Induced cortical oscillations in turtle cortex are coherent at the mesoscale of population activity, but not at the microscale of the membrane potential of neurons

Bursts of oscillatory neural activity have been hypothesized to be a core mechanism by which remote brain regions can communicate. Such a hypothesis raises the question to what extent oscillations are coherent across spatially distant neural populations. To address this question, we obtained local field potential (LFP) and membrane potential recordings from the visual cortex of turtle in response to visual stimulation of the retina. The time-frequency analysis of these recordings revealed pronounced bursts of oscillatory neural activity and a large trial-to-trial variability in the spectral and temporal properties of the observed oscillations. First, local bursts of oscillations varied from trial to trial in both burst duration and peak frequency. Second, oscillations of a given recording site were not autocoherent; i.e., the phase did not progress linearly in time. Third, LFP oscillations at spatially separate locations within the visual cortex were more phase coherent in the presence of visual stimulation than during ongoing activity. In contrast, the membrane potential oscillations from pairs of simultaneously recorded pyramidal neurons showed smaller phase coherence, which did not change when switching from black screen to visual stimulation. In conclusion, neuronal oscillations at distant locations in visual cortex are coherent at the mesoscale of population activity, but coherence is largely absent at the microscale of the membrane potential of neurons.

NEW & NOTEWORTHY Coherent oscillatory neural activity has long been hypothesized as a potential mechanism for communication across locations in the brain. In this study we confirm the existence of coherent oscillations at the mesoscale of integrated cortical population activity. However, at the microscopic level of neurons, we find no evidence for coherence among oscillatory membrane potential fluctuations. These results raise questions about the applicability of the communication through coherence hypothesis to the level of the membrane potential.

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Time-of-day influences on respiratory sequelae following maximal electroshock-induced seizures in mice

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Although specific mechanisms underlying SUDEP are not well understood, evidence suggests most SUDEP occurs due to seizure-induced respiratory arrest. SUDEP also tends to happen at night. Although this may be due to circumstances in which humans find themselves at night, such as being alone without supervision or sleeping prone, or to independent influences of sleep state, there are a number of reasons why the night (i.e., circadian influences) could be an independent risk factor for SUDEP. We explored this possibility. Adult male WT mice were instrumented for EEG, EMG, and EKG recording and subjected to maximal electroshock (MES) seizures during wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep during the nighttime/dark phase. These data were compared with data collected following seizures induced during the daytime/light phase. Seizures induced during the nighttime were similar in severity and duration to those induced during the daytime; however, seizures induced during the nighttime were associated with a lesser degree of respiratory dysregulation and postictal EEG suppression. Seizures induced during REM sleep during the nighttime were universally fatal, as is seen when seizures are induced during REM during the daytime. Taken together, these data implicate a role for time of day in influencing the physiological consequences of seizures that may contribute to seizure-induced death.

NEW & NOTEWORTHY Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP frequently occurs during the night, which has been attributed to an effect of sleep. We have shown that sleep state does indeed influence survival following a seizure. That SUDEP occurs during the night could also implicate a circadian influence. In this study we found that time of day independently affects the physiological consequences of seizures.

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Altered tactile sensitivity in children with attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is characterized by an inability to concentrate, heightened activity, and hypermotoric behavior, but sensory (e.g., tactile) problems are common. The literature on tactile impairments in ADHD is limited, with most work employing clinical observations or questionnaires. We studied tactile processing in children with ADHD and hypothesized that children with ADHD would show reduced performance in tasks closely linked to inhibition. Sixty-seven children with ADHD and 62 typically developing children (TDC) performed a battery of tasks grouped in domains: simple and choice reaction time; static and dynamic detection threshold (probing feedforward inhibition); amplitude discrimination without adaptation and with dual and single-site adaptation (probing lateral inhibition and adaptation); sequential and simultaneous frequency discrimination (previously linked to GABA); and temporal order judgment with and without a synchronous carrier stimulus. Children with ADHD could discriminate different amplitudes without adaptation, suggesting lateral inhibition is intact, but were negatively affected in all adaptation conditions, whereas TDC were only affected during single-site adaptation. Children with ADHD also showed normal frequency discrimination. Children with ADHD showed slower reaction times and higher detection threshold, likely driven by IQ and inattention, because reaction time and detection thresholds correlated with IQ and subtle motor signs. Children with ADHD showed a pattern of altered tactile processing on specific tasks, suggesting that higher cognitive function and cortical mechanisms related to adaptation are affected in ADHD, but no clear conclusion can be drawn toward impaired inhibition.

NEW & NOTEWORTHY This manuscript presents the first tactile psychophysical study testing different aspects of tactile processing in attention-deficit hyperactivity disorder (ADHD), using large cohort sizes of 67 children with ADHD and 65 Typically Developing Children. This study demonstrates impaired tactile processing in children with ADHD, on some, but not all tasks (showing this is not just due to attention), related to impaired cortical mechanisms. Furthermore, both IQ and soft motor skill abnormalities (common in ADHD) are correlated with tactile abnormalities.

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Face percept formation in human ventral temporal cortex

Loci in ventral temporal cortex are selectively active during viewing of faces and other objects, but it remains unclear whether these areas represent accumulation of simple visual information or processing of intact percept. We measured broadband electrocorticographic changes from implanted electrodes on the ventral temporal brain surface while showing patients noise-degraded images of faces and houses. In a subset of posterior fusiform gyrus face-selective regions, cortical activity decreased parametrically with noise increase, until the perceptual threshold was surpassed. At noise levels higher than the perceptual threshold, and for house stimuli, activity remained at baseline. We propose that this convergence of proportional and thresholded response may identify active areas where face percepts are extracted from simple visual features. These loci exist within a topological structure of face percept formation in the human ventral visual stream, preceded by category-nonselective activity in pericalcarine early visual areas and in concert with all-or-nothing activity in postperceptual subregions of the ventral temporal lobe. This topological organization suggests a physiological basis for the anatomy of face perception, explaining different perceptual deficits following temporal lobe injury.

NEW & NOTEWORTHY Philosophers have puzzled for millennia about how humans build abstract conceptual objects (house/face/tool) from the simple features of the world they see around them (line/patch/lighting). Understanding the biological foundation of this process requires detailed knowledge of the spatial-temporal characteristics of cerebral cortex. By examining the physiology of the human temporal lobe via implanted electrodes while showing subjects noise-degraded images, we find that face percept formation happens in specific subregions within known face-processing areas.

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A Comparison of Alkaline Water and Mediterranean Diet vs Proton Pump Inhibition for Treatment of Laryngopharyngeal Reflux.

Related Articles

A Comparison of Alkaline Water and Mediterranean Diet vs Proton Pump Inhibition for Treatment of Laryngopharyngeal Reflux.

JAMA Otolaryngol Head Neck Surg. 2017 Oct 01;143(10):1023-1029

Authors: Zalvan CH, Hu S, Greenberg B, Geliebter J

Abstract
Importance: Laryngopharyngeal reflux (LPR) is a common disorder with protean manifestations in the head and neck. In this retrospective study, we report the efficacy of a wholly dietary approach using alkaline water, a plant-based, Mediterranean-style diet, and standard reflux precautions compared with that of the traditional treatment approach of proton pump inhibition (PPI) and standard reflux precautions.
Objective: To determine whether treatment with a diet-based approach with standard reflux precautions alone can improve symptoms of LPR compared with treatment with PPI and standard reflux precautions.
Design, Setting, and Participants: This was a retrospective medical chart review of 2 treatment cohorts. From 2010 to 2012, 85 patients with LPR that were treated with PPI and standard reflux precautions (PS) were identified. From 2013 to 2015, 99 patients treated with alkaline water (pH >8.0), 90% plant-based, Mediterranean-style diet, and standard reflux precautions (AMS) were identified. The outcome was based on change in Reflux Symptom Index (RSI).
Main Outcomes and Measures: Recorded change in the RSI after 6 weeks of treatment.
Results: Of the 184 patients identified in the PS and AMS cohorts, the median age of participants in each cohort was 60 years (95% CI, 18-82) and 57 years (95% CI, 18-93), respectively (47 [56.3%] and 61 [61.7%] were women, respectively). The percentage of patients achieving a clinically meaningful (≥6 points) reduction in RSI was 54.1% in PS-treated patients and 62.6% in AMS-treated patients (difference between the groups, 8.05; 95% CI, -5.74 to 22.76). The mean reduction in RSI was 27.2% for the PS group and 39.8% in the AMS group (difference, 12.10; 95% CI, 1.53 to 22.68).
Conclusions and Relevance: Our data suggest that the effect of PPI on the RSI based on proportion reaching a 6-point reduction in RSI is not significantly better than that of alkaline water, a plant-based, Mediterranean-style diet, and standard reflux precautions, although the difference in the 2 treatments could be clinically meaningful in favor of the dietary approach. The percent reduction in RSI was significantly greater with the dietary approach. Because the relationship between percent change and response to treatment has not been studied, the clinical significance of this difference requires further study. Nevertheless, this study suggests that a plant-based diet and alkaline water should be considered in the treatment of LPR. This approach may effectively improve symptoms and could avoid the costs and adverse effects of pharmacological intervention as well as afford the additional health benefits associated with a healthy, plant-based diet.

PMID: 28880991 [PubMed - indexed for MEDLINE]

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TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules.

TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules.

Bioinformatics. 2017 Oct 27;:

Authors: Sanchez-Pulido L, Ponting CP

Abstract
Summary: The molecular functions of TMEM132 genes remain poorly understood and under-investigated despite their mutations associated with non-syndromic hearing loss, panic disorder and cancer. Here we show the full domain architecture of human TMEM132 family proteins solved using in-depth sequence and structural analysis. We reveal them to be five previously unappreciated cell adhesion molecules whose domain architecture has an early holozoan origin prior to the emergence of choanoflagellates and metazoa. The extra-cellular portions of TMEM132 proteins contain five conserved domains including three tandem immunoglobulin domains, and a cohesin domain homologue, the first such domain found in animals. These findings strongly predict a cellular adhesion function for TMEM132 family, connecting the extracellular medium with the intracellular actin cytoskeleton.
Contact: Luis.Sanchez-Pulido@igmm.ed.ac.uk.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29088312 [PubMed - as supplied by publisher]

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Genetic Testing of Non-familial Deaf Patients for CIB2 and GJB2 Mutations: Phenotype and Genetic Counselling.

Genetic Testing of Non-familial Deaf Patients for CIB2 and GJB2 Mutations: Phenotype and Genetic Counselling.

Biochem Genet. 2017 Oct 31;:

Authors: Shaikh H, Waryah AM, Narsani AK, Iqbal M, Shahzad M, Waryah YM, Shaikh N, Mahmood A

Abstract
CIB2 and GJB2 genes variants contribute significantly in familial cases of prelingual recessive hearing loss (HL). This study was aimed to determine the CIB2 and GJB2 variants and associated phenotype in 150 non-familial individuals with HL. After getting informed consent, 150 non-familial deaf patients were enrolled and blood samples were obtained for DNA extraction. Pure tone air conduction audiometry was performed. Coding exons of CIB2 and GJB2 genes were Sanger sequenced. A tetra primer ARMS assay was developed for recurrent CIB2 variant. Four bi-allelic GJB2 variants, c.71G>A p.(Trp24*), c.231G>A p.(Trp77*), c.235delC p.(Leu79Cysfs3*) and c.35delG p.(Gly11Leufs24*), were found in nine hearing impaired individuals. We also found four homozygotes and five carriers of c.380G>A p. (Arg127His) variant of controversial clinical significance. CIB2 sequencing revealed single recurrent variant c.272T>C p. (Phe91Ser) segregating with HL in ten individuals. Among our patients, c.71G>A (p.Trp24*) was the most common variant, accounted for 45% of GJB2 variants. Two known GJB2 variants, c.235delC p. (Leu79Cysfs3*) and c.310del14 p. (Lys105Argfs2*), are reported here for the first time in Pakistani population. Our data further support the benign nature of c.380G>A p. (Arg127His) variant. For CIB2, c.272T>C p. (Phe91Ser) is the second common cause of HL among our sporadic cases. Phenotypically, in our patients, individuals homozygous for GJB2 variants had profound HL, whereas CIB2 homozygotes had severe to profound prelingual HL. Our results suggest that GJB2 and CIB2 are common cause of HL in different Pakistani ethnicities.

PMID: 29086887 [PubMed - as supplied by publisher]

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Child Health in Elementary School Following California’s Paid Family Leave Program.

Related Articles

Child Health in Elementary School Following California's Paid Family Leave Program.

J Policy Anal Manage. 2017;36(4):790-827

Authors: Lichtman-Sadot S, Bell NP

Abstract
We evaluate changes in elementary school children health outcomes following the introduction of California's Paid Family Leave (PFL) program, which provided parents with paid time off following the birth of a child. Our health outcomes--overweight, ADHD, and hearing-related problems--are characterized by diagnosis rates that only pick up during early elementary school. Moreover, our health outcomes have been found to be negatively linked with many potential implications of extended maternity leave--increased breastfeeding, prompt medical checkups at infancy, reduced prenatal stress, and reduced non-parental care during infancy. Using the Early Childhood Longitudinal Studies (ECLS) within a difference-in-differences framework, our results suggest improvements in health outcomes among California elementary school children following PFL's introduction. Furthermore, the improvements are driven by children from less advantaged backgrounds, which is consistent with the notion that California's PFL had the greatest effect on leave-taking duration after childbirth mostly for less advantaged mothers who previously could not afford to take unpaid leave.

PMID: 28991423 [PubMed - indexed for MEDLINE]

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Genetic counseling in CHARGE syndrome: Diagnostic evaluation through follow up.

Genetic counseling in CHARGE syndrome: Diagnostic evaluation through follow up.

Am J Med Genet C Semin Med Genet. 2017 Oct 31;:

Authors: Hefner MA, Fassi E

Abstract
CHARGE syndrome (CS) is a complex genetic disorder causing multiple birth defects and sensory deficits (hearing, vision, balance, smell). Genetic counseling in CS must include not only the provision of factual information about CS, its cause, and inheritance, but also information about the developmental implications of CS features, referral to appropriate resources, and assistance with psychosocial adaptation to this information. CS should be considered in patients with any of the major diagnostic features: coloboma, choanal atresia, semicircular canal anomalies, or cranial nerve anomalies. The prime candidates in the differential are 22q11.2 deletion and Kabuki syndromes. Evaluation of features of CS, dysmorphology examination, and genetic testing can usually distinguish between the three conditions. Genetic counseling is important from early on, to help the family understand the process of genetic diagnosis, to interpret information coming from other specialists and to provide support and resources. Parents can easily be overwhelmed with the complexity of issues facing their child at diagnosis and in the future. CS is a substantial burden on a child, with high early mortality, multiple illnesses, hospitalizations and surgeries, and apparent medical fragility throughout life. The medical complexity of CS disrupts family life and contributes to delayed development. Multiple sensory deficits (impaired vision, hearing, and balance) further contribute to delayed motor and language development despite many individuals with CS having normal intelligence. Early referral to specialists in deafblindness and sensory deficits is essential. Resources are available to assist genetic counselors in diagnosis, follow-up, and management of patients with CS.

PMID: 29088501 [PubMed - as supplied by publisher]

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Ribeye protein is intrinsically dynamic but is stabilized in the context of the ribbon synapse.

Ribeye protein is intrinsically dynamic but is stabilized in the context of the ribbon synapse.

J Physiol. 2017 Oct 31;:

Authors: Chen Z, Chou SW, McDermott BM

Abstract
Ribeye protein is a major constituent of the synaptic ribbon, an organelle that coordinates rapid and sustained vesicle release to enable hearing and balance. The ribbon is considered to be a stable structure. However, under certain physiological conditions such as acoustic overexposure that results in temporary noise-induced hearing loss or perturbations of ion channels, ribbons may change shape or vanish altogether, suggesting greater plasticity than previously appreciated. The dynamic properties of ribeye proteins are unknown. Here we use transgenesis and imaging to explore the behaviours of ribeye proteins within the ribbon and also their intrinsic properties outside the context of the ribbon synapse in a control cell type, the skin cell. By fluorescence recovery after photobleaching (FRAP) on transgenic zebrafish larvae, we test whether ribeye proteins are dynamic in vivo in real time. In the skin, a cell type devoid of synaptic contacts, Ribeye a-mCherry exchanges with ribbon-like structures on a minute timescale (t1/2  = 3.2 min). In contrast, Ribeye a of the ear and lateral line and Ribeye b of the lateral line each exchange at ribbons of hair cells an order of magnitude slower (t1/2 of 125.6 min, 107.0 min, and 95.3 min, respectively) than Ribeye a of the skin. These basal exchange rates suggest that long-term ribbon presence may require ribeye renewal. Our studies demonstrate that ribeye proteins are inherently dynamic but are stabilized at the ribbons of sensory cells in vivo. This article is protected by copyright. All rights reserved.

PMID: 29086422 [PubMed - as supplied by publisher]

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CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival.

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival.

EMBO Mol Med. 2017 Oct 30;:

Authors: Michel V, Booth KT, Patni P, Cortese M, Azaiez H, Bahloul A, Kahrizi K, Labbé M, Emptoz A, Lelli A, Dégardin J, Dupont T, Aghaie A, Oficjalska-Pham D, Picaud S, Najmabadi H, Smith RJ, Bowl MR, Brown SD, Avan P, Petit C, El-Amraoui A

Abstract
Defects of CIB2, calcium- and integrin-binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type-IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyndromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2(-/-) mice display an early onset profound deafness and have normal balance and retinal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2(-/-) mice, unlike those of mice defective for the other five known USH1 proteins, begin only after birth and lead to regression of the stereocilia and rapid hair-cell death. This essential role of CIB2 in mechanotransduction and cell survival that, we show, is restricted to the cochlea, probably accounts for the presence in CIB2(-/-) mice and CIB2 patients, unlike in Usher syndrome, of isolated hearing loss without balance and vision deficits.

PMID: 29084757 [PubMed - as supplied by publisher]

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Comparison of the protective effects of direct ischemic preconditioning and remote ischemic preconditioning in a rabbit model of transient spinal cord ischemia

Abstract

Introduction

This study aimed to determine the relative potency of direct ischemic preconditioning (DIPC) and remote ischemic preconditioning (RIPC) for protection against ischemic spinal cord injury in rabbits and to explore the mechanisms involved.

Methods

In experiment 1, we compared the neurological and histopathological outcomes of DIPC, kidney RIPC, and limb RIPC. The DIPC and kidney RIPC groups received two cycles of 5-min occlusion/15-min reperfusion of the abdominal aorta and left renal artery, respectively. The limb RIPC group received two cycles of 10-min occlusion/10-min reperfusion of the femoral arteries bilaterally. Thirty minutes after the conditioning ischemia, spinal cord ischemia was produced by occluding the abdominal aorta for 15 min. In experiments 2 and 3, we investigated whether pretreatment using a free-radical scavenger, dimethylthiourea (DMTU), an adenosine A₁ receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or a mitochondrial ATP-sensitive potassium channel antagonist, 5-hydroxydecanoate (5HD), could attenuate the protective effects of DIPC. In experiment 4, comprehensive analysis of phosphorylated proteins in the spinal cord was performed using a Proteome Profiler Array followed by immunoblotting to elucidate the signal pathway activated by DIPC.

Results

In experiment 1, DIPC improved the neurological and histopathological outcomes, whereas kidney and limb RIPC had no protective effects. In experiments 2 and 3, strong protective effects of DIPC were reconfirmed but were not attenuated by DMTU, DPCPX, or 5HD. In experiment 4, DIPC induced phosphorylation of Akt2.

Conclusions

DIPC, but not kidney or limb RIPC, protected against ischemic spinal cord injury in rabbits. Akt2 might contribute to this protective effect.

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Genetic counseling in CHARGE syndrome: Diagnostic evaluation through follow up.

Genetic counseling in CHARGE syndrome: Diagnostic evaluation through follow up.

Am J Med Genet C Semin Med Genet. 2017 Oct 31;:

Authors: Hefner MA, Fassi E

Abstract
CHARGE syndrome (CS) is a complex genetic disorder causing multiple birth defects and sensory deficits (hearing, vision, balance, smell). Genetic counseling in CS must include not only the provision of factual information about CS, its cause, and inheritance, but also information about the developmental implications of CS features, referral to appropriate resources, and assistance with psychosocial adaptation to this information. CS should be considered in patients with any of the major diagnostic features: coloboma, choanal atresia, semicircular canal anomalies, or cranial nerve anomalies. The prime candidates in the differential are 22q11.2 deletion and Kabuki syndromes. Evaluation of features of CS, dysmorphology examination, and genetic testing can usually distinguish between the three conditions. Genetic counseling is important from early on, to help the family understand the process of genetic diagnosis, to interpret information coming from other specialists and to provide support and resources. Parents can easily be overwhelmed with the complexity of issues facing their child at diagnosis and in the future. CS is a substantial burden on a child, with high early mortality, multiple illnesses, hospitalizations and surgeries, and apparent medical fragility throughout life. The medical complexity of CS disrupts family life and contributes to delayed development. Multiple sensory deficits (impaired vision, hearing, and balance) further contribute to delayed motor and language development despite many individuals with CS having normal intelligence. Early referral to specialists in deafblindness and sensory deficits is essential. Resources are available to assist genetic counselors in diagnosis, follow-up, and management of patients with CS.

PMID: 29088501 [PubMed - as supplied by publisher]

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Ribeye protein is intrinsically dynamic but is stabilized in the context of the ribbon synapse.

Ribeye protein is intrinsically dynamic but is stabilized in the context of the ribbon synapse.

J Physiol. 2017 Oct 31;:

Authors: Chen Z, Chou SW, McDermott BM

Abstract
Ribeye protein is a major constituent of the synaptic ribbon, an organelle that coordinates rapid and sustained vesicle release to enable hearing and balance. The ribbon is considered to be a stable structure. However, under certain physiological conditions such as acoustic overexposure that results in temporary noise-induced hearing loss or perturbations of ion channels, ribbons may change shape or vanish altogether, suggesting greater plasticity than previously appreciated. The dynamic properties of ribeye proteins are unknown. Here we use transgenesis and imaging to explore the behaviours of ribeye proteins within the ribbon and also their intrinsic properties outside the context of the ribbon synapse in a control cell type, the skin cell. By fluorescence recovery after photobleaching (FRAP) on transgenic zebrafish larvae, we test whether ribeye proteins are dynamic in vivo in real time. In the skin, a cell type devoid of synaptic contacts, Ribeye a-mCherry exchanges with ribbon-like structures on a minute timescale (t1/2  = 3.2 min). In contrast, Ribeye a of the ear and lateral line and Ribeye b of the lateral line each exchange at ribbons of hair cells an order of magnitude slower (t1/2 of 125.6 min, 107.0 min, and 95.3 min, respectively) than Ribeye a of the skin. These basal exchange rates suggest that long-term ribbon presence may require ribeye renewal. Our studies demonstrate that ribeye proteins are inherently dynamic but are stabilized at the ribbons of sensory cells in vivo. This article is protected by copyright. All rights reserved.

PMID: 29086422 [PubMed - as supplied by publisher]

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CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival.

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival.

EMBO Mol Med. 2017 Oct 30;:

Authors: Michel V, Booth KT, Patni P, Cortese M, Azaiez H, Bahloul A, Kahrizi K, Labbé M, Emptoz A, Lelli A, Dégardin J, Dupont T, Aghaie A, Oficjalska-Pham D, Picaud S, Najmabadi H, Smith RJ, Bowl MR, Brown SD, Avan P, Petit C, El-Amraoui A

Abstract
Defects of CIB2, calcium- and integrin-binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type-IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyndromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2(-/-) mice display an early onset profound deafness and have normal balance and retinal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2(-/-) mice, unlike those of mice defective for the other five known USH1 proteins, begin only after birth and lead to regression of the stereocilia and rapid hair-cell death. This essential role of CIB2 in mechanotransduction and cell survival that, we show, is restricted to the cochlea, probably accounts for the presence in CIB2(-/-) mice and CIB2 patients, unlike in Usher syndrome, of isolated hearing loss without balance and vision deficits.

PMID: 29084757 [PubMed - as supplied by publisher]

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The Role of Templating in the Emergence of RNA from the Prebiotic Chemical Mixture.

The Role of Templating in the Emergence of RNA from the Prebiotic Chemical Mixture.

Life (Basel). 2017 Oct 31;7(4):

Authors: Tupper AS, Shi K, Higgs PG

Abstract
Biological RNA is a uniform polymer in three senses: it uses nucleotides of a single chirality; it uses only ribose sugars and four nucleobases rather than a mixture of other sugars and bases; and it uses only 3'-5' bonds rather than a mixture of different bond types. We suppose that prebiotic chemistry would generate a diverse mixture of potential monomers, and that random polymerization would generate non-uniform strands of mixed chirality, monomer composition, and bond type. We ask what factors lead to the emergence of RNA from this mixture. We show that template-directed replication can lead to the emergence of all the uniform properties of RNA by the same mechanism. We study a computational model in which nucleotides react via polymerization, hydrolysis, and template-directed ligation. Uniform strands act as templates for ligation of shorter oligomers of the same type, whereas mixed strands do not act as templates. The three uniform properties emerge naturally when the ligation rate is high. If there is an exact symmetry, as with the chase of chirality, the uniform property arises via a symmetry-breaking phase transition. If there is no exact symmetry, as with monomer selection and backbone regioselectivity, the uniform property emerges gradually as the rate of template-directed ligation is increased.

PMID: 29088116 [PubMed]

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The allergen-specificity of early peanut consumption and the impact on the development of allergic disease in the LEAP Study Cohort

Publication date: Available online 31 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): George du Toit, Peter H. Sayre, Graham Roberts, Kaitie Lawson, Michelle L. Sever, Henry T. Bahnson, Helen R. Fisher, Mary Feeney, Suzana Radulovic, Monica Basting, Marshall Plaut, Gideon Lack
BackgroundEarly introduction of dietary peanut in high-risk infants with severe eczema and/or egg allergy prevented peanut allergy at 5 years of age in the LEAP Study; the protective effect persisted after 12 months of avoiding peanuts in the LEAP-On Study. It is unclear whether this benefit is allergen and allergic-disease specific.ObjectiveTo assess the impact of early introduction of peanut on the development of allergic disease, food sensitization and aeroallergen sensitization.MethodsAsthma, eczema and rhinoconjunctivitis were diagnosed by clinical assessment. Reported allergic reactions and consumption of tree nuts and sesame were recorded by questionnaire. Sensitization to food and aeroallergens was determined by skin prick testing and specific IgE measurement.ResultsA high and increasing burden of food and aeroallergen sensitization and allergic disease was noted across study time points; 76% of LEAP participants had at least one allergic disease at 60 months of age. There were no differences in allergic disease between LEAP groups. There were small differences in sensitization and reported allergic reactions for select tree nuts; levels were higher in the LEAP consumption group. Significant resolution of eczema and sensitization to egg and milk occurred in LEAP participants; this was not affected by peanut consumption.ConclusionEarly consumption of peanut in infants at high risk of peanut allergy is allergen-specific and does not prevent the development of other allergic disease, sensitization to other foods and aeroallergens, or reported allergic reactions to tree nuts and sesame. Furthermore, peanut consumption does not hasten the resolution of eczema or egg allergy.

Teaser

The early consumption of peanut in high-risk infants is allergen-specific and protects against peanut allergy but does not prevent the development of sensitization to other allergens or allergic diseases.


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Academy of Prosthodontics centennial: The educational roots of our specialty

Publication date: Available online 31 October 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Stephen D. Campbell, Clark M. Stanford, Cortino Sukotjo, John R. Agar, Charles Goodacre




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Association Between Dietary Inflammation Index and The Risk of Colorectal Cancer: A Meta-Analysis.

Association Between Dietary Inflammation Index and The Risk of Colorectal Cancer: A Meta-Analysis.

Nutr Cancer. 2017 Oct 31;:1-9

Authors: Zhang C, Wang W, Zhang D

Abstract
OBJECTIVES: We performed a meta-analysis to assess the association and possible dose-response relationship between dietary inflammation index (DII)™ and colorectal cancer (CRC).
METHODS: A literature search was performed in PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) database for all relevant studies. The pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated by random effects model.
RESULTS: A total of eight studies were included in this meta-analysis. The pooled RRs of CRC, colon and rectal cancer for the highest versus lowest DII categories were 1.43 (95% CI 1.25-1.63), 1.37 (95% CI 1.16-1.62) and 1.44 (95% CI 1.23-1.69), respectively. A significant positive association was observed both in cohort studies (RR = 1.26, 95% CI 1.14-1.38) and case-control studies (RR = 1.81, 95% CI 1.48-2.22). Nonlinear associations between DII scores and the risk of CRC, colon and rectal cancer were found in the dose-response analyses, the results showed that the risks of CRC, colon and rectal cancer increased slowly when the DII score was above 1.30, 2.21, and 1.30, respectively.
CONCLUSION: Higher DII scores might increase CRC risk. Thus, people should adopt more anti-inflammatory diets such as those high in vegetables, fruits, whole grains, herbs, and spices.

PMID: 29087221 [PubMed - as supplied by publisher]

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A relapsed lower lip squamous cell carcinoma treated with curative electrochemotherapy in elderly patient.

A relapsed lower lip squamous cell carcinoma treated with curative electrochemotherapy in elderly patient.

Minerva Stomatol. 2017 Oct 31;:

Authors: Gargiulo M, Cortese A, Pantaleo G, Parascandalo S, Amato M

Abstract
INTRODUCTION: ECT is normally used in the treatment of basal cell carcinoma, cutaneous and subcutaneous tumours, metastases of melanoma, Kaposi sarcoma, because of its high power, safety and low toxicity. The ECT treatment efficacy depends on the drug concentration during the use, patient characteristics, the distribution of the electric field inside the tumour and the tumour characteristics.
AIM: The aim of this study was to evaluate the effect of ECT in a patient affected by relapsed lower lip squamous cell carcinoma, not candidate for traditional surgery but treated for persistent pain with swallowing and breathing difficulties.
MATERIALS AND METHODS: A 58-year-old caucasian man was referred with a relapsed lower lip squamous cell carcinoma. The patient showed a TNM staging system of T2N0M0. The patient was treated with ECT with midazolam, remifentanil and intravenous bleomycin therapy.
RESULTS: The results of the treatment performed on the patient in the study showed good subjective tolerance. The patient had no postoperative bleeding or swelling of the treated area. The 2 years follow up showed no local or regional relapse, echography was negative.
CONCLUSIONS: This study demonstrates that ECT is an effective therapeutic solution for relapsed lower lip squamous cell carcinoma. ECT treatment is a conservative surgery option with a reduced postoperative damage.

PMID: 29087094 [PubMed - as supplied by publisher]

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Adjunctive use of an Ethyl Lauroyl Arginate (LAE)-containing mouthwash in the nonsurgical therapy of periodontitis: a randomized clinical trial.

Adjunctive use of an Ethyl Lauroyl Arginate (LAE)-containing mouthwash in the nonsurgical therapy of periodontitis: a randomized clinical trial.

Minerva Stomatol. 2017 Oct 31;:

Authors: Pilloni A, Carere M, Orrù G, Scano A, Trezza C, Rojas MA, Zeza B

Abstract
BACKGROUND: This randomized clinical trial evaluated the clinical and microbiological effects of 0.147% ethyl lauroyl arginate (LAE)-containing mouthwash compared to 0.12% chlorhexidine (CHX) mouthwash in the treatment of periodontitis.
MATERIALS AND METHODS: Subjects were randomized to use 0.147% LAE and 0.12% CHX mouthwash after professional mechanical plaque removal (PMPR) twice daily 1 hour after brushing for 4 weeks. Periodontal pocket depth (PPD), bleeding on probing (FMBS) and dental plaque (FMPS) were measured at baseline, 4 weeks and 3 months. Microbiological samples were taken at baseline, at 4 weeks and 3 months after plaque recording and prior to PPD and BoP measurements.
RESULTS: Forty subjects were randomized to treatment. Both therapies resulted in reduced FMPS, FMBS and residual pockets at 4 weeks and 3 months. The differences were not statistically significant. There were no treatment-related adverse events. Total bacterial count and the specific pathogens were reduced at 4 weeks and 3 months by both mouthwashes with no statistical differences between them at neither periods of time.
CONCLUSIONS: 0.147% LAE-containing mouthwash could be an alternative to the use of 0.12% CHX in the non surgical therapy of periodontitis considering the similar clinical effects, more stable microbiological improvement and absence of adverse effects.

PMID: 29087093 [PubMed - as supplied by publisher]

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Death by suicide in Graves' disease and Graves' orbitopathy. A nationwide Danish register study.

Death by suicide in Graves' disease and Graves' orbitopathy. A nationwide Danish register study.

Thyroid. 2017 Oct 30;:

Authors: Ferløv-Schwensen C, Brix TH, Hegedus L

Abstract
BACKGROUND: Graves' disease is associated with excess morbidity and mortality, but little is known about unnatural manners of death and the potential relation with Graves' orbitopathy. Here we investigate the risk of unnatural death in Graves' patients with orbitopathy (GO) and without (GD), compared to matched control populations.
METHODS: Cohort study covering all adult Danes (≥18 years) diagnosed with GD or GO during 1995-2012. Median follow-up time was 7.9 years (range, 0-17.5). Utilizing the Danish Register of Causes of Death and the Danish National Patient Registry, 28,461 subjects with GD, and 3,965 with GO were identified and matched for age and gender with four subjects from the background population. Manner of death was identified and hazard ratios (HR) for mortality due to unnatural deaths (accident, suicide, violence/homicide, and unknown) were calculated using Cox regression analyses, adjusted for pre-existing somatic and psychiatric morbidity.
RESULTS: In Graves' disease overall there was an increased risk of death from unknown unnatural manners [HR: 2.01 (95% confidence interval: 1.17-3.45); P=0.012] and of suicide, although the latter difference was not with certainty statistically significant [HR 1.43 (1.00-2.04); P=0.053]. There was no significant difference in risk of death from suicide in GD subjects compared to their controls [HR 1.27 (0.85-1.89); P=0.253]. However, GO patients had a significantly higher risk of death from suicide [HR 2.71 (1.16-6.32); p=0.022].
CONCLUSIONS: Mortality by suicide was increased in Graves' disease, most significantly in patients with Graves' orbitopathy, also after adjustment for pre-existing somatic and psychiatric disease. These findings indicate that Graves' disease and Graves' orbitopathy may have a significant role in the pathophysiological mechanisms of suicidal behavior. Beyond independent confirmation, reasons for this need to be explored in order to introduce preventive measures.

PMID: 29084476 [PubMed - as supplied by publisher]

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A Case Series of the Probability Density and Cumulative Distribution of Laryngeal Disease in a Tertiary Care Voice Center.

Related Articles

A Case Series of the Probability Density and Cumulative Distribution of Laryngeal Disease in a Tertiary Care Voice Center.

Ann Otol Rhinol Laryngol. 2017 Nov;126(11):748-754

Authors: de la Fuente J, Garrett CG, Ossoff R, Vinson K, Francis DO, Gelbard A

Abstract
OBJECTIVE: To examine the distribution of clinic and operative pathology in a tertiary care laryngology practice.
METHODS: Probability density and cumulative distribution analyses (Pareto analysis) was used to rank order laryngeal conditions seen in an outpatient tertiary care laryngology practice and those requiring surgical intervention during a 3-year period.
RESULTS: Among 3783 new clinic consultations and 1380 operative procedures, voice disorders were the most common primary diagnostic category seen in clinic (n = 3223), followed by airway (n = 374) and swallowing (n = 186) disorders. Within the voice strata, the most common primary ICD-9 code used was dysphonia (41%), followed by unilateral vocal fold paralysis (UVFP) (9%) and cough (7%). Among new voice patients, 45% were found to have a structural abnormality. The most common surgical indications were laryngotracheal stenosis (37%), followed by recurrent respiratory papillomatosis (18%) and UVFP (17%).
CONCLUSIONS: Nearly 55% of patients presenting to a tertiary referral laryngology practice did not have an identifiable structural abnormality in the larynx on direct or indirect examination. The distribution of ICD-9 codes requiring surgical intervention was disparate from that seen in clinic. Application of the Pareto principle may improve resource allocation in laryngology, but these initial results require confirmation across multiple institutions.

PMID: 28949246 [PubMed - indexed for MEDLINE]

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The direct basal ganglia pathway is hyperfunctional in focal dystonia.

The direct basal ganglia pathway is hyperfunctional in focal dystonia.

Brain. 2017 Oct 26;:

Authors: Simonyan K, Cho H, Hamzehei Sichani A, Rubien-Thomas E, Hallett M

Abstract
Focal dystonias are the most common type of isolated dystonia. Although their causative pathophysiology remains unclear, it is thought to involve abnormal functioning of the basal ganglia-thalamo-cortical circuitry. We used high-resolution research tomography with the radioligand 11C-NNC-112 to examine striatal dopamine D1 receptor function in two independent groups of patients, writer's cramp and laryngeal dystonia, compared to healthy controls. We found that availability of dopamine D1 receptors was significantly increased in bilateral putamen by 19.6-22.5% in writer's cramp and in right putamen and caudate nucleus by 24.6-26.8% in laryngeal dystonia (all P ≤ 0.009). This suggests hyperactivity of the direct basal ganglia pathway in focal dystonia. Our findings paralleled abnormally decreased dopaminergic function via the indirect basal ganglia pathway and decreased symptom-induced phasic striatal dopamine release in writer's cramp and laryngeal dystonia. When examining topological distribution of dopamine D1 and D2 receptor abnormalities in these forms of dystonia, we found abnormal separation of direct and indirect pathways within the striatum, with negligible, if any, overlap between the two pathways and with the regions of phasic dopamine release. However, despite topological disorganization of dopaminergic function, alterations of dopamine D1 and D2 receptors were somatotopically localized within the striatal hand and larynx representations in writer's cramp and laryngeal dystonia, respectively. This finding points to their direct relevance to disorder-characteristic clinical features. Increased D1 receptor availability showed significant negative correlations with dystonia duration but not its severity, likely representing a developmental endophenotype of this disorder. In conclusion, a comprehensive pathophysiological mechanism of abnormal basal ganglia function in focal dystonia is built upon upregulated dopamine D1 receptors that abnormally increase excitation of the direct pathway, downregulated dopamine D2 receptors that abnormally decrease inhibition within the indirect pathway, and weakened nigro-striatal phasic dopamine release during symptomatic task performance. Collectively, these aberrations of striatal dopaminergic function underlie imbalance between direct and indirect basal ganglia pathways and lead to abnormal thalamo-motor-cortical hyperexcitability in dystonia.

PMID: 29087445 [PubMed - as supplied by publisher]

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MRSA chronic bacterial laryngitis: A growing problem.

MRSA chronic bacterial laryngitis: A growing problem.

Laryngoscope. 2017 Oct 31;:

Authors: Carpenter PS, Kendall KA

Abstract
OBJECTIVES: Chronic bacterial infection of the larynx is characterized by long-standing hoarseness and exudative laryngitis. Prolonged antibiotic therapy is required to clear the infection, and methicillin-resistant staphylococcus aureus (MRSA) may be the responsible pathogen. The objective of this study was to describe the presentation, comorbidities, treatment response, and underlying etiology- including the incidence of MRSA-in our patient population with chronic bacterial laryngitis.
METHODS: A review of patients with a diagnosis of chronic bacterial laryngitis from 2012 to 2016 was performed. Diagnosis of chronic bacterial laryngitis was based on clinical history and findings on flexible laryngoscopy. In selected cases, the diagnosis of bacterial laryngitis was confirmed by operative biopsy. Information regarding clinical presentation and course was collected.
RESULTS: Twenty-eight patients were included in the study. Twenty-three were treated empirically with Amoxicillin-clavulonic acid for a minimum of 21 days. Twelve of the 23 (52%) had recurrence or nonresolution of infection. Seven of the 12 nonresponders (58%) were found to have MRSA by laryngeal tissue culture. Five patients were treated initially with Sulfamethoxazole and trimethoprim, and all resolved the infection without the need for further treatment. There was a nonstatistically significant increase in smoking and reflux in the MRSA population compared to the non-MRSA group.
CONCLUSION: MRSA infection was documented in 30% of patients overall with chronic bacterial laryngitis. Based on the results of the study, a treatment algorithm for management of this unusual patient population is suggested.
LEVEL OF EVIDENCE: 4. Laryngoscope, 2017.

PMID: 29086424 [PubMed - as supplied by publisher]

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Contemporary management of advanced laryngeal cancer.

Contemporary management of advanced laryngeal cancer.

Laryngoscope Investig Otolaryngol. 2017 Oct;2(5):307-309

Authors: Britt CJ, Gourin CG

Abstract
The treatment of advanced laryngeal cancer has undergone a paradigm shift in recent years, with an increase in chemoradiation for organ preservation and a decrease in primary surgery. This review will summarize the contemporary management of advanced laryngeal cancer and discuss treatment-related toxicity and strategies to improve outcomes.
LEVEL OF EVIDENCE: NA.

PMID: 29085911 [PubMed]

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[About a case of laryngeal location of SAPHO].

Related Articles

[About a case of laryngeal location of SAPHO].

Rev Med Interne. 2017 Oct;38(10):700-703

Authors: Vatin L, Jean E, Rivière D, Montava M, Giovanni A, Dessi P, Lagier A

Abstract
INTRODUCTION: Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) is a syndrome that combines dermatological, articular and osseous inflammatory manifestations. Bilateral laryngeal immobility relative to cricoarytenoid joint origin is very uncommon. This article presents a case of bilateral cricoarytenoid joint ankylosis in a SAPHO syndrome context.
CASE REPORT: A 53-year-old patient presenting with a two year history of intermittent bouts of dyspnea. A SAPHO syndrome was discussed on repeated thoracic CT-scan. The link between dyspnea and SAPHO syndrome had not been made immediately given the absence of any known anteriority. However, having ruled out other etiologies and after having had to perform a tracheotomy due a worsening of the respiratory condition, this diagnosis was considered. Treatment by corticosteroids and infliximab permitted a clinical improvement of the patient.
CONCLUSION: This clinical case report should increase awareness of possible cricoarytenoid joint involvement in SAPHO.

PMID: 28320544 [PubMed - indexed for MEDLINE]

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What is propensity score modelling?

Related Articles

What is propensity score modelling?

Emerg Med J. 2017 Mar;34(3):129-131

Authors: Campbell MJ

Abstract
Propensity score methodology is being increasingly used to try and make inferences about treatments when randomised trials are either impossible or not conducted and the only data are from observational studies. This paper reviews the basis of propensity scores and the current state of knowledge about them. It uses and critiques a current paper in the Emergency Medicine Journal to illustrate the methodology.

PMID: 28143814 [PubMed - indexed for MEDLINE]

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Effect of cricoid pressure on laryngeal view during prehospital tracheal intubation: a propensity-based analysis.

Related Articles

Effect of cricoid pressure on laryngeal view during prehospital tracheal intubation: a propensity-based analysis.

Emerg Med J. 2017 Mar;34(3):132-137

Authors: Caruana E, Chevret S, Pirracchio R

Abstract
BACKGROUND: The benefit of cricoid pressure during tracheal intubation is still debated and, due to its potential negative impact on laryngeal views, its routine use is questioned. The goal of this study was to estimate its impact on laryngeal view.
METHODS: All patients intubated in the prehospital setting were included. Three different propensity score (PS) models were used and compared in terms of the balance achieved between those patients who received cricoid pressure and those who did not. The PS model that optimised the balance was retained in order to estimate the relationship between cricoid pressure and the following outcomes: difficult laryngoscopy, intubation-related complications and difficult intubation.
RESULTS: Among the 1195 patients included, 499 (41.7%) received cricoid pressure. The optimal PS included seven variables (cardiac arrest, altered neurological status, shock, respiratory distress, gender, obesity, patient's position). After PS matching, no significant risk difference (RD) in the rate of difficult laryngoscopy was found between the patients who received cricoid pressure and those who did not (RD=0.001, 95% CI -0.07 to 0.08, p=0.50). No significant difference was found in terms of difficult intubation (RD=0.06, 95% CI -0.13 to 0.25, p=0.28) and in terms of prevalence of complications, except for airway trauma that were more frequent in cricoid pressure group (RD=0.03, 95% CI 0.002 to 0.05, p=0.01).
CONCLUSIONS: No significant relationship was found between the use of cricoid pressure for prehospital intubation and difficult laryngoscopy. Cricoid pressure was found to be associated with more airway trauma. This finding could question its routine use.

PMID: 27694275 [PubMed - indexed for MEDLINE]

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BRAF peptide vaccine facilitates therapy of murine BRAF-mutant melanoma

Abstract

Approximately, 50% of human melanomas are driven by BRAF mutations, which produce tumors that are highly immunosuppressive and often resistant to vaccine therapy. We introduced lipid-coated calcium phosphate nanoparticles (LCP NPs) as a carrier to efficiently deliver a tumor-specific antigen, the BRAF^V600E peptide, to drive dendritic cell (DC) maturation and antigen presentation in C57BL6 mice. The BRAF peptide vaccine elicited a robust, antigen-specific cytotoxic T cell response and potent tumor growth inhibition in a murine BRAF-mutant melanoma model. Advanced BRAF-specific immune response was illustrated by IFN-γ production assay and cytotoxic T lymphocyte (CTL) assay. Remodeling of immunosuppressive modules within the tumor microenvironment further facilitated CTL infiltration. Thus, using LCP NPs to deliver the BRAF peptide vaccine is a promising strategy for the BRAF-mutant melanoma therapy.

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Immune-suppressive effects of IL-6 on T-cell-mediated anti-tumor immunity

Abstract

Accompanied by the growing clinical applications of immunotherapy in treatment for cancer patients, the development of novel therapeutic approaches to reverse the immune-suppressive environment in cancer patients is eagerly anticipated, because the success of cancer immunotherapy is currently limited by immune-suppressive effects in tumor-bearing hosts. Interleukin (IL)-6, a pleotropic pro-inflammatory cytokine, participates in tumor cell-autonomous processes that are required for their survival and growth, and is therefore known as a poor prognostic factor in cancer patients. In addition, an emerging roles of IL-6 in modulating multiple functions of immune cells including T cells, dendritic cells, and macrophages, are responsible for the dysfunction of innate and adaptive immunity against tumors. Therefore, the IL-6-targeting approach is of value as a promising strategy for desensitization and prevention of immune-suppressive effects, and should be an effective treatment when combined with current immunotherapies. The aim of this review is to discuss the immune-suppressive aspects of IL-6, notably with modification of T-cell functions in cancer patients, and their relationship to anti-tumor immune-responses and cancer immunotherapy.

This article is protected by copyright. All rights reserved.

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BRAF peptide vaccine facilitates therapy of murine BRAF-mutant melanoma

Abstract

Approximately, 50% of human melanomas are driven by BRAF mutations, which produce tumors that are highly immunosuppressive and often resistant to vaccine therapy. We introduced lipid-coated calcium phosphate nanoparticles (LCP NPs) as a carrier to efficiently deliver a tumor-specific antigen, the BRAF^V600E peptide, to drive dendritic cell (DC) maturation and antigen presentation in C57BL6 mice. The BRAF peptide vaccine elicited a robust, antigen-specific cytotoxic T cell response and potent tumor growth inhibition in a murine BRAF-mutant melanoma model. Advanced BRAF-specific immune response was illustrated by IFN-γ production assay and cytotoxic T lymphocyte (CTL) assay. Remodeling of immunosuppressive modules within the tumor microenvironment further facilitated CTL infiltration. Thus, using LCP NPs to deliver the BRAF peptide vaccine is a promising strategy for the BRAF-mutant melanoma therapy.

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Recycling drug screen repurposes hydroxyurea as a sensitizer of glioblastomas to temozolomide targeting de novo DNA synthesis, irrespective of molecular subtype

Abstract

Background

Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide; TMZ). The five-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through MGMT (O6-methylguanine DNA methyltransferase) promoter methylation status in the tumor.

Methods

A drug screening aimed at evaluating the potential recycling and repurposing of known drugs was conducted in TMZ-resistant GBM cell lines and primary cultures of newly diagnosed GBM with different MGMT promoter methylation status, phenotypic/genotypic background and subtype, and validated with sphere formation, cell migration assays, and quantitative invasive orthotopic in vivo models.

Results

We identified hydroxyurea (HU) synergized with TMZ in cells and in vivo models, irrespective of MGMT promoter methylation status, subtype, and/or stemness. HU acts specifically on the S-phase of the cell cycle by inhibiting the M2 unit of enzyme ribonucleotide reductase. Knockdown of this enzyme using RNA interference and other known chemical inhibitors exerted a similar effect to HU in combination with TMZ both in vitro and in vivo.

Conclusions

We demonstrate preclinical efficacy of repurposing hydroxyurea in combination with TMZ for adjuvant glioblastoma therapy. This combination benefit is of direct clinical interest given the extensive use of TMZ and the associated problems with TMZ-related resistance and treatment failure.

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Carcinoma mucoepidermoide de bajo grado de glándula salival menor de lengua en un paciente pediátrico

Publication date: Available online 31 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): María Fernanda Vargas Gamarra, José María Perolada Vilmaña, Miguel Armengot Carceller




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Effect of luting agent on the load to failure and accelerated-fatigue resistance of lithium disilicate laminate veneers

Publication date: Available online 1 November 2017
Source:Dental Materials
Author(s): Marco M.M. Gresnigt, Mutlu Özcan, Marco Carvalho, Priscilla Lazari, Marco S. Cune, Peywand Razavi, Pascal Magne
ObjectiveThe aim of this study was to investigate the influence of the luting agent on the application of laminate veneers (LVs) in an accelerated fatigue and load-to-failure test after thermo-cyclic aging.MethodsSound maxillary central incisors (N=40) were randomly divided into four groups to receive LVs (Li2Si2O5) that were adhesively bonded: Group CEMF: Adhesive cement (Variolink Esthetic LC), fatigue test; Group CEMLF: Adhesive cement, load-to-failure test; Group COMF: Resin composite (Enamel HFO), fatigue test; Group COMLF: Resin composite, load-to-failure test. The specimens were thermo-mechanically aged (1.2×10⁶ cycles at 1.7Hz/50N, 8000 cycles 5–55°C) and then subjected to either accelerated fatigue (5Hz, 25N increasing after each 500 cycles) or load to failure (1mm/min). Failure types were classified and data analyzed using chi-square, Kaplan Meier survival, Log Rank (Mantel–Cox) and independent-samples t-test.ResultsAfter thermo-mechanical aging, fracture resistance (p<0.000) was higher in the composite groups. Kaplan Meier survival rates showed significant difference (p<0.001) between the composite (mean load: 1165N; mean cycles: 22.595) and the cement groups (mean load: 762.5N; mean cycles: 14.569). The same differences were observed in the load to failure test (cement M=629.4N, SD±212.82 and composite M=927.59N, SD±261.06); t (18)=−2.80, p=0.01. Failure types were observed as fractures and chipping in group CEMF, all other groups were predominantly adhesive failures between the luting agent and the laminate veneer.SignificanceThe delivery of laminate veneers using a direct restorative composite rather than a resin cement resulted in significantly less chipping and fractures, higher fracture strength in both accelerated fatigue and load-to-failure.



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BRAF peptide vaccine facilitates therapy of murine BRAF-mutant melanoma

Abstract

Approximately, 50% of human melanomas are driven by BRAF mutations, which produce tumors that are highly immunosuppressive and often resistant to vaccine therapy. We introduced lipid-coated calcium phosphate nanoparticles (LCP NPs) as a carrier to efficiently deliver a tumor-specific antigen, the BRAF^V600E peptide, to drive dendritic cell (DC) maturation and antigen presentation in C57BL6 mice. The BRAF peptide vaccine elicited a robust, antigen-specific cytotoxic T cell response and potent tumor growth inhibition in a murine BRAF-mutant melanoma model. Advanced BRAF-specific immune response was illustrated by IFN-γ production assay and cytotoxic T lymphocyte (CTL) assay. Remodeling of immunosuppressive modules within the tumor microenvironment further facilitated CTL infiltration. Thus, using LCP NPs to deliver the BRAF peptide vaccine is a promising strategy for the BRAF-mutant melanoma therapy.

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Unnoticed maternal Graves’ disease revealed by the baby’s low free thyroxine in newborn screening: an underestimated condition supporting thyroid disease screening among pregnant women

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The 150 most important questions in cancer research and clinical oncology series: questions 67–75

Abstract

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and potential collaborations among researchers all over the world. In this article, 9 more questions are presented as followed. Question 67. How could we overcome the resistance of hepatocellular carcinoma against chemotherapeutics? Question 68. Is pursuit of non-covalent small-molecule binders of RAS proteins viable as a strategy of cancer drug discovery? Question 69. In what oligomeric structures do RAS proteins signal? Question 70. How can we achieve non-invasive early detection and diagnosis of lung cancer? Question 71. Does genetic information influence the volatolome enabling diagnosis of lung cancer with genetic mutations via cell headspace or breath analysis? Question 72. Is heavy ion beam radiotherapy effective to kill cancer stem cells? Question 73. Is there any diversity among different types of cancer in terms of sensitivity to heavy ion beam radiotherapy? Question 74. Can targeted alpha-particle therapy augment the effect of carbon ion radiotherapy on malignancies? Question 75. How does chromosomal instability drive tumor progression?

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Comparing ultrasound-guided and fiberscope-guided intubation

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BRAF peptide vaccine facilitates therapy of murine BRAF-mutant melanoma

Abstract

Approximately, 50% of human melanomas are driven by BRAF mutations, which produce tumors that are highly immunosuppressive and often resistant to vaccine therapy. We introduced lipid-coated calcium phosphate nanoparticles (LCP NPs) as a carrier to efficiently deliver a tumor-specific antigen, the BRAF^V600E peptide, to drive dendritic cell (DC) maturation and antigen presentation in C57BL6 mice. The BRAF peptide vaccine elicited a robust, antigen-specific cytotoxic T cell response and potent tumor growth inhibition in a murine BRAF-mutant melanoma model. Advanced BRAF-specific immune response was illustrated by IFN-γ production assay and cytotoxic T lymphocyte (CTL) assay. Remodeling of immunosuppressive modules within the tumor microenvironment further facilitated CTL infiltration. Thus, using LCP NPs to deliver the BRAF peptide vaccine is a promising strategy for the BRAF-mutant melanoma therapy.

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A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

Abstract

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II–IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 10⁵ peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4⁺ and CD8⁺ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

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Reliability of an adherence monitoring sensor embedded in an oral appliance used for treatment of obstructive sleep apnea

Summary

The aim of this study was to test if digitally registered use of a Mandibular Advancement Device (MAD) by a built-in thermal sensor was reliable compared to a self-reported diary of MAD use. Eighty consecutive patients referred to a specialist outpatient sleep medicine clinic (HUS) were recruited. Patients of both genders aged from 25 to 70 years with a diagnosis of mild to moderate or severe OSA, were included. All participants signed a written informed consent when they received the MAD. For the purpose of this reliability study, we found it sufficient to include the first 30 nights of MAD use in the reliability analysis. At the 30^th night follow-up visit, the self-reported diary with duration of MAD use was returned and data on the duration of MAD use with the built-in sensor were retrieved. From a total of 2400 nights, complete data from both methods were retrieved for 2108 nights (84.6%). Missing data were largely a result of missing self-reported diaries, whereas technical failure occurred in 6 nights (0.002%). The relative reliability was very high with ICC_3,1 0.847 and the absolute reliability for digitally registered MAD usage was calculated to - 0.17 (95% CI: 1.47 to -1.81) hours in decimal conversion. Objectively collected data from built-in thermal sensors in MADs is as reliable as that of the self-report assessments. This opens new possibilities for more accurate measurements of MAD adherence.

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Analysis of masticatory muscle coordination during unilateral single-tooth clenching using muscle functional MRI

Abstract

Background

In a previous study, we used muscle functional magnetic resonance imaging to show that the anterior movement of the occlusal point increased the activity of the superior head of the ipsilateral lateral pterygoid muscle (ipsilateral SHLP) during unilateral single-tooth clenching.

Objective

The purpose of this study was to verify the hypothesis that the increased activity of the ipsilateral SHLP described above serves to antagonize the occlusal force acting on the condyle.

Methods

In total, nine healthy volunteers were requested to perform left unilateral clenching at the first molar or first premolar region for one minute at 20% or 40% maximum voluntary clenching force. Changes in the mean proton transverse relaxation time (∆T2) were examined from the magnetic resonance images obtained before and after each clenching act as an index of the activity in all masticatory muscles. Correlation analyses of the mean ΔT2 for each volume of interest were performed with the first molar or premolar clenches to analyze the correlation between the activities in each muscle.

Results

A statistically significant correlation was exhibited between the ipsilateral temporal and ipsilateral SHLP (r = 0.651, p = 0.003) during first premolar clenching. However, no significant correlations were observed in the ipsilateral SHLP during first molar clenching.

Conclusion

The results of this study suggest that the ipsilateral SHLP may contribute to the pulling of the mandibular condyle forward against the occlusal force generated by the ipsilateral temporal muscle.

This article is protected by copyright. All rights reserved.

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A multi-centre randomized clinical trial of oral hygiene interventions following stroke – a 6-months trial

Abstract

Background

Maintaining good oral hygiene is important following stroke.

Objectives

This study aimed to evaluate the effectiveness of two oral health promotion (OHP) programmes to reduce dental plaque levels following stroke.

Methods

A multi-center randomized clinical control trial was conducted among patients hospitalised following stroke in Malaysia. Patients were randomly allocated to two OHP groups: i) control group who received the conventional method for plaque control - daily manual tooth brushing with a standardized commercial toothpaste, ii) test group - who received an intense method for plaque control - daily powered tooth brushing with 1% Chlorhexidine gel. Oral health assessments were performed at baseline, at 3-months and 6-months post intervention. Within and between group changes in dental plaque were assessed over time. Regression analyses were conducted on dental plaque levels at 6-months controlling for OHP group, medical, dental and socio-demographic status.

Results

The retention rate was 62.7% (54/86 subjects). Significant within-group changes of dental plaque levels were evident among the test group (p<0.001) and the control group (p<0.001). No significant between-group changes of dental plaque levels were apparent (p>0.05). Regression analyses identified that baseline plaque levels (adjusted ß=0.79, p<0.001) and baseline functional dependency level (adjusted ß=-0.27, p<0.05) were associated with dental plaques levels at the end of the trial (6-months).

Conclusion

Both, 'Conventional' and 'Intense' oral health promotion programmes may successfully reduce dental plaque during stroke rehabilitation and are of comparable effectiveness. Baseline dental plaque levels and functional dependency level were key factors associated with dental plaque levels at follow-up at 6-months.

This article is protected by copyright. All rights reserved.

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Visualization of the cavum septi pellucidi, cavum Vergae, and cavum veli interpositi using magnetic resonance imaging

Abstract

Purpose

The morphology of the cavum septi pellucidi (CSP), cavum Vergae (CV), and cavum veli interpositi (CVI) has been infrequently explored with neuroimaging. The aim of the present study was to delineate these cavities using magnetic resonance (MR) imaging.

Methods

A total of 71 patients were enrolled in the present study. Following initial examinations with conventional MR sequences, constructive interference in steady-state (CISS) sequence was performed in the coronal and sagittal sections for 60 and 11 patients, respectively.

Results

The coronal CISS images at the level of the aqueduct showed two distinct morphologies of the CV roof, one formed by the fornices with varying degrees of conjugation and the other formed by the corpus callosum with completely separated fornices. Appearance of the CSP was classified into four distinct types. Furthermore, the CVI presented two distinct appearances.

Conclusions

Typically, the CSP, CV, and CVI present with asymptomatic conditions with morphological variabilities. Visualization of the CSP, CV, and CVI using the CISS sequences may be useful when managing lesions affecting these cavities.

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A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

Abstract

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II–IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 10⁵ peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4⁺ and CD8⁺ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

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Hematopoietic stem cell transplantation in Niemann–Pick disease type B monitored by chitotriosidase activity

Abstract

Here, we report a patient with Niemann–Pick disease type B, with early severe onset of disease and pulmonary involvement, treated with hematopoietic stem cell transplant (HSCT) from a bone marrow matched unrelated donor. We confirm that HSCT is feasible and potentially beneficial for patients with severe phenotype. Noteworthy, we discussed the potential usefulness of the activity of peripheral chitotriosidase for the longitudinal evaluation of HSCT success and effectiveness.

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Single-cell whole exome and targeted sequencing in NPM1/FLT3 positive pediatric acute myeloid leukemia

Abstract

Background

The small portion of leukemic stem cells (LSCs) in acute myeloid leukemia (AML) present in children and adolescents is often masked by the high background of AML blasts and normal hematopoietic cells. The aim of the current study was to establish a simple workflow for reliable genetic analysis of single LSC-enriched blasts from pediatric patients.

Procedure

For three AMLs with mutations in nucleophosmin 1 and/or fms-like tyrosine kinase 3, we performed whole genome amplification on sorted single-cell DNA followed by whole exome sequencing (WES). The corresponding bulk bone marrow DNAs were also analyzed by WES and by targeted sequencing (TS) that included 54 genes associated with myeloid malignancies.

Results

Analysis revealed that read coverage statistics were comparable between single-cell and bulk WES data, indicating high-quality whole genome amplification. From 102 single-cell variants, 72 single nucleotide variants and insertions or deletions (70%) were consistently found in the two bulk DNA analyses. Variants reliably detected in single cells were also present in TS. However, initial screening by WES with read counts between 50–72× failed to detect rare AML subclones in the bulk DNAs.

Conclusions

In summary, our study demonstrated that single-cell WES combined with bulk DNA TS is a promising tool set for detecting AML subclones and possibly LSCs.

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An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001

Abstract

Purpose

This study compared the relative incidence of treatment-related toxicities and the event-free and overall survival between Hispanic and non-Hispanic children undergoing therapy for acute lymphoblastic leukemia (ALL) on Dana-Farber Cancer Institute ALL Consortium protocol 05-001.

Patients and methods

Secondary analysis of prospectively collected data from a phase III multicenter study in children and adolescents of 1–18 years with previously untreated ALL.

Results

Between 2005 and 2011, 794 eligible patients enrolled on DFCI 05-001, 730 of whom were included in this analysis (19% [N = 150] Hispanic, 73% [N = 580] non-Hispanic). Hispanic patients were more likely to be ≥10 years of age (32% vs. 24%, P = 0.045) at diagnosis. Toxicity analyses revealed that Hispanic patients had significantly lower cumulative incidence of bone fracture (P < 0.001) and osteonecrosis (ON; P = 0.047). In multivariable risk regression, the risk of ON was significantly lower in Hispanic patients ≥10 years (HR 0.23; P = 0.006). Hispanic patients had significantly lower 5-year event-free survival (EFS) (79.4%; 95% CI: 71.6–85.2) and overall survival (OS) (89.2%; 95% CI: 82.7–93.4) than non-Hispanic patients (EFS: 87.5%; 95% CI: 84.5–90.0, P = 0.004; OS: 92.7%; 95% CI: 90.2–94.6, P = 0.006). Exploratory analyses revealed differences between Hispanic and non-Hispanic patients in the frequency of common variants in genes related to toxicity or ALL outcome.

Conclusion

Hispanic children treated for ALL on DFCI 05-001 had fewer bone-related toxicities and inferior survival than non-Hispanic patients. While disease biology is one explanatory variable for outcome disparities, these findings suggest that biologic and non-biologic mechanisms affecting drug delivery and exposure in this population may be important contributing factors as well.

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A pediatric brain tumor consortium phase II trial of capecitabine rapidly disintegrating tablets with concomitant radiation therapy in children with newly diagnosed diffuse intrinsic pontine gliomas

Abstract

Background

We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG).

Patients and methods

Children 3–17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m²/dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m²/dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10.

Results

Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites.

Conclusion

Capecitabine did not improve the outcome for children with newly diagnosed DIPG.

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Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegaspargase treated with PEGylated Erwinia asparaginase, pegcrisantaspase: A report from the Children's Oncology Group

Abstract

Background

Erwinia asparaginase is a Food and Drug Administration approved agent for the treatment of acute lymphoblastic leukemia (ALL) for patients who develop hypersensitivity to Escherichia coli derived asparaginases. Erwinia asparaginase is efficacious, but has a short half-life, requiring six doses to replace one dose of the most commonly used first-line asparaginase, pegaspargase, a polyethylene glycol (PEG) conjugated E. coli asparaginase. Pegcristantaspase, a recombinant PEGylated Erwinia asparaginase with improved pharmacokinetics, was developed for patients with hypersensitivity to pegaspargase. Here, we report a series of patients treated on a pediatric phase 2 trial of pegcrisantaspase.

Procedure

Pediatric patients with ALL or lymphoblastic lymphoma and hypersensitivity to pegaspargase enrolled on Children's Oncology Group trial AALL1421 (Jazz 13-011) and received intravenous pegcrisantaspase. Serum asparaginase activity (SAA) was monitored before and after dosing; immunogenicity assays were performed for antiasparaginase and anti-PEG antibodies and complement activation was evaluated.

Results

Three of the four treated patients experienced hypersensitivity to pegcrisantaspase manifested as clinical hypersensitivity reactions or rapid clearance of SAA. Immunogenicity assays demonstrated the presence of anti-PEG immunoglobulin G antibodies in all three hypersensitive patients, indicating a PEG-mediated immune response.

Conclusions

This small series of patients, nonetheless, provides data, suggesting preexisting immunogenicity against the PEG moiety of pegaspargase and poses the question as to whether PEGylation may be an effective strategy to optimize Erwinia asparaginase administration. Further study of larger cohorts is needed to determine the incidence of preexisting antibodies against PEG-mediated hypersensitivity to pegaspargase.

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A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

Abstract

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II–IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 10⁵ peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4⁺ and CD8⁺ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

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Unnoticed maternal Graves’ disease revealed by the baby’s low free thyroxine in newborn screening: an underestimated condition supporting thyroid disease screening among pregnant women

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Visualization of the cavum septi pellucidi, cavum Vergae, and cavum veli interpositi using magnetic resonance imaging

Abstract

Purpose

The morphology of the cavum septi pellucidi (CSP), cavum Vergae (CV), and cavum veli interpositi (CVI) has been infrequently explored with neuroimaging. The aim of the present study was to delineate these cavities using magnetic resonance (MR) imaging.

Methods

A total of 71 patients were enrolled in the present study. Following initial examinations with conventional MR sequences, constructive interference in steady-state (CISS) sequence was performed in the coronal and sagittal sections for 60 and 11 patients, respectively.

Results

The coronal CISS images at the level of the aqueduct showed two distinct morphologies of the CV roof, one formed by the fornices with varying degrees of conjugation and the other formed by the corpus callosum with completely separated fornices. Appearance of the CSP was classified into four distinct types. Furthermore, the CVI presented two distinct appearances.

Conclusions

Typically, the CSP, CV, and CVI present with asymptomatic conditions with morphological variabilities. Visualization of the CSP, CV, and CVI using the CISS sequences may be useful when managing lesions affecting these cavities.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xK0iAY

A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

Abstract

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II–IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 10⁵ peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4⁺ and CD8⁺ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

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Does HPV status influence survival after vulvar cancer?

Abstract

High-risk human papillomavirus (HPV) infection is essential in the carcinogenesis of a substantial part of anogenital and oropharyngeal cancers and has additionally been shown to be a possible predictive marker for survival, especially in oropharyngeal cancer. Studies examining the influence of HPV status on survival after vulvar cancer have been conflicting and limited by small study populations. Therefore, the aim of this review and meta-analysis was to examine whether HPV status influences survival after vulvar cancer, which, to our knowledge, has not been done before. We conducted a systematic search of PubMed, Cochrane Library and Embase to identify studies examining survival after histologically verified and HPV tested vulvar cancer. A total of 18 studies were eligible for inclusion. Study-specific and pooled HRs of the 5-year OS and DFS were calculated using a fixed effects model. The I² statistic was used to describe heterogeneity. The studies included a total of 1638 women with HPV tested vulvar cancers of which 541 and 1097 were HPV positive and HPV negative, respectively. Fifteen studies included only squamous cell carcinomas. We found a pooled HR of 0.61 (95%CI: 0.48–0.77) and 0.75 (95%CI: 0.57–1.00) for 5-year OS and DFS, respectively. Across study heterogeneity was moderate to high (OS: I² = 51%; DFS: I² = 73%). In conclusion, women with HPV positive vulvar cancers have a superior survival compared to women with HPV negative, which could be of great clinical interest and provides insight into the differences in the natural history of HPV positive and negative vulvar cancers. This article is protected by copyright. All rights reserved.

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Primordial Odontogenic Tumor: A case report with histopathological analyses

Primordial odontogenic tumor (POT) is a benign mixed epithelial and mesenchymal odontogenic tumor included into the current World Health Organization (WHO) classification of Head and Neck tumours in 2017. As far as the authors have confirmed, only eight cases of this tumor have been reported so far. This paper reports a case of POT that occurred in the right mandible of a 5-year-old patient. Panoramic radiograph showed a well-defined homogeneous radiolucency displacing the unerupted second deciduous molar to the deep part of the mandible. Histopathologically, the tumor was composed of cell-rich mesenchymal tissue with myxoid areas, surrounded by columnar epithelium and non-keratinized cuboidal epithelium in the outer layers. The histopathological diagnosis was POT. The expression patterns of cytokeratins (CK) 14, 18, 19, vimentin and CD34 suggested that the grade of differentiation of the POT was approximately equivalent to that of normal primary tooth germ tissues in cap stage to late bell stage.

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The potential significance of alpha-enolase (ENO1) in lung adenocarcinomas – A utility of the immunohistochemical expression in pathologic diagnosis

We herein analyzed the relationships among the immunohistochemical expression of alpha-enolase (ENO1) and clinicopathological factors in order to define the significance of ENO1 in lung adenocarcinomas (ADCs). ENO1 expression was detected in most of the ADCs examined (95.8%), but not in bronchial and alveolar epithelia. ENO1 expression was typically observed in the cytoplasm among most ADCs (95.8%), but was also detected in the nucleus (56.3%). The levels were significantly higher in terminal respiratory unit (TRU) cytological subtype ADCs. Neither cytoplasmic nor nuclear expression was associated with any other clinicopathological factors including post-operative survival and growth activity. These results suggest that ENO1 is a crucial factor promoting neoplastic transformation exclusively in TRU subtype ADCs. We also investigated the potential utility of the immunohistochemical expression of ENO1 to differentiate TRU-type ADC cells from the reactive hyperplasia of pneumocytes and bronchiolar epithelial cells because difficulties are associated with discriminating these lesions in small biopsy specimens. The sensitivity and specificity of ENO1 (cytoplasmic/nuclear) were 87.5%/37.5% and 88.9%/100%, respectively, which are superior to those of p53 (18.8% and 100%). ENO1 has potential as a biomarker to assist in the histopathological detection of TRU subtype ADC cells.

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A Case of Congenital Infantile Fibrosarcoma of the Bowel Presenting as a Neonatal Intussusception

Neonatal intussusception of the intestinal tract is rare. However, most neonatal intussusceptions have an organic lead point. For the lead point to be a neoplasm is extremely rare. We report a case that presented with neonatal intussusception with a congenital infantile fibrosarcoma as the lead point. The detection of ETV6-NTRK3 gene fusion was useful, although the definitive diagnosis was achieved by a comprehensive evaluation including this gene analysis, standard histology and immunohistochemistry. Neonatal intussusception should be suspected to be caused by a neoplasm. If pathological diagnosis is difficult, molecular analysis should be utilized to diagnose congenital infantile fibrosarcoma.

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Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study

Abstract

Introduction

We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β₂-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.

Methods

This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV₁) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV₁ at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.

Results

In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV₁ at week 8 [FEV₁ change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV₁ at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34–3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.

Conclusion

In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV₁ at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.

Trial Registration

ClinicalTrials.gov identifier NCT02799784.

Funding

GlaxoSmithKline.

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