did not show altered growth between enrollment and six months. Conversely, EAEC co-infection with any other pathogen was negatively associated with delta weight-for-length (WLZ) (p 0.05) z-scores between 0 and 6 months. The presence of two or more pathogens without EAEC was not significantly associated with delta WLZ and WAZ. The most frequent EAEC co-infections included Campylobacter spp. heat-labile toxin-producing enterotoxigenic E. coli, Cryptosporidium spp., and atypical enteropathogenic E. coli. Myeloperoxidase levels were increased with EAEC co-infection (p

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Changes in Proteases, Antiproteases and Bioactive Proteins From Mother's Breast Milk to the Premature Infant Stomach.

Objectives: Our previous studies suggested that human milk proteases begin to hydrolyze proteins in the mammary gland and continue within the term infant stomach. No research has measured milk protease and pepsin activity in the gastric aspirates of preterm infants after human milk feeding. This study investigated how the concentrations of human milk proteases and protease inhibitors changed in the premature infant stomach. Methods: Human milk and infant gastric samples were collected from 18 preterm-delivering mother-infant pairs (24-32 wk gestational age). Paired human milk and gastric samples were collected across postnatal age (2-47 days). Protease concentrations were determined by spectrophotometric or fluorometric assays, and the concentrations of protease inhibitors and bioactive proteins were determined by ELISA. Paired t-tests were applied to compare enzymes, antiproteases and bioactive proteins between human milk and gastric samples. Results: Our study reveals that although human milk proteases, including carboxypeptidase B2, kallikrein, plasmin, cathepsin D, elastase, thrombin and cytosol aminopeptidase are present in the preterm infant stomach, only plasmin and cathepsin D can actively hydrolyze proteins at gastric pH. ELISA and peptidomic evidence suggest that all milk antiproteases as well as lactoferrin and immunoglobulin A are partially digested in the preterm stomach. Conclusions: Most human milk proteases are active in milk but not at preterm infant gastric pH. Only cathepsin D and plasmin have potential to continue degrading milk proteins within the preterm infant stomach. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Variceal Hemorrhage and Adverse Liver Outcomes in Patients With Cystic Fibrosis Cirrhosis.

Objectives: Cirrhosis occurs in 5-10% of CF (cystic fibrosis) patients, often accompanied by portal hypertension. We analyzed three adverse liver outcomes, variceal bleeding (VB), liver transplant (LT), and liver death (LD), and risk factors for these in CF Foundation Patient Registry (CFFPR) subjects with reported cirrhosis. Methods: We determined 10-year incidence rates for VB, LT, LD, and all-cause mortality (ACM), and examined risk factors using competing risk models and Cox-proportional hazard regression. Results: From 2003-2012, 943 participants (41% female, mean age 18.1 years) had newly reported cirrhosis; 24.7% required insulin, 85% had prior pseudomonas. Seventy-three subjects had reported VB; 38 with first VB and new cirrhosis reported simultaneously and 35 with VB after cirrhosis report. 10-year cumulative VB, LT, and LD rates were 6.6% (95% Confidence Interval (CI): 4.0, 9.1%), 9.9% (95% CI: 6.6%, 13.2%), and 6.9% (95% CI: 4.0%, 9.8%), respectively, with an ACM of 39.2% (95% CI: 30.8, 36.6%). ACM was not increased in subjects with VB compared to those without (HR 1.10, 95% CI: 0.59, 2.08). CF related diabetes (CFRD (hazard ratio (HR): 3.141, 95% CI:1.56, 6.34) and VB (HR: 4.837, 95% CI: 2.33, 10.0) were associated with higher LT risk while only worse lung function was associated with increased LD in multivariate analysis. Death rate among subjects with VB was 24% with LT and 20.4% with native liver. Conclusions: VB is an uncommon complication of CF cirrhosis and can herald the diagnosis, but does not affect ACM. Adverse liver outcomes and ACM are frequent by 10 years after cirrhosis report. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Emerging Breast Imaging Technologies on the Horizon

Early detection of breast cancers by mammography in conjunction with adjuvant therapy have contributed to reduction in breast cancer mortality. Mammography remains the 'gold-standard′ for breast cancer screening, but is limited by tissue superposition. Digital breast tomosynthesis and more recently, dedicated breast computed tomography have been developed to alleviate the tissue superposition problem. However, all of these modalities rely upon x-ray attenuation contrast to provide anatomical images and there are ongoing efforts to develop and clinically translate alternative modalities.

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Letter from the Editor

The current issue of Seminars in Ultrasound CT and MRI is devoted to imaging of the chest and covers a wide range of topics.

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Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer.

A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R2=0.429), whereas EETS and DPR were less correlated with OS (R2=0.0682, 0.186). EETS was well correlated with DPR (R2=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Folic acid exerts antidepressant effects by upregulating brain-derived neurotrophic factor and glutamate receptor 1 expression in brain.

Folic acid is a vitamin with a variety of pharmacological effects. The present study aims to explore the beneficial effects of folic acid on chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and its possible mechanisms. The behavioral tests including open-field test, tail suspension test, and forced swimming test were used to evaluate the antidepressant effects of folic acid. Then the changes of brain 5-hydroxytryptamine (5-HT) concentration, brain-derived neurotrophic factor (BDNF), glutamate receptor 1 (GluR1) expression levels, and synaptic organization were assessed to explore the antidepressant mechanisms of folic acid. Our results showed that CUMS caused significant depression-like behaviors, neuropathological changes, and decreased brain 5-HT concentration, BDNF, and GluR1 expression in the hippocampus and association cortex. In conclusion, the results showed that folic acid significantly improved depression-like behaviors in CUMS-induced rats, and its antidepressant effects might be related to the increase of brain 5-HT concentration, BDNF and GluR1 expression, and repair of synaptic organization in the brain. (C) 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins

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Time course of changes in corticospinal excitability after short-term forearm/hand immobilization.

The short-term joint immobilization induces a decrease of corticospinal excitability; however, detailed time course of the immobilization-induced central nervous system changes and their extent have not yet been clarified. To evaluate the time course of changes in corticospinal excitability during forearm/hand immobilization for 24 h and investigate the effect on muscle strength, adhesive casting tape was used to immobilize the nondominant forearm/hand. The amplitude of the motor-evoked potential of the flexor pollicis brevis muscle induced by transcranial magnetic stimulation was measured during immobilization and after cast removal. The muscle strength was evaluated after the termination of immobilization. The resting motor-evoked potential recorded from flexor pollicis brevis muscle showed a significant decrease 3 h after initiation of immobilization and gradually declined further until the end of immobilization. It then increased over 2 h after cast removal, but was still significantly below baseline. However, no significant difference from baseline was observed at 3 h. Both pinch power and integrated electromyogram were significantly reduced by immobilization, and then gradually returned to baseline after the cast was removed. These results indicate that short-term forearm/hand immobilization rapidly reduces corticospinal excitability, and this change is rapidly reversed after resumption of movement. (C) 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins

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Retrospective cohort study of combined approach for trunk reconstruction using arteriovenous loops and free flaps

Defect reconstruction of the trunk can be performed using microsurgical free flap transplantation. In cases of missing or inappropriate recipient vessels, microsurgical defect reconstruction of the trunk can be achieved by combining free flaps with arteriovenous loops. Here we present our 5-year experience of trunk reconstruction using AV loops and free flaps in a retrospective evaluation. We analyzed 32 cases of trunk reconstruction using a combined approach of free flap transplantation and arteriovenous loops between 2011 and 2016 regarding postoperative complications and perioperative course.

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Investigation of blood perfusion by laser speckle contrast imaging in stretched and rotated skin flaps in a porcine model

Dear Sir,

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Lymphatic vessel density and VEGF-C expression as independent predictors of melanoma metastases: methodological issues

Dear Editor-in-Chief,

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Current status and trends of breast reconstruction in argentina

Over the last decade, there has been an exponential increase in implant-based breast reconstructions correlated with a proportional decrease in autologous reconstruction in the US.1,2 We aimed to determine the breast reconstruction trends in Argentina through a survey of plastic surgeons who were invited to answer a multiple-choice anonymous questionnaire sent through email.

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Effect of distal venous drainage on the survival of four-territory flaps with no pedicle vein: results from a rat model

Venous super-drainage can improve flap survival not only because it prevents congestion, but also because it affects the dominant circulation in multi-territory thin skin flaps. We aimed to evaluate the survival of various flap areas and detect vascular changes in artery-based, four-territory skin flaps after different distal venous drainage procedures.

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Measuring the patient perspective on latissimus dorsi donor site outcomes following breast reconstruction

There is little evidence about the long-term donor site outcome of latissimus dorsi breast reconstruction and no patient-reported outcome measures designed specifically for the procedure.

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The role of ultrasound technology in plastic surgery

The modern medical era is in part characterized by the increased availability of portable imaging devices. Ultrasound devices are used for either high-resolution non-invasive imaging or as a focused acoustic energy source capable of sculpting and shaping tissue. Given the broad scope of the field, plastic and reconstructive surgeons have the unique ability to implement and tailor the use of ultrasound in a variety of clinical situations. This article will review novel uses for ultrasound in the field of plastic surgery.

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Prognostic significance of corticotroph staining in radiosurgery for non-functioning pituitary adenomas: a multicenter study

Abstract

Silent corticotroph staining pituitary adenoma (SCA) represents an uncommon subset of Non-Functioning adenomas (NFAs), hypothesized to be more locally aggressive. In this retrospective multicenter study, we investigate the safety and effectiveness of Stereotactic Radiosurgery (SRS) in patients with SCA compared with other non-SCA NFA's. Eight centers participating in the International Gamma-Knife Research Foundation (IGKRF) contributed to this study. Outcomes of 50 patients with confirmed SCAs and 307 patients with confirmed non-SCA NFA's treated with SRS were evaluated. Groups were matched. SCA was characterized by a lack of clinical evidence of Cushing disease, yet with positive immunostaining for corticotroph. Median age was 55.2 years (13.7–87). All patients underwent at least one trans-sphenoidal tumor resection prior to SRS. SRS parameters were comparable as well. Median follow-up 40 months (6-163). Overall tumor control rate (TCR) 91.2% (n = 280). In the SCA group, TCR were 82% (n = 41) versus 94.1% (n = 289) for the control-NFA (p = 0.0065). The SCA group showed a significantly higher incidence of new post-SRS visual deficit (p < 0.0001) assigned to tumor progression and growth, and post-SRS weakness and fatigue (p < 0.0001). In univariate and multivariate analysis, only the status of silent corticotroph staining (p = 0.005, p = 0.009 respectively) and margin dose (p < 0.0005, p = 0.0037 respectively) significantly influenced progression rate. A margin dose of ≥17 Gy was noted to influence the adenoma progression rate in the entire cohort (p = 0.003). Silent corticotroph staining represents an independent factor for adenoma progression and hypopituitarism after SRS. A higher margin dose may convey a greater chance of TCR.

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Flared sign of flail mandible on computed tomography: an unstable fracture associated with a compromised airway

A mandibular fracture alone rarely causes a life-threatening injury. The aim of this paper was to emphasise the importance of prompt identification of the radiological signs of a flail mandible in a patient with maxillofacial trauma who eventually needed definitive management of her airway.

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UK temporomandibular joint replacement database: a report on one-year outcomes

Alloplastic temporomandibular joint (TMJ) replacements are increasingly subspecialised, and supraregional centres that treat sufficient numbers to ensure high standards are emerging. Having recently reported the introduction of a national TMJ joint replacement database that is endorsed by the British Association of TMJ Surgeons (BATS), we now present the first-year outcomes. This was a review of all data in the BATS National Case Registration of TMJ Replacement as of June 2014. A total of 252 one-year outcome records were available.

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Survival after surgery for oral cancer: a 30-year experience

Oral squamous cell carcinoma is the most common intraoral malignancy, for which we advocate radical primary resection with adjuvant treatment where indicated. The main aims of this paper are to identify the overall survival of a consecutive series of patients and to relate survival to clinical and pathological factors. Kaplan–Meier curves were produced for site, sex, TNM status, and use of postoperative radiotherapy. The data were analysed using IBM SPSS Statistics for Windows and probabilities of less than 0.05 were accepted as significant.

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Removal of recurrent intraorbital tumour using a system of augmented reality

The most crucial step in the management of pleomorphic adenoma of the lacrimal gland is choosing the optimal approach for excision. We report the successful removal of a recurrent pleomorphic adenoma of the lacrimal gland in a 42-year-old woman using a specific microscope-based system of augmented reality.

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Liquid dynamic medicine and N-of-1 clinical trials: a change of perspective in oncology research

The increasing use of genomics to define the pattern of actionable mutations and to test and validate new therapies for individual cancer patients, and the growing application of liquid biopsy to dynamically t...

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Early mobilization programme improves functional capacity after major abdominal cancer surgery: a randomized controlled trial

Abstract

Background: Major abdominal oncology surgery is associated with substantial postoperative loss of functional capacity, and exercise may be an effective intervention to improve outcomes. The aim of this study was to assess efficacy, feasibility and safety of a supervised postoperative exercise programme.Methods: We performed a single-blind, parallel-arm, randomized trial in patients who underwent major abdominal oncology surgery in a tertiary university hospital. Patients were randomized to an early mobilization postoperative programme based on supervised aerobic exercise, resistance and flexibility training or to standard rehabilitation care. The primary outcome was inability to walk without human assistance at postoperative day 5 or hospital discharge.Results: A total of 108 patients were enrolled, 54 into the early mobilization programme group and 54 into the standard rehabilitation care group. The incidence of the primary outcome was nine (16.7%) and 21 (38.9%), respectively (P=0.01), with an absolute risk reduction of 22.2% [95% confidence interval (CI) 5.9–38.6] and a number needed to treat of 5 (95% CI 3–17). All patients in the intervention group were able to follow at least partially the exercise programme, although the performance among them was rather heterogeneous. There were no differences between groups regarding clinical outcomes or complications related to the exercises.Conclusions: An early postoperative mobilization programme based on supervised exercises seems to be safe and feasible and improves functional capacity in patients undergoing major elective abdominal oncology surgery. However, its impact on clinical outcomes is still unclear.Clinical trial registration: NCT01693172.

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Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care

Abstract

Purpose

Several medications may interact with levothyroxine (LT4) intestinal absorption or metabolism, thus reducing its bioavailability. We investigated the variability of thyroid stimulating hormone (TSH) levels and prescribed daily dosages (PDDs) of LT4 before and during potential drug–drug interactions (DDIs) in users of tablets vs. oral liquid LT4 formulations.

Methods

By using the Italian general practice Health Search Database (HSD), we retrospectively selected adult patients with at least one LT4 prescription from 2012 to 2015 and at least 1 year of clinical history recorded. The incident prescription of interacting medications (e.g., proton pump inhibitors, calcium or iron salts) was the index date. Analysis was carried out using a self-controlled study design.

Results

Overall, 3965 users of LT4 formed the study cohort (84.1% women, mean age 56 ± 16.5 years). TSH variability on the entry date was greater among liquid LT4 users than in those prescribed with tablets as shown by the difference between 75th and 25th centile, which were 3.01 and 3.8, respectively. The incidence rate ratio (IRR) for TSH variability did not differ between groups, before and during exposure to DDIs. In contrast, PDDs less likely increased during the exposure to DDI with oral liquid LT4 compared with tablets (IRR = 0.84; 95% CI: 0.77–0.92), especially in patients with post-surgical hypothyroidism (IRR = 0.75; 95% CI: 0.64–0.85).

Conclusions

In clinical practice, the use of oral liquid LT4 is not associated with increased PDDs, compared with tablets formulation, during exposure to DDIs. These results support the need for individualizing LT4 formulation to prescribe, especially in patients with various comorbidities and complex therapeutic regimens.

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Impact of etiology, age and gender on onset and severity of hyponatremia in patients with hypopituitarism: retrospective analysis in a specialised endocrine unit

Abstract

Background

Hyponatremia can unmask hypopituitarism and secondary adrenal insufficiency. This is important, since the need to screen for steroid deficiency, in patients with hyponatremia is often neglected.

Patients and methods

In a retrospective study, twenty-five patients (13f/12m, age 58.9 ± 18.6 years) with hyponatremia (119.7 ± 10.5 mmol/L) were identified among 260 in-patients treated for hypopituitarism in our specialized endocrine unit, over the last decade. We analyzed clinical characteristics, etiology, and severity of hypopituitarism in patients who presented with hyponatremia.

Results

Hyponatremia was recorded in 9.6% of our patients with hypopituitarism. In 80.7% it was the key to diagnosis of hypopituitarism. All patients with hyponatremia were steroid deficient with complete hypopituitarism compared to 75% (steroid deficient) and 60% (complete hypopituitarism) of the patients in the cohort. The most common etiology of hypopituitarism was non-functioning pituitary macro adenoma (NFPA) (n = 128, 49.2%). Patients with hyponatremia were divided into two groups, based on the etiology of hypopituitarism: Group 1. with NFPA n = 15 (5F/10M), mean age 71.47 ± 4.8 years, who were significantly older compared to patients with hyponatremia from other rare causes of hypopituitarism in Group 2. n = 10 (8F/2M), mean age 40.2 ± 15.3 years (p < 0.01), such as: congenital hypopituitarism(n = 2), Sheehan's syndrome (n = 2), intracranial aneurysm (n = 2), lymphocytic hypophysitis (n = 1), traumatic brain injury (n = 1), surgery and radiotherapy for astrocytoma (n = 1), pituitary metastasis from bronchial carcinoma (n = 1). Hyponatremia was more severe in Group 2. compared to Group 1. (113.5 ± 10.9 mmol/L vs. 124.3 ± 8.1 mmol/L, p < 0.01). Older age (p = 0.0001) and number of endocrine deficiencies (p < 0.05) were identified as predictive factors for hyponatremia by multivariate analysis in patients with hypopituitarism.

Conclusion

Hyponatremia is an important presenting feature of pituitary disease and a strong indicator of life-threatening steroid deficiency. Old age and severity of hypopituitarism are major risk factors for hyponatremia. In older patients NFPA is the most common etiology, while other rare causes of hypopituitarism are more prevalent in younger patients with hyponatremia.

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Correction

Publication date: Available online 13 September 2017
Source:Archives of Physical Medicine and Rehabilitation





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Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care

Abstract

Purpose

Several medications may interact with levothyroxine (LT4) intestinal absorption or metabolism, thus reducing its bioavailability. We investigated the variability of thyroid stimulating hormone (TSH) levels and prescribed daily dosages (PDDs) of LT4 before and during potential drug–drug interactions (DDIs) in users of tablets vs. oral liquid LT4 formulations.

Methods

By using the Italian general practice Health Search Database (HSD), we retrospectively selected adult patients with at least one LT4 prescription from 2012 to 2015 and at least 1 year of clinical history recorded. The incident prescription of interacting medications (e.g., proton pump inhibitors, calcium or iron salts) was the index date. Analysis was carried out using a self-controlled study design.

Results

Overall, 3965 users of LT4 formed the study cohort (84.1% women, mean age 56 ± 16.5 years). TSH variability on the entry date was greater among liquid LT4 users than in those prescribed with tablets as shown by the difference between 75th and 25th centile, which were 3.01 and 3.8, respectively. The incidence rate ratio (IRR) for TSH variability did not differ between groups, before and during exposure to DDIs. In contrast, PDDs less likely increased during the exposure to DDI with oral liquid LT4 compared with tablets (IRR = 0.84; 95% CI: 0.77–0.92), especially in patients with post-surgical hypothyroidism (IRR = 0.75; 95% CI: 0.64–0.85).

Conclusions

In clinical practice, the use of oral liquid LT4 is not associated with increased PDDs, compared with tablets formulation, during exposure to DDIs. These results support the need for individualizing LT4 formulation to prescribe, especially in patients with various comorbidities and complex therapeutic regimens.

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Impact of etiology, age and gender on onset and severity of hyponatremia in patients with hypopituitarism: retrospective analysis in a specialised endocrine unit

Abstract

Background

Hyponatremia can unmask hypopituitarism and secondary adrenal insufficiency. This is important, since the need to screen for steroid deficiency, in patients with hyponatremia is often neglected.

Patients and methods

In a retrospective study, twenty-five patients (13f/12m, age 58.9 ± 18.6 years) with hyponatremia (119.7 ± 10.5 mmol/L) were identified among 260 in-patients treated for hypopituitarism in our specialized endocrine unit, over the last decade. We analyzed clinical characteristics, etiology, and severity of hypopituitarism in patients who presented with hyponatremia.

Results

Hyponatremia was recorded in 9.6% of our patients with hypopituitarism. In 80.7% it was the key to diagnosis of hypopituitarism. All patients with hyponatremia were steroid deficient with complete hypopituitarism compared to 75% (steroid deficient) and 60% (complete hypopituitarism) of the patients in the cohort. The most common etiology of hypopituitarism was non-functioning pituitary macro adenoma (NFPA) (n = 128, 49.2%). Patients with hyponatremia were divided into two groups, based on the etiology of hypopituitarism: Group 1. with NFPA n = 15 (5F/10M), mean age 71.47 ± 4.8 years, who were significantly older compared to patients with hyponatremia from other rare causes of hypopituitarism in Group 2. n = 10 (8F/2M), mean age 40.2 ± 15.3 years (p < 0.01), such as: congenital hypopituitarism(n = 2), Sheehan's syndrome (n = 2), intracranial aneurysm (n = 2), lymphocytic hypophysitis (n = 1), traumatic brain injury (n = 1), surgery and radiotherapy for astrocytoma (n = 1), pituitary metastasis from bronchial carcinoma (n = 1). Hyponatremia was more severe in Group 2. compared to Group 1. (113.5 ± 10.9 mmol/L vs. 124.3 ± 8.1 mmol/L, p < 0.01). Older age (p = 0.0001) and number of endocrine deficiencies (p < 0.05) were identified as predictive factors for hyponatremia by multivariate analysis in patients with hypopituitarism.

Conclusion

Hyponatremia is an important presenting feature of pituitary disease and a strong indicator of life-threatening steroid deficiency. Old age and severity of hypopituitarism are major risk factors for hyponatremia. In older patients NFPA is the most common etiology, while other rare causes of hypopituitarism are more prevalent in younger patients with hyponatremia.

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Editorial Board

Publication date: September 2017
Source:Pathology - Research and Practice, Volume 213, Issue 9





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Full Monte Carlo-based biological treatment plan optimization system for intensity modulated carbon ion therapy on GPU

Publication date: Available online 12 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Nan Qin, Chenyang Shen, Min-Yu Tsai, Marco Pinto, Zhen Tian, Georgios Dedes, Arnold Pompos, Steve B. Jiang, Katia Parodi, Xun Jia
PurposeOne of the major benefits of carbon ion therapy is enhanced biological effectiveness at the Bragg peak region. For intensity modulated carbon ion therapy (IMCT), it is desirable to employ Monte Carlo (MC) methods to compute properties of each pencil-beam spot for treatment planning, because of their accuracy in modeling physics processes and estimating biological effects. We have previously developed goCMC, a graphics processing unit (GPU)-oriented MC engine for carbon ion therapy. The purpose of this study is to build a biological treatment plan optimization system based on goCMC.Methods and MaterialsThe repair-misrepair-fixation model was implemented to compute spatial distribution of linear-quadratic model parameters for each spot. A treatment plan optimization module was developed to minimize the difference between the prescribed and actual biological effect. We employed a gradient-based algorithm to solve the optimization problem. The system was embedded in the Varian Eclipse treatment planning system under a client-server architecture to achieve a user-friendly planning environment. We tested the system with a 1-dimensional homogeneous water case and 3-dimensional patient cases.ResultsOur system generated treatment plans with biological spread-out Bragg peaks covering the targeted regions, while sparing critical structures. Using four NVidia GTX 1080 GPUs, total computation time including spot simulation, optimization, and final dose calculation was 0.6 hours for the prostate case (8282 spots), 0.2 hours for the pancreas case (3795 spots), and 0.3 hours for the brain case (6724 spots). The computation time was dominated by MC spot simulation.ConclusionsWe have built a biological treatment plan optimization system for IMCT that performs simulations by a fast MC engine, goCMC. To our knowledge, this is the first time that full MC-based IMCT inverse planning has been achieved in a clinically viable timeframe.



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21st Surgical Research Days. Section of Surgical Research of the German Society of Surgery. September 21-23, 2017, Cologne, Germany: Abstracts

Eur Surg Res 2017;58:275-328

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Spasticity may obscure motor learning ability after stroke

Previous motor learning studies based on adapting movements of the hemiparetic arm in stroke subjects have not accounted for spasticity occurring in specific joint ranges (spasticity zones), resulting in equivocal conclusions about learning capacity. We compared the ability of participants with stroke to rapidly adapt elbow extension movements to changing external load conditions outside and inside spasticity zones. Participants with stroke (n=12, aged: 57.8±9.6 years) and healthy age-matched controls (n=8, 63.5±9.1 years) made rapid 40-50° horizontal elbow extension movements from an initial (3°) to a final (6°) target. Sixteen blocks (6-10 trials/block) consisting of alternating loaded (30% MVC) and non-loaded trials were made in one (controls) or two sessions (stroke; 1 wk apart). For the stroke group, the tonic stretch reflex threshold angle at which elbow flexors began to be activated during passive elbow extension was used to identify the beginning of the spasticity zone. The task was repeated in joint ranges that did or did not include the spasticity zone. Error correction strategies were identified by the angular positions before correction and compared between groups and sessions. Changes in load condition from no-load to load and vice-versa resulted in undershoot and overshoot errors respectively. Stroke subjects corrected errors in 1-4 trials compared to 1-2 trials in controls. When movements did not include the spasticity zone, there was an immediate decrease in the number of trials needed to restore accuracy, suggesting that the capacity to learn may be preserved after stroke but masked by the presence of spasticity.

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Contribution of sensory feedback to plantar flexor muscle activation during push-off in adults with cerebral palsy.

Introduction: Exaggerated sensory activity has been assumed to contribute to functional impairment following lesion of the central motor pathway. However, recent studies have suggested that sensory contribution to muscle activity during gait is reduced in stroke patients and children with cerebral palsy (CP). We investigated whether this also occurs in CP adults and whether daily treadmill training is accompanied by alterations in sensory contribution to muscle activity. Materials and Methods: 17 CP adults and 12 uninjured individuals participated. The participants walked on a treadmill while a robotized ankle-foot orthosis applied unload perturbations at the ankle hereby removing sensory feedback naturally activated during push-off. Reduction of electromyographic (EMG) activity in the soleus muscle caused by unloads was compared and related to kinematics and ankle joint stiffness measurements. Similar measures were obtained after 6 weeks of gait training. Results: Sensory contribution to soleus EMG activation was reduced in CP adults compared with uninjured adults. The lowest contribution of sensory feedback was found in participants with lowest maximal gait speed. This was related to increased ankle plantar flexor stiffness. 6 weeks of gait training did not alter the contribution of sensory feedback. Conclusion: Exaggerated sensory activity is unlikely to contribute to impaired gait in CP adults, since sensory contribution to muscle activity during gait was reduced compared with uninjured individuals. Increased passive stiffness around the ankle joint is likely to diminish sensory feedback during gait so that a larger part of plantar flexor muscle activity must be generated by descending motor commands.

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Influence of Biases in Numerical Magnitude allocation on Human Pro-Social Decision Making

Over the past decade neuroscientific research has attempted to probe the neurobiological underpinnings of human pro-social decision-making. Such research has almost ubiquitously employed tasks such as the dictator game or similar variations (i.e. ultimatum game). Considering the explicit numerical nature of such tasks, it is surprising that the influence of numerical cognition upon decision-making during task performance remains unknown. Whilst performing these tasks, participants typically tend to anchor upon a 50:50 split that necessitates an explicit numerical judgement (i.e. number-pair bisection). Accordingly, we hypothesise that the decision-making process during the dictator game recruits overlapping cognitive processes to those known to be engaged during number-pair bisection. We observed that biases in numerical magnitude allocation correlated with the formulation of decisions during the dictator game. That is, intrinsic biases towards smaller numerical magnitudes were associated with the formulation of less favourable decisions, whereas biases towards larger magnitudes were associated with more favourable choices. We proceeded to corroborate this relationship by subliminally and systematically inducing biases in numerical magnitude towards either higher or lower numbers using a visuo-vestibular stimulation paradigm. Such subliminal alterations in numerical magnitude allocation led to proportional and corresponding changes to an individual's decision-making during the dictator game. Critically, no relationship was observed between neither intrinsic nor induced biases in numerical magnitude on decision-making when assessed using a non-numerical based pro-social questionnaire. Our findings demonstrate numerical influences upon decisions formulated during the dictator game and highlight the necessity to control for confounds associated with numerical cognition in human decision-making paradigms.

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Diversity in Spatial Scope of Contrast Adaptation among Mouse Retinal Ganglion Cells

Retinal ganglion cells adapt to changes in visual contrast by adjusting their response kinetics and sensitivity. While much work has focused on the time scales of these adaptation processes, less is known about the spatial scale of contrast adaptation. For example, do small, localized contrast changes affect a cell's signal processing across its entire receptive field? Previous investigations have provided conflicting evidence, suggesting either that contrast adaptation occurs locally within subregions of a ganglion cell's receptive field or globally over the receptive field in its entirety. Here, we investigated the spatial extent of contrast adaptation in ganglion cells of the isolated mouse retina through multielectrode-array recordings. We applied visual stimuli so that ganglion cell receptive fields contained regions where the average contrast level changed periodically as well as regions with constant average contrast level. This allowed us to analyze temporal stimulus integration and sensitivity separately for stimulus regions with and without contrast changes. We found that the spatial scope of contrast adaptation depends strongly on cell identity, with some ganglion cells displaying clear local adaptation, whereas others, in particular large transient ganglion cells, adapted globally to contrast changes. Thus, the spatial scope of contrast adaptation in mouse retinal ganglion cells appears to be cell-type specific. This could reflect differences in mechanisms of contrast adaptation and may contribute to the functional diversity of different ganglion cell types.

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Stability of Hand Force Production: I. Hand Level Control Variables and Multi-Finger Synergies

We combined the theory of neural control of movement with referent coordinates and the uncontrolled manifold hypothesis to explore synergies stabilizing the hand action in accurate four-finger pressing tasks. In particular, we tested a hypothesis on two classes of synergies - those among the four fingers and those within a pair of control variables - stabilizing hand action under visual feedback and disappearing without visual feedback. Subjects performed four-finger total force and moment production tasks under visual feedback; the feedback was later partially or completely removed. The "inverse piano" device was used to lift and lower the fingers smoothly at the beginning and at the end of each trial. These data were used to compute pairs of hypothetical control variables. Inter-trial analysis of variance within the finger force space was used to quantify multi-finger synergies stabilizing both force and moment. A data permutation method was used to quantify synergies among control variables. Under visual feedback, synergies in the spaces of finger forces and hypothetical control variables were found to stabilize total force. Without visual feedback, the subjects showed a force drift to lower magnitudes and a moment drift toward pronation. This was accompanied by disappearance of the four-finger synergies and strong attenuation of the control-variable synergies. The indices of the two types of synergies correlated with each other. The findings are interpreted within the scheme with multiple levels of abundant variables.

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Surface electrodes record and label brain neurons in insects

We used suction electrodes to reliably record the activity of identified ascending auditory interneurons from the anterior surface of the brain in crickets. Electrodes were gently attached to the sheath covering the projection area of the ascending interneurons and the ring-like auditory neuropil in the protocerebrum. The specificity and selectivity of the recordings were determined by the precise electrode location, which could easily be changed without causing damage to the tissue. Different non-auditory fibres were recorded at other spots of the brain surface; stable recordings lasted for several hours. The same electrodes were used to deliver fluorescent tracers into the nervous system by means of electrophoresis. This allowed us to retrograde label the recorded auditory neurons, and to reveal their cell body and dendritic structure in the first thoracic ganglion. By adjusting the amount of dye injected, we specifically stained the ring-like auditory neuropil in the brain, demonstrating the clusters of cell bodies contributing to it. Our data provide a proof that surface electrodes are a versatile tool to analyse neural processing in small brains of invertebrates.

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The superior colliculus and the steering of saccades toward a moving visual target

Following the suggestion that a command encoding the current target location feeds the oculomotor system during interceptive saccades, we tested the involvement of the deep superior colliculus (dSC). Extracellular activity of 52 saccade-related neurons was recorded in three monkeys while they generated saccades to targets that were static or moving along the preferred axis, away from (outward) or toward a fixated target (inward) with a constant speed (20°/s). Vertical and horizontal motions were tested when possible. Movement field (MF) parameters (boundaries, preferred vector and firing rate) were estimated after spline fitting the relation between the average firing rate during the motor burst and saccade amplitude. During radial target motions, the inner MF boundary shifted in the motion direction for some, but not all, neurons. Likewise, for some neurons, the lower boundaries were shifted upward during upward motions, the upper boundaries downward during downward motions. No consistent change was observed during horizontal motions. For some neurons, the preferred vectors were also shifted in the motion direction for outward, upward and "toward the midline" target motions. The shifts of boundary and preferred vector were not correlated. The burst firing rate was consistently reduced during interceptive saccades. Our study shows an involvement of dSC neurons in steering the interceptive saccade. When observed, the shifts of boundary in the direction of target motion correspond to commands related to past target locations. The absence of shift in the opposite direction implies that dSC activity does not issue predictive commands related to the future target location.

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METHODOLOGICAL CONSIDERATIONS FOR A CHRONIC NEURAL INTERFACE WITH THE CUNEATE NUCLEUS OF MACAQUES

While the response properties of neurons in the somatosensory nerves and anterior parietal cortex have been extensively studied, little is known about the encoding of tactile and proprioceptive information in the cuneate nucleus (CN) or external cuneate nucleus (ECN), the first recipients of upper limb somatosensory afferent signals. The major challenge in characterizing neural coding in CN/ECN has been to record from these tiny, difficult to access brainstem structures. Most previous investigations of CN response properties have been carried out in decerebrate or anesthetized animals, thereby eliminating the well-documented top-down signals from cortex, which likely exert a strong influence on CN responses. Seeking to fill this gap in our understanding of somatosensory processing, we describe an approach to chronically implant arrays of electrodes in the upper limb representation in the brain stem in primates. First, we describe the topography of CN/ECN in Rhesus macaques, including its somatotopic organization and the layout of its submodalities (touch and proprioception). Second, we describe the design of electrode arrays and the implantation strategy to obtain stable recordings. Third, we show sample responses of CN/ECN neurons in brainstem obtained from awake, behaving monkeys. With this method, we are in a position to characterize, for the first time, somatosensory representations in CN and ECN of primates.

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Characterization of ion channels and O2 sensitivity in gill neuroepithelial cells of the anoxia-tolerant goldfish (Carassius auratus)

The neuroepithelial cell (NEC) of the fish gill is an important model for O₂ sensing in vertebrates; however, a complete picture of the chemosensory mechanisms in NECs is lacking, and O₂ chemoreception in vertebrates that are tolerant to anoxia has yet not been explored. Using whole-cell patch-clamp recording, we characterized four types of ion channels in NECs isolated from the anoxia-tolerant goldfish. A Ca²⁺-dependent K⁺ current (I_KCa) peaked at ~20 mV, was potentiated by increased intracellular Ca²⁺, and was reduced by 100 μM Cd²⁺. A voltage-dependent inward current in Ba²⁺ solution, with peak at 0 mV, confirmed the presence of Ca²⁺ channels. A voltage-dependent K⁺ current (I_KV) was inhibited by 20 mM tetraethylammonium and 5 mM 4-aminopyridine, revealing a background K⁺ current (I_KB) with open rectification. Mean resting membrane potential of –45.2 +/- 11.6 mV did not change upon administration of hypoxia (P_O2 = 11 mmHg), nor were any of the K⁺ currents sensitive to changes in P_O2 during whole-cell recording. By contrast, when the membrane and cytosol were left undisturbed during Fura-2 or FM1-43 imaging experiments, hypoxia increased intracellular Ca²⁺ concentration and initiated synaptic vesicle activity. 100 μM Cd²⁺ and 50 μM nifedipine eliminated uptake of FM1-43. We conclude that Ca²⁺ influx via L-type Ca²⁺ channels is correlated with vesicular activity during hypoxic stimulation. In addition, we suggest that expression of I_KCa in gill NECs is species specific and, in goldfish, may contribute to an attenuated response to acute hypoxia.

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Comparison of three models of saccade disconjugacy in strabismus

In pattern strabismus the horizontal and vertical misalignments vary with eye position along the orthogonal axis. The disorder is typically described in terms of overaction or underaction of oblique muscles. Recent behavioral studies in humans and monkeys, however, have reported that such actions are insufficient to fully explain the patterns of directional and amplitude disconjugacy of saccades. There is mounting evidence that the oculomotor abnormalities associated with strabismus are at least partially attributable to neurophysiological abnormalities. A number of control systems models have been developed to simulate the kinematic characteristics of saccades in normal primates. In the present study we sought to determine whether these models could simulate the abnormalities of saccades in strabismus by making two assumptions: 1) in strabismus the burst generator gains differ for the two eyes and 2) abnormal cross-talk exists between the horizontal and vertical saccadic circuits in brainstem. We tested three models, distinguished by the location of the horizontal-vertical cross-talk. All three models were able to simulate amplitude and directional saccade disconjugacy, postsaccadic drift, and a pattern strabismus for static fixation, but they made different predictions about the dynamics of saccades. By assuming that crosstalk occurs at multiple nodes, the Distributed Crosstalk Model correctly predicted the dynamics of saccades. These new models make additional predictions that can be tested with future neurophysiological experiments.

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Hyperpolarization-activated cyclic-nucleotide gated channels potentially modulate axonal excitability at different thresholds

Hyperpolarization-activated cyclic-nucleotide gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying (Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterise sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 health subjects (45 studies in total). Tracking targets were set to 20%, 40% and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90-100 ms was significantly increased in lower threshold sensory axons (F=11.195, P<0.001). In motor axons, the hyperpolarizing I/V gradient was significantly increased in lower threshold axons (F=3.191, P < 0.05). The minimum I/V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets.

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Introduction to special section on digital technology and cancer survivorship

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Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications

Summary

Background Data on completeness of reporting of phase I cancer clinical trials in publications are lacking. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching primary publications published prior to November 1, 2016. Reporting in primary publications was compared with the ClinicalTrials.gov database using a 28-point score (2=complete; 1=partial; 0=no reporting) for 14 items related to study design, outcome measures and safety profile. Inconsistencies between primary publications and ClinicalTrials.gov were recorded. Linear regression was used to identify factors associated with incomplete reporting. Results After a review of 583 trials in ClinicalTrials.gov, 163 matching primary publications were identified. Publications reported outcomes that did not appear in ClinicalTrials.gov in 25% of trials. Outcomes were upgraded, downgraded or omitted in publications in 47% of trials. The overall median reporting score was 23/28 (interquartile range 21–25). Incompletely reported items in >25% publications were: inclusion criteria (29%), primary outcome definition (26%), secondary outcome definitions (53%), adverse events (71%), serious adverse events (80%) and dates of study start and database lock (91%). Higher reporting scores were associated with phase I (vs phase I/II) trials (p<0.001), multicenter trials (p<0.001) and publication in journals with lower impact factor (p=0.004). Conclusions Reported results in primary publications for early phase cancer trials are frequently inconsistent or incomplete compared with ClinicalTrials.gov entries. ClinicalTrials.gov may provide more comprehensive data from new cancer drug trials.

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Eribulin in advanced breast cancer: safety, efficacy and new perspectives

Future Oncology, Ahead of Print.


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Racial and Insurer-Based Disparities of Care Exist Among Thyroid Cancer Patients in the United States

Clinical Thyroidology Sep 2017, Vol. 29, No. 9: 351-353.


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Large Retrospective Study Confirms the 2015 American Thyroid Association Guidelines for Classifying Small Thyroid Nodules on Ultrasound

Clinical Thyroidology Sep 2017, Vol. 29, No. 9: 344-347.


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Conflicting Occurrence of Thyroid-Stimulating or Blocking Antibodies Is Seen in 4 to 9% of Patients with Autoimmune Thyroid Disease

Clinical Thyroidology Sep 2017, Vol. 29, No. 9: 335-337.


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Hypothyroid Symptoms in Pregnant Women Fail to Predict Hypothyroid Status

Clinical Thyroidology Sep 2017, Vol. 29, No. 9: 332-334.


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A Deiodinase 2 Polymorphism May Lower Serum T3 and Tissue T3 in Levothyroxine-Treated Patients

Clinical Thyroidology Sep 2017, Vol. 29, No. 9: 338-340.


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Moderate-Risk versus High-Risk RET Mutation Does Not Impact Medullary Thyroid Cancer Outcomes in MEN2A Patients

Clinical Thyroidology Sep 2017, Vol. 29, No. 9: 348-350.


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Is There a Distinct Pattern of Mutations in Benign Adenomatous Nodules?

Clinical Thyroidology Sep 2017, Vol. 29, No. 9: 341-343.


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Does Empathy, a Central Element of the Art of Medicine, Proscribe Using “Good Cancer” Themes in Clinical Practice?

Clinical Thyroidology Sep 2017, Vol. 29, No. 9: 354-357.


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Superior properties of Fc-comprising scTRAIL fusion proteins

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In the present study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of epidermal growth factor receptor (EGFR)-targeting dimeric scTRAIL fusion proteins (Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL) as well as two non-targeted dimeric scTRAIL molecules (EHD2-scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on anti-tumor activity. All EGFR-targeted dimeric scTRAIL molecules showed similar binding properties and comparable cell death induction in vitro, exceeding the activity of the respective non-targeted dimeric format and monomeric scTRAIL. Superior properties were observed for the Fc fusion proteins with respect to production and in vivo half-life. In vivo studies using a Colo205 xenograft model revealed potent anti-tumor activity of all EGFR-targeting formats and Fc-scTRAIL and furthermore highlighted the higher efficacy of fusion proteins comprising an Fc part. Despite enhanced in vitro cell death induction of targeted scTRAIL molecules, however, comparable anti-tumor activities were found for the EGFR-targeting scFv-Fc-scTRAIL and the non-targeting Fc-scTRAIL in vivo.

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CCR5-dependent homing of T regulatory cells to the tumor microenvironment contributes to skin squamous cell carcinoma development

Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Tregs) have a critical role in the modulation of an anti- tumor immune response, and consequently the SCC development. Since the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5 and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Treg cells and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4+CD25+CCR5+, CD4+CD25-CCR5+ or CD8+CCR5+ conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4+CD25+CCR5+ cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In the present study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of anti-tumor cells such as cytotoxic CD8+ T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment.

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Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo. We used small hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial-mesenchymal transition in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the epithelial-mesenchymal transition in vitro. Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared to no treatment or single agent treatments (P<0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC.

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PD-1 status in CD8+ T cells associates with survival and anti-PD-1 therapeutic outcomes in head and neck cancer

Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T cell function and prognostic impact, since PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (p = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TIL were more frequent in HPV- patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease free survival (DFS) and higher hazard ratio for recurrence (p<0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1 based immunotherapy.

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ANGPTL1 interacts with integrin {alpha}1{beta}1 to suppress HCC angiogenesis and metastasis by inhibiting JAK2/STAT3 signaling

Downregulation of tumor suppressor signaling plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). Here we report that downregulation of the angiopoietin-like protein ANGPTL1 is associated with vascular invasion, tumor thrombus, metastasis and poor prognosis in HCC. Ectopic expression of ANGPTL1 in HCC cells effectively decreased their in vitro and in vivo tumorigenicity, cell motility and angiogenesis. shRNA-mediated depletion of ANGPTL1 exerted opposing effects. ANGPTL1 promoted apoptosis via inhibition of the STAT3/Bcl-2 mediated anti-apoptotic pathway and decreased cell migration and invasion via downregulation of transcription factors SNAIL and SLUG. Furthermore, ANGPTL1 inhibited angiogenesis by attenuating ERK and AKT signaling and interacted with integrin α1β1 receptor to suppress the downstream FAK/Src-JAK-STAT3 signaling pathway. Taken together, these results suggest ANGPTL1 as a prognostic biomarker and novel therapeutic agent in HCC.

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Structurally novel antiestrogens elicit differential responses from constitutively active mutant estrogen receptors in breast cancer cells and tumors

Many ERα-positive breast cancers develop resistance to endocrine therapy via mutation of estrogen receptors (ER) whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ER, we describe here our development and characterization of three chemically novel AE that effectively suppress proliferation of breast cancer cells and tumors. Our AE are effective against wild type and Y537S and D538G ER, the two most commonly occurring constitutively active ER. The 3 new AE suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared to WT ER, mutants exhibited ~10 to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER-containing MCF7 and T47D cells revealed that AE responses were compound, cell-type and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER-expressing tumor xenografts in NOD/SCID-gamma mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ER to different AE and make clear the value of having a toolkit of AE for treatment of endocrine therapy-resistant tumors driven by different constitutively active ER.

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Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance.

Myeloid-derived suppressor cells (MDSCs) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti-Jagged1/2 blocking antibody CTX014 on MDSC-mediated T cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, impacted the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T cell tolerance, increased the infiltration of reactive CD8+ T-cells into tumors, and enhanced the efficacy of T cell-based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas co-injection of MDSC-like cells from anti-Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy.

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Optical coherence tomography detects necrotic regions and volumetrically quantifies multicellular tumor spheroids

Three-dimensional (3D) tumor spheroid models have gained increased recognition as important tools in cancer research and anti-cancer drug development. However, currently available imaging approaches employed in high-throughput screening drug discovery platforms e.g. bright field, phase contrast, and fluorescence microscopies, are unable to resolve 3D structures deep inside (>50 μm) tumor spheroids. In this study, we established a label-free, non-invasive optical coherence tomography (OCT) imaging platform to characterize 3D morphological and physiological information of multicellular tumor spheroids (MCTS) growing from ~250 μm up to ~600 μm in height over 21 days. In particular, tumor spheroids of two cell lines glioblastoma (U-87 MG) and colorectal carcinoma (HCT 116) exhibited distinctive evolutions in their geometric shapes at late growth stages. Volumes of MCTS were accurately quantified using a voxel-based approach without presumptions of their geometries. In contrast, conventional diameter-based volume calculations assuming perfect spherical shape resulted in large quantification errors. Furthermore, we successfully detected necrotic regions within these tumor spheroids based on increased intrinsic optical attenuation, suggesting a promising alternative of label-free viability tests in tumor spheroids. Therefore, OCT can serve as a promising imaging modality to characterize morphological and physiological features of MCTS, showing great potential for high-throughput drug screening.

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Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 1–8. ©2017 AACR.

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Obesity modulates diaphragm curvature in subjects with and without COPD

Background: Obesity is a common co-morbidity of COPD and has been associated with worse outcomes. However, it is unknown whether the interaction between obesity and COPD modulates diaphragm shape and consequently its function. The body mass index has been used as a correlate of obesity. We tested the hypothesis that the shape of the diaphragm muscle and size of the ring of its insertion in Non-COPD and COPD subjects are modulated by BMI. Methods: We recruited 48 COPD patients with post-bronchiodilator FEV1/FVC < 0.7 and 29 age-matched smoker/ex-smoker control (Non-COPD) subjects, who underwent chest CT at lung volumes ranging from FRC to TLC. We then computed maximum principle diaphragm curvature in the midcostal region of the left hemidiaphragm at end of inspiration during quiet breathing (EI) and at total lung capacity (TLC). Results: The radius of maximum curvature of diaphragm muscle increased with BMI in both COPD and Non-COPD subjects. The size of diaphragm ring of insertion on the chest wall also increased significantly with increasing BMI. Surprisingly, COPD severity did not appear to cause significant alteration in diaphragm shape except in normal weight subjects at TLC. Conclusion: Our data uncovered important factors such as BMI, the size of the diaphragm ring of insertion, and disease severity that modulate the structure of the ventilatory pump in Non-COPD and COPD subjects.

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Long-term treatment with the ghrelin receptor antagonist, [D-Lys3]-GHRP-6 does not improve glucose homeostasis in non-obese diabetic MKR mice

Ghrelin secretion has been associated with increased caloric intake and adiposity. The expressions of ghrelin and its receptor (GHS-R1a) in pancreas have raised the interest about the role of ghrelin in glucose homeostasis. Most of the studies showed that ghrelin promoted hyperglycaemia and inhibited insulin secretion. This raised the interest in using GHS-R1a antagonists as therapeutic targets for type 2 diabetes. Available data of GHS-R antagonists are on a short-term basis. Moreover, the complexity of GHS-R1a signalling makes it difficult to understand the mechanism of action of GHS-R1a antagonists. This study examined the possible effects of long-term treatment with a GHS-R1a antagonist, [D-Lys3]-GHRP-6 on glucose homeostasis, food intake and indirect calorimetric parameters in non-obese diabetic MKR mice. Our results showed that [D-Lys3]-GHRP-6 (200nmol/mouse), reduced pulsatile growth hormone secretion and body fat mass as expected, but worsened glucose and insulin intolerances and increased cumulative food intake unexpectedly. In addition, a significant increase in blood glucose and decreases in plasma insulin and c-peptide levels were observed in MKR mice following long-term [D-Lys3]-GHRP-6 treatment, suggested a direct inhibition of insulin secretion. Immunofluorescence staining of pancreatic islets showed a proportional increase in somatostatin positive cells and a decrease in insulin positive cells in [D-Lys3]-GHRP-6 treated mice. Furthermore, [D-Lys3]-GHRP-6 stimulated food intake on long-term treatment via reduction of POMC gene expression and antagonized GH secretion via reduced GHRH gene expression in hypothalamus. These results demonstrate that [D-Lys3]-GHRP-6 is not completely opposite to ghrelin and may not be a treatment option for type 2 diabetes.

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Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy

In 2010, 5-year-old Emily Whitehead was diagnosed with acute lymphoblastic leukemia (ALL). Though her parents were told that if you had to have a kid with cancer, ALL was the best one to have, Emily's course was hardly typical. After two rounds of chemotherapy, necrotizing fasciitis developed in…

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A consensus-based approach to evidence-based clinical practice

Publication date: Available online 12 September 2017
Source:Dental Materials
Author(s): Jean-François Roulet




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Academy of Dental Materials guidance—Resin composites: Part II—Technique sensitivity (handling, polymerization, dimensional changes)

Publication date: Available online 13 September 2017
Source:Dental Materials
Author(s): J.L. Ferracane, T.J. Hilton, J.W. Stansbury, D.C. Watts, N. Silikas, N. Ilie, S. Heintze, M. Cadenaro, R. Hickel
ObjectiveThe objective of this work, commissioned by the Academy of Dental Materials, was to review and critically appraise test methods to characterize properties related to critical issues for dental resin composites, including technique sensitivity and handling, polymerization, and dimensional stability, in order to provide specific guidance to investigators planning studies of these properties.MethodsThe properties that relate to each of the main clinical issues identified were ranked in terms of their priority for testing, and the specific test methods within each property were ranked. An attempt was made to focus on the tests and methods likely to be the most useful, applicable, and supported by the literature, and where possible, those showing a correlation with clinical outcomes. Certain methods are only briefly mentioned to be all-inclusive. When a standard test method exists, whether from dentistry or another field, this test has been identified. Specific examples from the literature are included for each test method.ResultsThe properties for evaluating resin composites were ranked in the priority of measurement as follows: (1) porosity, radiopacity, sensitivity to ambient light, degree of conversion, polymerization kinetics, depth of cure, polymerization shrinkage and rate, polymerization stress, and hygroscopic expansion; (2) stickiness, slump resistance, and viscosity; and (3) thermal expansion.SignificanceThe following guidance is meant to aid the researcher in choosing the most appropriate test methods when planning studies designed to assess certain key properties and characteristics of dental resin composites, specifically technique sensitivity and handling during placement, polymerization, and dimensional stability.



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Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity

Summary

Lysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC₅₀ of 6.56 μM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking. Demethylation inhibition by LDD2269 was confirmed with a cell-based assay using antibodies against methylated histone at lysines 9 and 36. HCT-116 colon cancer cell line proliferation was suppressed by LDD2269, which also interfered with soft-agar growth and migration of HCT-116 cells. AnnexinV staining and PARP cleavage experiments showed apoptosis induction by LDD2269. Derivatives of LDD2269 were synthesized and the structure–activity relationship was explored. LDD2269 is reported here as a strong inhibitor of KDM4A in in vitro and cell-based systems, with anti-tumor functions.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2f6L3xZ