Αρχειοθήκη ιστολογίου

Κυριακή 23 Δεκεμβρίου 2018

Reporting of Sample Size Parameters in Randomized Controlled Trials Published in Prosthodontic Journals

ABSTRACT

Purpose

An important consideration in the proper planning of randomized controlled trials (RCTs) is the determination of sample size. A study may fail to answer its research question if the sample size is inadequate, while a large enough sample size may be impractical to implement. The purpose of this study is to describe the reporting of sample size methodology and parameters used in RCTs published in prosthodontic journals.

Materials and Methods

A MEDLINE search for publications categorized as RCTs was conducted for articles in The Journal of Prosthodontics and The Journal of Prosthetic Dentistry published from 2008–2017. The Abstract and Methodology sections of RCTs identified were reviewed, and the following data recorded: reporting of method used to calculate sample size and reporting of parameters used for sample size calculation ‐ type I error (α), type II error (β) or power, minimal clinically relevant difference (MCRD), and variability.

Results

The search strategy retrieved 96 articles; 42 met inclusion criteria for RCTs and were reviewed. Fifty percent (21) of RCTs reported how sample size was determined, but only 17% (7) of RCTs reported all 4 parameters. Type I error (α) was reported in 90% (38) of RCTs, 38% (16) reported power, while only 26% (11) and 12% (5) reported MCRD and variability, respectively.

Conclusion

Methodology and parameters used for sample size determination are inadequately reported in RCTs published in prosthodontic journals.

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Cognitive impairment and drug responsiveness in mesial temporal lobe epilepsy.

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Cognitive impairment and drug responsiveness in mesial temporal lobe epilepsy.

Epilepsy Behav. 2018 Dec 18;90:162-167

Authors: Celiker Uslu S, Yuksel B, Tekin B, Sariahmetoglu H, Atakli D

Abstract
OBJECTIVES: Mesial temporal lobe epilepsy (MTLE) is the most common form of partial epilepsies. Seizures of MTLE with hippocampal sclerosis (MTLE-HS) are typically resistant to antiepileptic drug (AED) therapy. Although memory disturbances in patients with MTLE-HS are expected, verbal attention and frontal lobe functions may also be impaired. We aimed to examine the relationship between the clinical features and cognitive functions of patients by comparing cognitive test scores of patients with MTLE with few seizures (drug-responsive group) and those with frequent seizures (pharmacoresistant group).
METHODS: Seventy-nine patients with MTLE-HS and 30 healthy controls were enrolled. Thirty-four patients were accepted as the drug-responsive group (DrG), and 45 patients were included in the pharmacoresistant group (PRG). Tests evaluating attention, memory, and executive functions were performed on all participants.
RESULTS: Forty-nine (62%) female and 30 (38%) male patients with MTLE-HS, and 14 (46.7%) female and 16 (53.3%) male controls participated in the study. The mean age of the patients and controls was 33.53 ± 9.60 (range, 18-57) years and 35.90 ± 7.98 (range, 18-56) years, respectively. Both the DrG and PRG showed poorer performances in tests evaluating memory and frontal lobe functions when compared with the control group (CG). Additionally, attention test results were significantly worse in the PRG than in the DrG.
CONCLUSION: It is reasonable to say that increased seizure frequency is the main causative factor of verbal attention deficit due to the poorer attention test results in the PRG. Poor performances in memory and frontal lobe function tests of all patients with MTLE-HS emphasized the importance of the mutual connection between the temporal lobe and prefrontal cortices.

PMID: 30576963 [PubMed - as supplied by publisher]



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Seizure-precipitating factors in dogs with idiopathic epilepsy.

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Seizure-precipitating factors in dogs with idiopathic epilepsy.

J Vet Intern Med. 2018 Dec 21;:

Authors: Forsgård JA, Metsähonkala L, Kiviranta AM, Cizinauskas S, Junnila JJT, Laitinen-Vapaavuori O, Jokinen TS

Abstract
BACKGROUND: Stress, sleep deprivation, and infectious diseases are important seizure-precipitating factors in human epilepsy patients. However, these factors have not been thoroughly studied in epileptic dogs.
OBJECTIVE: Seizure-precipitating factors are common in dogs with idiopathic epilepsy and the occurrence of these factors associate with the dogs' signalment, personality, and epilepsy-related factors.
ANIMALS: Fifty dogs with diagnosed idiopathic epilepsy from the hospital populations of University Veterinary Teaching Hospital of University of Helsinki and Referral Animal Hospital Aisti.
METHODS: In a retrospective cross-sectional observational study, owners were interviewed about their dogs' possible seizure-precipitating factors according to a predefined questionnaire. The dogs were identified and selected by searching the medical records of the participating animal hospitals.
RESULTS: The prevalence of seizure-precipitating factors in the study population was 74% (37/50). The most frequently reported factors included stress-related situations, sleep deprivation, weather, and hormonal factors. In dogs with focal onset seizures, the number of precipitating factors was 1.9 (95% CI 1.1-3.4) times higher compared to dogs with generalized seizures.
CONCLUSIONS AND CLINICAL IMPORTANCE: Seizure-precipitating factors are common in dogs with idiopathic epilepsy, and the nature of these factors is consistent with those of human patients. Aside from antiepileptic medication, acknowledging and avoiding seizure-precipitating factors could help veterinarians achieve better treatment outcomes.

PMID: 30576009 [PubMed - as supplied by publisher]



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Feed-forward and Feedback Control in Astrocytes for Ca2+-based Molecular Communications Nanonetworks.

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Feed-forward and Feedback Control in Astrocytes for Ca2+-based Molecular Communications Nanonetworks.

IEEE/ACM Trans Comput Biol Bioinform. 2018 Dec 18;:

Authors: Barros M, Dey S

Abstract
Synaptic plasticity depends on the gliotransmitters' concentration in the synaptic channel. And, an abnormal concentration of gliotransmitters is linked to neurodegenerative diseases, including Alzheimer's, Parkinson's, and epilepsy. In this paper, a theoretical investigation of the cause of the abnormal concentration of gliotransmitters and how to achieve its control is presented through a Ca2+-signalling-based molecular communications framework. A feed-forward and feedback control technique is used to manipulate IP3 values to stabilise the concentration of Ca2+ inside the astrocytes. The theoretical analysis of the given model aims i) to stabilize the Ca2+ concentration around a particular desired level in order to prevent abnormal gliotransmitters' concentration (extremely high or low concentration can result in neurodegeneration), ii) to improve the molecular communication performance that utilises Ca2+ signalling, and maintain gliotransmitters' regulation remotely. It shows that the refractory periods from Ca2+ can be maintained to lower the noise propagation resulting in smaller time-slots for bit transmission, which can also improve the delay and gain performances. The proposed approach can potentially lead to novel nanomedicine solutions for the treatment of neurodegenerative diseases, where a combination of nanotechnology and gene therapy approaches can be used to elicit the regulated Ca2+ signalling in astrocytes, ultimately improving neuronal activity.

PMID: 30575545 [PubMed - as supplied by publisher]



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The effects of Bu Yang Huan Wu Tang on post-stroke epilepsy: a nationwide matched study.

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The effects of Bu Yang Huan Wu Tang on post-stroke epilepsy: a nationwide matched study.

Clin Epidemiol. 2018;10:1839-1850

Authors: Weng SW, Chen TL, Yeh CC, Lane HL, Liao CC, Shih CC

Abstract
Objective: To compare the long-term risk of epilepsy in stroke patients who use Bu Yang Huan Wu Tang (BYHWT) and those who do not.
Methods: In the Taiwanese national insurance claims data, we identified newly diagnosed stroke patients receiving inpatient care in the years 2000-2004. Using propensity score-matched pairs to balance the baseline characteristics, we selected eligible stroke patients who did (n=8,971) and did not (n=8,971) receive BYHWT. These two groups were followed up until the end of 2009 to track the occurrence of epilepsy. We used Cox proportional hazard models to calculate the adjusted HRs and 95% CIs for post-stroke epilepsy during the follow-up period according to BYHWT use.
Results: Compared with the control group, stroke patients with BYHWT had a reduced risk of epilepsy during the 5-9 years of the follow-up period (HR 0.69, 95% CI 0.61-0.77). The association between BYHWT and reduced post-stroke epilepsy was significant in various subgroups of stroke patients. There was a dose-dependent decrease in the frequency of epilepsy with increasing quantities of BYHWT use from 1 package (HR 0.77, 95% CI 0.66-0.90) to ≥6 packages (HR 0.52, 95% CI 0.42-0.65).
Conclusion: Stroke patients who received BYHWT therapy had a reduced long-term risk of epilepsy, and the beneficial effect could be observed in various subgroups. However, future clinical trials will be necessary to corroborate the present findings and identify the biochemical mechanism involved.

PMID: 30573993 [PubMed]



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Postoperative Outcomes of Magnetic Resonance Imaging (MRI)-Guided Laser Interstitial Thermal Therapy (LITT) in the Treatment of Drug-Resistant Epilepsy: A Meta-Analysis.

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Postoperative Outcomes of Magnetic Resonance Imaging (MRI)-Guided Laser Interstitial Thermal Therapy (LITT) in the Treatment of Drug-Resistant Epilepsy: A Meta-Analysis.

Med Sci Monit. 2018 Dec 21;24:9292-9299

Authors: Xue F, Chen T, Sun H

Abstract
BACKGROUND Drug-resistant epilepsy is a common neurological disease in adults and children. This study aimed to undertake a systematic review of the literature with meta-analysis of the data from published studies to assess the effectiveness of magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (LITT) in treatment-resistant epilepsy. MATERIAL AND METHODS The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, MEDLINE, and EMBASE databases were systematically searched for indexed publications in the English language up to May 2018. Data on the prevalence, outcome using the Engel Epilepsy Surgery Outcome Scale (Class I to IV), and postoperative complications were analyzed with 95% confidence intervals (CIs). The Methodological Index for Non-Randomized Studies (MINORS) was used to assess the risk of bias in the included studies. RESULTS Sixteen published studies that included a total of 269 patients with treatment resistant epilepsy were identified. The prevalence of Engel Class I, II, III and IV were 61% (95% CI, 0.54-0.68; I²=14.5%; P=0.302), 12% (95% CI, 0.07-0.16; I²=86.8%; P=0.000), 16% (95% CI, 0.10-0.22; I²=3.0%; P=0.397), and 15% (95% CI, 0.08-0.22; I²=13.2%; P=0.330), respectively. The prevalence of postoperative complications was 24% (95% CI, 0.16-0.32; I2=0%; P=0.629). CONCLUSIONS Meta-analysis of data from 16 studies that included 269 patients with treatment-resistant epilepsy showed that MRI-guided LITT significantly reduced the frequency of seizures and reduced postoperative complications, supporting the safety and effectiveness of MRI-guided LITT in the treatment of drug-resistant epilepsy.

PMID: 30573725 [PubMed - in process]



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Predicting de novo psychopathology after epilepsy surgery: A 3-year cohort study.

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Predicting de novo psychopathology after epilepsy surgery: A 3-year cohort study.

Epilepsy Behav. 2018 Dec 17;:

Authors: Novais F, Pestana LC, Loureiro S, Andrea M, Figueira ML, Pimentel J

Abstract
OBJECTIVE: The aim of this study was to determine the potential risk factors for de novo psychiatric syndromes after epilepsy surgery.
METHODS: Refractory epilepsy surgery candidates were recruited from our Refractory Epilepsy Reference Centre. Psychiatric evaluations were made before surgery and every year, during a 3-year follow-up period. Demographic, psychiatric, and neurological data were recorded. The types of surgeries considered were resective surgery (resection of the epileptogenic zone) and palliative surgery (deep brain stimulation of the anterior nuclei of the thalamus (ANT-DBS)). A survival analysis model was used to determine pre- and postsurgical predictors of de novo psychiatric events after surgery.
RESULTS: One hundred and six people with refractory epilepsy submitted to epilepsy surgery were included. Sixteen people (15%) developed psychiatric disorders that were never identified before surgery. Multilobar epileptogenic zone (p = 0.001) and DBS of the ANT-DBS (p = 0.003) were found to be significant predictors of these events.
CONCLUSION: People with more generalized epileptogenic activity and those who undergo ANT-DBS seem to present an increased susceptibility for the development of mental disorders, after neurosurgical interventions, for the treatment of refractory epilepsy. People considered to be at higher risk should be submitted to more frequent routine psychiatric assessments.

PMID: 30573340 [PubMed - as supplied by publisher]



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'I hate wasting the hospital's time': Experiences of emergency department admissions of Australian people with epilepsy.

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'I hate wasting the hospital's time': Experiences of emergency department admissions of Australian people with epilepsy.

Epilepsy Behav. 2018 Dec 17;:

Authors: Peterson CL, Walker C, Coleman H

Abstract
AIM: This paper investigates the reasons and extent of hospital emergency department (ED) attendance by people with epilepsy in Wave 4 of The Australian Longitudinal Survey 2016-17.
METHOD: Wave 4 had 393 respondents who completed the survey, which included questions relating to their use of hospital and healthcare services. Of these, 121 (31%; 82 females) reported one or more admissions to the ED within the previous 12 months. We conducted a mixed methods analysis - using quantitative measures to explore the type and number of admissions, factors relating to increased admissions, and a qualitative approach to explore respondent experiences of their admissions.
RESULTS: Over half of the admissions reported were seizure-related, including injuries occurring as a result of seizures. More than 15% of respondents had more than four ED visits during the preceding 12 months of the survey. Those who had experienced seizures within the previous 12 months, irrespective of frequency, were more likely to have attended the ED compared with those who had not experienced a recent seizure. Self-reported income was another major factor in ED use. Experiences of hospitalization demonstrated frustration at being taken to the ED, loss of autonomy, and experiences of inappropriate care due to poor understanding of epilepsy. Some respondents did not want to waste the ED time as they felt that a rest was all they needed following a seizure.
DISCUSSION: The rates of hospitalization for seizure-related reasons are in line with the findings of other epilepsy-related studies, as is the increased hospitalization rate of those from less well-off backgrounds. This study provided a valuable picture of the opinions and attitudes of people with epilepsy towards their healthcare services.
CONCLUSION: While this is an analysis of a small cohort, the consistency of reported experiences suggests that ED is not always felt to be appropriate following a seizure, and misunderstanding around the appropriate treatment of epilepsy continues in healthcare services.

PMID: 30573339 [PubMed - as supplied by publisher]



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Case report of a novel PCDH19 frameshift mutation in a girl with epilepsy and mental retardation limited to females.

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Case report of a novel PCDH19 frameshift mutation in a girl with epilepsy and mental retardation limited to females.

Medicine (Baltimore). 2018 Dec;97(51):e13749

Authors: Zhang X, Chen N, Ma A, Wang X, Sun W, Gao Y

Abstract
RATIONALE: Epilepsy with mental retardation limited to females (EFMR) is a rare type of X-linked epilepsy disorder, affecting heterozygous females disproportionately. The pathogenesis of EFMR has been identified as mutations in the protocadherin 19 (PCDH19) gene. To data, more than 60 different mutations in PCDH19 have been identified. Most of them are located at exon 1, but we describe a novel deletion mutation c.2468delT at exon 3 of PCDH19.
PATIENT CONCERNS: The patient was an 11-year-old girl with onset of seizures at the age of 18 months and followed by progressive intellectual disability (ID) later.
DIAGNOSIS: The girl was diagnosed as EFMR when a novel deletion mutation c.2468delT at exon 3 of PCDH19 was found. The deletion mutation c.2468delT was predicted to have caused a frameshift mutation of amino acid at position 823 (p.L823fs). There was no family history of seizures or ID. Her father was asymptomatic, but the mutation screening shows that he had a hemizygous mutation c.2468delT at the same site of PCDH19. The secondary structure of PCDH19 (wide type) showed that the sequences undergoing frameshift mutations were located in the cytoplasm and contain 9 phosphorylation sites. The p.L823fs mutation caused a totally different amino sequence after position of 823, thereby resulting in the disappearance of phosphorylation sites. The frameshift mutation of amino acid at position 823 might affect its binding capability with GABAA receptor and results in migration and morphological maturation of hippocampal neurons.
INTERVENTIONS: The patient has received antiepileptic treatments, including sodium valproate, carbamazepine, levetiracetam, topiramate and clonazepam et al. OUTCOMES:: The antiepileptic treatment effects were limited.
LESSONS: This case report describes a novel PCDH19 gene mutation (c.2468delT) at exon 3 in a girl suffering from EFMR. The deletion mutation was predicted to cause a frameshift mutation-p.L823fs, which is highly conserved across different species.

PMID: 30572518 [PubMed - in process]



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Dysembryoplastic neuroepithelial tumours: clinical, radiological, pathological features and outcome.

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Dysembryoplastic neuroepithelial tumours: clinical, radiological, pathological features and outcome.

Br J Neurosurg. 2018 Aug;32(4):436-441

Authors: Isler C, Erturk Cetin O, Ugurlar D, Ozkara C, Comunoglu N, Kizilkilic O, Oz B, Kayadibi Y, Tanriverdi T, Uzan M

Abstract
OBJECT: To analyse the clinical, imaging and histopathological data of patients who were diagnosed to have Dysembrioplastic Neuroepithelial Tumour (DNET) and underwent surgery between 1995-2015.
MATERIALS AND METHODS: Age at seizure onset, age at surgery, gender, disease duration, seizure outcome of 44 patients were analysed together with Magnetic Resonance Imaging (MRI) of 21 patients. MRI types were classified as type 1 (cystic/polycystic-like, well-delineated, strongly hypointense T1), type 2 (nodularlike,heterogeneous), type 3 (dysplastic-like, iso/hyposignal T1, poor delineation, gray-white matter blurring).
RESULTS: Histopathological classification revealed simple form in 19, complex in 14 and non-specific in 11 patients. Lobar distribution of the lesions was as follows: 21 Temporal (47.7%), 12 parietal (27.3%), 8 frontal (18.2%) and 3 occipital (6.8%). Type 1 MRI was observed in 10, type 2 was in 7, and type 3 in 4 patients on radiological evaluation. All cases with type 1 MRI corresponded to either simple or complex forms and all cases with type 3 MRI corresponded to nonspecific form. The histopathological distribution of cases with type 2 MRI was 4 as non-specific, 2 as simple, 1 as complex. There was no significant difference in the age of onset, age at operation and duration of epilepsy between the patients with different MRI subtypes. The majority of patients (N:36) had Engel I outcome (81,8%). In groups with Engel II and III outcome, duration of epilepsy was significantly higher (p:0,014) and simple form of DNET has significantly higher seizure freedom after surgery compared to complex and nonspecific forms of DNET (p:0,002).
CONCLUSION: Patients with DNET constitute a group with favorable outcomes after epilepsy surgery especially with early referral to surgery. Longer duration of epilepsy was associated with worse seizure outcome for DNET patients. There was significant correlation between radiological and histopathological types of DNET especially in type 1 and 3.

PMID: 29792345 [PubMed - indexed for MEDLINE]



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Intense olfactory stimulation blocks seizures in an experimental model of epilepsy.

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Intense olfactory stimulation blocks seizures in an experimental model of epilepsy.

Epilepsy Behav. 2018 02;79:213-224

Authors: Delfino-Pereira P, Bertti-Dutra P, de Lima Umeoka EH, de Oliveira JAC, Santos VR, Fernandes A, Marroni SS, Del Vecchio F, Garcia-Cairasco N

Abstract
There are reports of patients whose epileptic seizures are prevented by means of olfactory stimulation. Similar findings were described in animal models of epilepsy, such as the electrical kindling of amygdala, where olfactory stimulation with toluene (TOL) suppressed seizures in most rats, even when the stimuli were 20% above the threshold to evoke seizures in already kindled animals. The Wistar Audiogenic Rat (WAR) strain is a model of tonic-clonic seizures induced by acute acoustic stimulation, although it also expresses limbic seizures when repeated acoustic stimulation occurs - a process known as audiogenic kindling (AK). The aim of this study was to evaluate whether or not the olfactory stimulation with TOL would interfere on the behavioral expression of brainstem (acute) and limbic (chronic) seizures in the WAR strain. For this, animals were exposed to TOL or saline (SAL) and subsequently exposed to acoustic stimulation in two conditions that generated: I) acute audiogenic seizures (only one acoustic stimulus, without previous seizure experience before of the odor test) and II) after AK (20 acoustic stimuli [2 daily] before of the protocol test). We observed a decrease in the seizure severity index of animals exposed only to TOL in both conditions, with TOL presented 20s before the acoustic stimulation in both protocols. These findings were confirmed by behavioral sequential analysis (neuroethology), which clearly indicated an exacerbation of clusters of specific behaviors such as exploration and grooming (self-cleaning), as well as significant decrease in the expression of brainstem and limbic seizures in response to TOL. Thus, these data demonstrate that TOL, a strong olfactory stimulus, has anticonvulsant properties, detected by the decrease of acute and AK seizures in WARs.

PMID: 29346088 [PubMed - indexed for MEDLINE]



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Verbal learning and memory outcome in selective amygdalohippocampectomy versus temporal lobe resection in patients with hippocampal sclerosis.

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Verbal learning and memory outcome in selective amygdalohippocampectomy versus temporal lobe resection in patients with hippocampal sclerosis.

Epilepsy Behav. 2018 02;79:180-187

Authors: Foged MT, Vinter K, Stauning L, Kjær TW, Ozenne B, Beniczky S, Paulson OB, Madsen FF, Pinborg LH, Danish Epilepsy Surgery Group

Abstract
PURPOSE: With the advent of new very selective techniques like thermal laser ablation to treat drug-resistant focal epilepsy, the controversy of resection size in relation to seizure outcome versus cognitive deficits has gained new relevance. The purpose of this study was to test the influence of the selective amygdalohippocampectomy (SAH) versus nonselective temporal lobe resection (TLR) on seizure outcome and cognition in patients with mesial temporal lobe epilepsy (MTLE) and histopathological verified hippocampal sclerosis (HS).
METHODS: We identified 108 adults (>16years) with HS, operated between 1995 and 2009 in Denmark. Exclusion criteria are the following: Intelligence below normal range, right hemisphere dominance, other native languages than Danish, dual pathology, and missing follow-up data. Thus, 56 patients were analyzed. The patients were allocated to SAH (n=22) or TLR (n=34) based on intraoperative electrocorticography. Verbal learning and verbal memory were tested pre- and postsurgery.
RESULTS: Seizure outcome did not differ between patients operated using the SAH versus the TLR at 1year (p=0.951) nor at 7years (p=0.177). Verbal learning was more affected in patients resected in the left hemisphere than in the right (p=0.002). In patients with left-sided TLR, a worsening in verbal memory performance was found (p=0.011). Altogether, 73% were seizure-free for 1year and 64% for 7years after surgery.
CONCLUSION: In patients with drug-resistant focal MTLE, HS and no magnetic resonance imaging (MRI) signs of dual pathology, selective amygdalohippocampectomy results in sustained seizure freedom and better memory function compared with patients operated with nonselective temporal lobe resection.

PMID: 29306849 [PubMed - indexed for MEDLINE]



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Patients' perspectives on management and barriers of regular antiepileptic drug intake.

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Patients' perspectives on management and barriers of regular antiepileptic drug intake.

Epilepsy Behav. 2018 02;79:162-168

Authors: May TW, Berkenfeld R, Dennig D, Scheid B, Hausfeld H, Walther S, Specht U

Abstract
PURPOSE: The aim of our study was to assess the management of drug intake and potential barriers to adherence reported by two different patient groups.
METHODS: The study was performed in cooperation with the Regional Chamber of Pharmacists of Rhineland-Palatinate and three neurologists in private practice specialized in epileptology. In total, 108 patients surveyed in 43 pharmacies (Group P) and 118 patients treated by the specialized neurologists (Group N) completed anonymously a questionnaire on intake of antiepileptic drugs (AEDs). The statistical evaluation was performed using nonparametric tests and logistic regression analyses.
RESULTS: Group N more often used adherence aids, compared with Group P (68.6% vs. 46.3%, p<0.01), and the number of doses per day was significantly lower in Group N (Mann-Whitney test, p=0.046), but the percentage of patients who reported problems with the regular intake of their medication did not differ significantly between groups (Group N vs. P: 47.0% vs. 40.0%). If patients noticed that they missed a dose, 45.3% completely skipped the missed dose (Group N vs. P: 43.0% vs. 48.1%, n.s.). In a multivariate analysis, significant risk factors of problems with regular drug intake were age<25yrs. (p<0.01) and patient-reported adverse effect of AED (p<0.01), followed by the number of AED doses per day (p<0.05), while gender, intake habits, usage of adherence aids, and patient-rated efficacy of AEDs were not significant.
CONCLUSION: Patients treated by neurologists specialized in epileptology did not report less problems with adherence than patients surveyed in pharmacies. Since barriers for a regular intake are diverse, the use of a short questionnaire on management of drug intake may lead to an individually tailored counseling of patients to improve adherence.

PMID: 29291547 [PubMed - indexed for MEDLINE]



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Clinical correlates of negative health events in a research sample with epilepsy.

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Clinical correlates of negative health events in a research sample with epilepsy.

Epilepsy Behav. 2018 02;79:225-229

Authors: Kumar N, Colon-Zimmermann K, Fuentes-Casiano E, Liu H, Tatsuoka C, Cassidy KA, Kahriman M, Chen P, Sajatovic M

Abstract
AIMS: In spite of advances in care, people with epilepsy experience negative health events (NHEs), such as seizures, emergency department (ED) visits, and hospitalizations. Being able to identify characteristics that are associated with NHE risk can help inform care approaches that reduce complications and burden. This analysis using baseline data from a larger randomized epilepsy self-management clinical trial assessed the relationship between demographic and clinical variables vs. seizure-related complications among people with epilepsy.
METHODS: Data were derived from a baseline sample of a larger prospective study of 120 individuals with epilepsy who experienced an NHE within the last 6months. Demographic characteristics, depression assessed with the 9-item Patient Health Questionnaire (PHQ-9) and the Montgomery-Asberg Depression rating scale (MADRS), quality of life assessed with the 10-item Quality of Life in Epilepsy Inventory (QOLIE-10), self-efficacy assessed the Epilepsy Self-Efficacy Scale (ESES), social support assessed with the Multidimensional Scale of Perceived Social Support (MSPSS), self-management assessed with the Epilepsy Self-Management Scale (ESMS), and stigma assessed with the Epilepsy Stigma Scale (ESS) were all examined in association with past 6-month NHE frequency and 30-day seizure frequency.
RESULTS: Except for lower levels of education and lower levels of income being associated with higher 30-day and 6-month seizure frequency, demographic variables were generally not significantly associated with NHEs. Higher 30-day seizure frequency was associated with greater depression severity on PHQ-9 (p<0.01) and MADRS (p<0.01). Higher 6-month seizure frequency was also associated with greater depression severity on PHQ-9 (p<.001) and MADRS (p=0.03). Both 30-day and 6-month seizure frequency were significantly negatively associated with QOLIE-10 (p<0.001). Both 30day (p=0.01) and 6-month (p=0.03) seizure frequency were associated with worse stigma on ESS. Total NHE count was associated with more severe depression on PHQ-9 (p=0.02), and MADRS (p=0.04), worse quality of life on QOLIE-10 (p<0.01), and more stigma on ESS (p=0.03).
CONCLUSIONS: Consistent with previous literature, more frequent seizures were associated with worse depression severity and quality of life. A finding that is less established is that higher seizure frequency is also associated with worse epilepsy-related stigma. Epilepsy self-management approaches need to address depression and stigma as well as seizure control.

PMID: 29279188 [PubMed - indexed for MEDLINE]



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Evaluation of the "non-epileptic" patient in a tertiary center epilepsy clinic.

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Evaluation of the "non-epileptic" patient in a tertiary center epilepsy clinic.

Epilepsy Behav. 2018 02;79:100-105

Authors: Pana R, Labbé A, Dubeau F, Kobayashi E

Abstract
PURPOSE: The epilepsy clinic at the Montreal Neurological Institute receives a high volume of referrals. Despite most patients assessed in the clinic eventually being diagnosed with epilepsy, other disorders causing alteration of consciousness or paroxystic symptoms that could be misdiagnosed as seizures are seen frequently. The incidence and clinical characteristics of such patients have not yet been determined. We aimed to determine the proportion and clinical characteristics of patients referred to our epilepsy clinic who had a final diagnosis other than epilepsy.
METHODS: We performed a retrospective chart analysis of consecutive patient referrals to the epilepsy clinic from January 2013 to January 2015, inclusively.
RESULTS: Four hundred four patient referrals were evaluated, 106 (or 26%) had a final diagnosis other than epilepsy. Referrals came primarily from general practitioners and nonneurology specialists. Although most patients had a normal routine electroencephalography (EEG) prior to the clinic visit, sleep-deprived EEG and cardiac investigations were rarely performed. Patients received a final diagnosis other than epilepsy after 1 to 2 visits in 92% of cases and with minimal paraclinical investigations. Prolonged video-EEG recording was required in 27% of patients. The most common diagnoses were syncope (33%), psychiatric symptoms (20%), followed by migraine (10%), and psychogenic nonepileptic seizures (9%).
CONCLUSIONS: A significant proportion of patients seen in our tertiary care epilepsy clinic is in fact, not patients with epilepsy. Enhanced knowledge of these differential diagnosis and important anamnesis components to rule out seizures will help improve guidelines for referral to Epilepsy clinic and cost-effectively optimize the use of paraclinical investigations.

PMID: 29268170 [PubMed - indexed for MEDLINE]



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Does Valproic Acid/Na Valproate Suppress Auditory Startle Reflex in Patients With Epilepsy?

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Does Valproic Acid/Na Valproate Suppress Auditory Startle Reflex in Patients With Epilepsy?

Clin EEG Neurosci. 2018 Nov;49(6):407-413

Authors: Kızıltan ME, Leba LK, Gündüz A, Pazarcı N, Özkara Ç, Yeni N

Abstract
BACKGROUND AND OBJECTIVE: Auditory startle response (ASR) was normal in juvenile myoclonic epilepsy whereas it was suppressed in progressive myoclonic epilepsy. However, both groups were using valproic acid/Na valproate (VPA) in different doses. Therefore, we aimed to analyze whether VPA has an impact on ASR in a cohort of epilepsy. For this purpose, we included patients with epilepsy and analyzed ASR in patients who were using VPA.
PATIENTS AND METHOD: We included 51 consecutive patients who had epilepsy and were using VPA between January 2014 and January 2016. Two control groups of 37 epilepsy patients using other antiepileptic drugs (AEDs) and of 25 healthy subjects were also constituted. All participants underwent investigations of ASR and startle response to somatosensory inputs (SSS) under similar conditions.
RESULTS: An analysis of patients using VPA, not using VPA and healthy subjects revealed significantly longer latency and lower probability of orbicularis oculi (O.oc) and sternocleidomastoid responses after auditory stimulation, decreased total ASR probability and longer latency of O.oc response after somatosensory stimulation in patient groups compared with healthy subjects. Multivariate analysis showed type of AED had a role in the generation of abnormalities. VPA, carbamazepine, and multiple AED use caused suppression of ASR. Total ASR probability was decreased or O.oc latency got longer with longer duration of VPA use whereas serum VPA level at the time of investigation did not correlate with total ASR probability.
DISCUSSION: Both ASR and SSS are suppressed by the effect of VPA, especially in patients using for a long period and in patients using other AEDs with VPA. Given the fact that VPA leads to long-standing synaptic changes of dopaminergic transmission, abnormalities of this network may be the more likely cause.

PMID: 29262725 [PubMed - indexed for MEDLINE]



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"By working together and caring for one another we can win this fight": A qualitative exploration of a traditional healer's perspectives of care of people with epilepsy in a South African urban township in Cape Town.

Icon for Elsevier Science Related Articles

"By working together and caring for one another we can win this fight": A qualitative exploration of a traditional healer's perspectives of care of people with epilepsy in a South African urban township in Cape Town.

Epilepsy Behav. 2018 02;79:230-233

Authors: Keikelame MJ, Swartz L

Abstract
There is a gap in knowledge about the construction of care in the Global South where biomedical care remains largely inaccessible to many people, resulting in people seeking health care from the indigenous sector of health care. As part of a larger study, in this, article we present findings from a single individual interview with an indigenous healer using a semi-structured interview guide that was based on Kleinman's Explanatory Model Framework. Key themes that emerged from the thematic analysis of our indigenous healer's audio-recorded transcribed transcript were about "care". The four overarching subthemes were the following: (i) care in the family, (ii) care in the community, (iii) care in the health system, and (iv) respondents' construction of care. A key feature of care, for this healer, is its explicit location in lineages of community - care is seen not as an individual or organizational issue, but part of the shared social fabric. We argue that it is crucial to attend to the lay understandings and practices of care which reflect diverse ways of understanding care and relationality in context. Future research is needed to close this gap.

PMID: 29249449 [PubMed - indexed for MEDLINE]



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Protocol for treatment of Achilles tendon ruptures; a systematic review with network meta-analysis

Achilles tendon ruptures are a common injury and are increasing in incidence. Several management strategies exist for both non-operative and operative care, with each strategy offering unique risks and benefit...

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Life satisfaction and positive and negative feelings of workers: a systematic review protocol

In this article, conceptualization of well-being is a starting point. According to Diener, subjective well-being refers to all kinds of evaluation, both positive and negative, people make about their own lives...

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Effect of the duration of antimicrobial exposure on the development of antimicrobial resistance (AMR) for macrolide antibiotics: protocol for a systematic review with a network meta-analysis

Antimicrobial resistance generates a huge health and economic burden and has the potential to become the leading cause of death globally, but its underlying drivers are yet to be fully described. The associati...

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Prediction of exertional lower extremity musculoskeletal injury in tactical populations: protocol for a systematic review and planned meta-analysis of prospective studies from 1955 to 2018

Musculoskeletal injuries (MSI) represent more than half of all injuries in tactical populations (i.e., military service and public safety workers including police, firefighters, emergency medical services (EMS...

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Barriers and facilitating factors in the prevention of diabetes type II and gestational diabetes in vulnerable groups: protocol for a scoping review

There is a significant worldwide increase in type 2 diabetes mellitus and gestational diabetes (T2DM/GDM) linked to a range of associated comorbidities and rising healthcare costs. It has been shown that an in...

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Next-Generation Sequencing-Based Assessment of JAK2, PD-L1, and PD-L2 Copy Number Alterations at 9p24.1 in Breast Cancer: Potential Implications for Clinical Management.

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Next-Generation Sequencing-Based Assessment of JAK2, PD-L1, and PD-L2 Copy Number Alterations at 9p24.1 in Breast Cancer: Potential Implications for Clinical Management.

J Mol Diagn. 2018 Dec 18;:

Authors: Gupta S, Vanderbilt CM, Cotzia P, Arias Stella JA, Chang JC, Zehir A, Benayed R, Nafa K, Razavi P, Hyman DM, Baselga J, Berger MF, Ladanyi M, Arcila ME, Ross DS

Abstract
Genomic amplification at 9p24.1, including the loci for JAK2, PD-L1, and PD-L2, has recently been described as a mechanism of resistance in post-chemotherapy, triple-negative breast cancer. This genomic signature holds significant promise as a prognostic biomarker and has implications for targeted therapy with JAK2 inhibitors, as well as with immunotherapy. To guide future screening strategies, we determined the frequency of these alterations. A total of 5,399 cases were included in the study. This encompassed 2,890 institutional cases tested by the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay and 2,509 cases from The Cancer Genome Atlas (TCGA). The combined incidence of 9p24.1 amplifications in both the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and TCGA cohorts was 1.0% (56 of 5399 cases), and showed a greater than 10-fold higher incidence in triple-negative breast cancer (triple-negative: 5.1%, non-triple-negative: 0. 5%).Tumor mutation burden and stromal tumor infiltrating lymphocytes, parameters used to assess response to immunotherapy, were not significantly higher for these cases. The significance of genomic losses at 9p24.1 is unclear and further studies are needed. Herein, we studied the spectrum of copy number alterations in breast cancer cases within our institutional clinical sequencing cohort and those profiled by TCGA, to determine the frequency of genomic alterations that may predict response or resistance to JAK2 inhibitors and/or immunotherapy.

PMID: 30576871 [PubMed - as supplied by publisher]



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Inter- and intra-tumor heterogeneity of SMAD4 loss in head and neck squamous cell carcinomas.

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Inter- and intra-tumor heterogeneity of SMAD4 loss in head and neck squamous cell carcinomas.

Mol Carcinog. 2018 Dec 21;:

Authors: Hernandez AL, Wang Y, Somerset HL, Keysar SB, Aisner DL, Marshall C, Bowles DW, Karam SD, Raben D, Jimeno A, Varella-Garcia M, Wang XJ

Abstract
Reports regarding the frequency of SMAD4 loss in human head and neck squamous cell carcinoma (HNSCC) vary significantly. We have shown that SMAD4 deletion contributes to HNSCC initiation and progression. Therefore, accurately detecting genetic SMAD4 loss is critical to determine prognosis and therapeutic interventions in personalized medicine. We developed a SMAD4 fluorescence in situ hybridization (FISH) assay to identify chromosomal SMAD4 loss at the single cell level of primary HNSCC specimens and patient derived xenograft (PDX) tumors derived from HNSCCs. SMAD4 heterozygous loss was detected in 35% of primary HNSCCs and 41.3% of PDX tumors. Additionally, 4.3% of PDX tumors had SMAD4 homozygous loss. These frequencies of SMAD4 loss were similar to those in The Cancer Genome Atlas (TCGA). However, we identified significant heterogeneities of SMAD4 loss (partial or complete) among cells within each tumor. We also found that aneuploidy (monosomy and polysomy) contributed greatly to how to define chromosomal SMAD4 deletion. Furthermore, in cultured PDX tumors, SMAD4 mutant cells outcompeted SMAD4 wildtype cells, resulting in establishing homogenous SMAD4 mutant HNSCC cell lines with partial or complete genomic SMAD4 loss, suggesting a survival advantage of SMAD4 mutant cells. Taken together, our study reveals inter- and intra-tumor heterogeneities of SMAD4 chromosomal loss in HNSCCs. Further, SMAD4 FISH assay provides a platform for future clinical diagnosis of SMAD4 chromosomal loss that potentially serves as a molecular marker for prognosis and therapeutic intervention in cancer patients. This article is protected by copyright. All rights reserved.

PMID: 30575147 [PubMed - as supplied by publisher]



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The VAMPIRE Challenge: A Multi-Institutional Validation Study of CT Ventilation Imaging.

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The VAMPIRE Challenge: A Multi-Institutional Validation Study of CT Ventilation Imaging.

Med Phys. 2018 Dec 21;:

Authors: Kipritidis J, Tahir BA, Cazoulat G, Hofman MS, Siva S, Callahan J, Hardcastle N, Yamamoto T, Christensen GE, Reinhardt JM, Kadoya N, Patton TJ, Gerard SE, Duarte I, Archibald-Heeren B, Byrne M, Sims R, Ramsay S, Booth JT, Eslick E, Hegi-Johnson F, Woodruff HC, Ireland RH, Wild JM, Cai J, Bayouth J, Brock K, Keall PJ

Abstract
PURPOSE: CT ventilation imaging (CTVI) is being used to achieve functional avoidance lung cancer radiation therapy in three clinical trials (NCT02528942, NCT02308709, NCT02843568). To address the need for common CTVI validation tools, we have built the Ventilation And Medical Pulmonary Image Registration Evaluation (VAMPIRE) Dataset, and present the results of the first VAMPIRE Challenge to compare relative ventilation distributions between different CTVI algorithms and other established ventilation imaging modalities.
METHODS: The VAMPIRE Dataset includes 50 pairs of 4DCT scans and corresponding clinical or experimental ventilation scans, referred to as reference ventilation images (RefVIs). The dataset includes 25 humans imaged with Galligas 4DPET/CT, 21 humans imaged with DTPA-SPECT and 4 sheep imaged with Xenon-CT. For the VAMPIRE Challenge, 16 subjects were allocated to a training group (with RefVI provided) and 34 subjects were allocated to a validation group (with RefVI blinded). 7 research groups downloaded the Challenge dataset and uploaded CTVIs based on deformable image registration (DIR) between the 4DCT inhale/exhale phases. Participants used DIR methods broadly classified into B-splines, Free-form, Diffeomorphisms or Biomechanical modeling, with CT ventilation metrics based on the DIR evaluation of volume change, Hounsfield Unit change, or various hybrid approaches. All CTVIs were evaluated against the corresponding RefVI using the voxel-wise Spearman coefficient rS, and Dice similarity coefficients evaluated for low function lung (DSClow) and high function lung (DSChigh).
RESULTS: A total of 37 unique combinations of DIR method and CT ventilation metric were either submitted by participants directly or derived from participant-submitted DIR motion fields using the in-house software, VESPIR. The rS and DSC results reveal a high degree of inter-algorithm and inter-subject variability among the validation subjects, with algorithm rankings changing by up to 10 positions depending on the choice of evaluation metric. The algorithm with the highest overall cross-modality correlations used a biomechanical model based DIR with a hybrid ventilation metric, achieving a median (range) of 0.49 (0.27-0.73) for rS, 0.52 (0.36-0.67) for DSClow and 0.45 (0.28-0.62) for DSChigh. All other algorithms exhibited at least one negative rS value, and/or one DSC value less than 0.5.
CONCLUSIONS: The VAMPIRE Challenge results demonstrate that the cross-modality correlation between CTVIs and the RefVIs vary not only with the choice of CTVI algorithm, but also with the choice of RefVI modality, imaging subject, and the evaluation metric used to compare relative ventilation distributions. This variability may arise from the fact that each of the different CTVI algorithms and RefVI modalities provides a distinct physiologic measurement. Ultimately this variability, coupled with the lack of a 'gold standard,' highlight the ongoing importance of further validation studies before CTVI can be widely translated from academic centers to the clinic. It is hoped that the information gleaned from the VAMPIRE Challenge can help inform future validation efforts. This article is protected by copyright. All rights reserved.

PMID: 30575051 [PubMed - as supplied by publisher]



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HTX-019 via 2-min injection or 30-min infusion in healthy subjects.

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HTX-019 via 2-min injection or 30-min infusion in healthy subjects.

Future Oncol. 2018 Dec 21;:

Authors: Ottoboni T, Lauw M, Keller MR, Cravets M, Manhard K, Clendeninn N, Quart B

Abstract
AIM: HTX-019 (CINVANTI® [aprepitant injectable emulsion]) is a neurokinin 1 receptor antagonist approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 is free of polysorbate 80 and other synthetic surfactants and showed bioequivalence to and a more favorable safety profile than fosaprepitant when administered as a 30-min infusion in healthy subjects. The shortage of small-volume parenteral solutions led to a recommendation to administer HTX-019 by intravenous push. The objectives were to evaluate pharmacokinetics, tolerability and safety following HTX-019 administration by injection versus infusion.
MATERIALS & METHODS: Study comprised Part A, a pilot Phase I, single-center, randomized, pharmacokinetic, safety and tolerability, open-label study, followed by Part B, a two-sequence crossover study of HTX-019 130 mg in healthy adults, via injection and infusion. Blood samples were evaluated for aprepitant pharmacokinetics and bioequivalence. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, clinical laboratory testing and electrocardiograms.
RESULTS: In Part A, 24 subjects were randomly assigned to three cohorts (n = 8 per cohort) and received HTX-019 130 mg, administered intravenously over 15 min (cohort 1), 5 min (cohort 2) or 2 min (cohort 3). Progression to Part B occurred after acceptable tolerability was established in cohorts 2 and 3. In Part B, 50 randomized subjects received a 2-min injection (9 ml/min) and 30-min infusion (296 ml/h) of HTX-019 130 mg. Bioequivalence was demonstrated for HTX-019 injection and infusion. Both administration methods via a peripheral line were well tolerated; 8 subjects experienced 11 TEAEs (6 related) following injection and 9 experienced 14 TEAEs (9 related) following infusion. Headache and fatigue were the most prevalent treatment-related TEAEs; 1 subject per group experienced feeling hot ≤30 min after drug administration.
CONCLUSION: Pharmacokinetic and tolerability profiles of 2-min HTX-019 injection support this potential alternative administration method for CINV prevention.

PMID: 30574797 [PubMed - as supplied by publisher]



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The Impact of the Law in Helping or Hindering Fertility Preservation for Children with Cancer Facing Gonadotoxic Therapies.

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The Impact of the Law in Helping or Hindering Fertility Preservation for Children with Cancer Facing Gonadotoxic Therapies.

J Law Med. 2018 Dec;26(2):322-333

Authors: Allan S, Gook D, Jayasinghe Y

Abstract
Children diagnosed with cancer who require treatment with chemotherapy and/or radiation therapy have ever-increasing survival rates. However, as a result of such treatment they face the added, and significant, burden of infertility into their futures. Options for fertility preservation and future reproduction for such children do exist, but some such options continue to be considered experimental. Collaborative multidisciplinary teams support children and their families to make decisions about such options in the treatment environment. When collection of gonadal tissue from children is consented to in such circumstances, it is subject to stringent institutional clinical and human research ethics review, often in both the pediatric oncology setting and the fertility setting in which it will be preserved, examined and, potentially, used. Laws and guidelines may support the collection and use of reproductive tissue from children for treatment and research, subject to meeting consent requirements concerning the child and/or their parent(s). This article examines such laws across Australia. It also examines the legal complexities found in some jurisdictions that may hinder research and practice, consequently having a negative impact on the prospects for children with cancer, in relation to their fertility preservation and possibilities for future reproduction.

PMID: 30574721 [PubMed - in process]



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Performance measures for endoscopic retrograde cholangiopancreatography and endoscopic ultrasound: A European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative.

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Performance measures for endoscopic retrograde cholangiopancreatography and endoscopic ultrasound: A European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative.

United European Gastroenterol J. 2018 Dec;6(10):1448-1460

Authors: Domagk D, Oppong KW, Aabakken L, Czakó L, Gyökeres T, Manes G, Meier P, Poley JW, Ponchon T, Tringali A, Bellisario C, Minozzi S, Senore C, Bennett C, Bretthauer M, Hassan C, Kaminski MF, Dinis-Ribeiro M, Rees CJ, Spada C, Valori R, Bisschops R, Rutter MD

Abstract
The European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology present a short list of key performance measures for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP). We recommend that endoscopy services across Europe adopt the following seven key and one minor performance measures for EUS and ERCP, for measurement and evaluation in daily practice at centre and endoscopist level: 1 Adequate antibiotic prophylaxis before ERCP (key performance measure, at least 90%); 2 antibiotic prophylaxis before EUS-guided puncture of cystic lesions (key performance measure, at least 95%); 3 bile duct cannulation rate (key performance measure, at least 90%); 4 tissue sampling during EUS (key performance measure, at least 85%); 5 appropriate stent placement in patients with biliary obstruction below the hilum (key performance measure, at least 95%); 6 bile duct stone extraction (key performance measure, at least 90%); 7 post-ERCP pancreatitis (key performance measure, less than 10%); and 8 adequate documentation of EUS landmarks (minor performance measure, at least 90%). This present list of quality performance measures for ERCP and EUS recommended by the ESGE should not be considered to be exhaustive; it might be extended in future to address further clinical and scientific issues.

PMID: 30574315 [PubMed]



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Apalutamide in the treatment of castrate-resistant prostate cancer: evidence from clinical trials.

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Apalutamide in the treatment of castrate-resistant prostate cancer: evidence from clinical trials.

Ther Adv Urol. 2018 Dec;10(12):445-454

Authors: Koshkin VS, Small EJ

Abstract
Apalutamide (ARN-509) is a second-generation androgen receptor (AR) antagonist that was developed to inhibit AR-mediated prostate cancer cell proliferation. Following the initial promising clinical efficacy results in phase I and II clinical trials of patients with metastatic castrate-resistant prostate cancer (CRPC), apalutamide has been investigated in several phase III trials. Particular interest has focused on the development of effective therapy for the prevention of disease progression in patients with nonmetastatic (nm or M0) CRPC, especially patients who have a rapid prostate-specific antigen (PSA) doubling time that is indicative of shorter bone metastasis-free survival and associated with significant morbidity and mortality. The results from the phase III SPARTAN trial were recently published and reported a significant benefit of apalutamide relative to placebo in patients with nmCRPC and a high risk of metastatic progression. The study noted marked improvement in the primary endpoint of metastasis-free survival as well as several relevant secondary clinical endpoints, including time to symptomatic progression. These results led to the United States Food and Drug Administration (US FDA) approval of apalutamide in the nmCRPC setting in February 2018. This review summarizes the clinical development of apalutamide, culminating with the pivotal SPARTAN trial as well as other phase III trials which may further expand potential indications for this agent in the near future.

PMID: 30574205 [PubMed]



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Good local tumor control but lethal hemorrhage after apatinib treatment for intractable squamous carcinoma of the floor of the mouth: a case report.

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Good local tumor control but lethal hemorrhage after apatinib treatment for intractable squamous carcinoma of the floor of the mouth: a case report.

Onco Targets Ther. 2018;11:8909-8913

Authors: Zhu X, Liu M, Lv J, Guo L, Li C, Dong L, Liu B

Abstract
The treatment of repeatedly recurrent carcinoma of the floor of the mouth (FOM) is challenging. There is no standard strategy for such patients with poor physical condition after multiple lines of treatment. Angiogenesis is a key in tumor initiation, growth, and dissemination. Apatinib, a potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), has been approved for the treatment of late-stage gastric or gastroesophageal junction adenocarcinoma that is resistant to at least two lines of chemotherapy. Its application in intractable FOM squamous carcinoma has never been described before. Herein, we present the case of a heavily treated patient with FOM squamous carcinoma undergoing a third local relapse in the right region of the neck and anterior cervical region. Oral apatinib was administered daily at a dose of 250 mg. There was clear and rapid efficacy that led to complete remission. However, giant, deep ulcers formed due to tumor necrosis. The patient eventually died of massive bleeding resulting from the major cervical vascular rupture caused by tumor necrosis and erosion. This case is novel and instructional, highlighting that apatinib might be effective, with manageable toxicity, for certain patients with refractory head and neck squamous cell carcinoma (HNSCC). The advantages and disadvantages of apatinib should be carefully evaluated, and close surveillance and quick intervention as required are critical to reduce fatal cancer-associated complications. The role of apatinib in recurrent or metastatic HNSCC needs to be clarified by multicenter trials in the near future.

PMID: 30573977 [PubMed]



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Rapid diagnosis of IDH1-mutated gliomas by 2-HG detection with gas chromatography mass spectrometry.

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Rapid diagnosis of IDH1-mutated gliomas by 2-HG detection with gas chromatography mass spectrometry.

Lab Invest. 2018 Dec 20;:

Authors: Xu H, Xia YK, Li CJ, Zhang JY, Liu Y, Yi W, Qin ZY, Chen L, Shi ZF, Quan K, Yang ZX, Guan KL, Xiong Y, Ng HK, Ye D, Hua W, Mao Y

Abstract
The metabolic genes encoding isocitrate dehydrogenase (IDH1, 2) are frequently mutated in gliomas. Mutation of IDH defines a distinct subtype of glioma and predicts therapeutic response. IDH mutation has a remarkable neomorphic activity of converting α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which is now commonly referred to as an oncometabolite and biomarker for gliomas. PCR-sequencing (n = 220), immunohistochemistry staining (IHC, n = 220), and gas chromatography mass spectrometry (GC-MS, n = 87) were applied to identify IDH mutation in gliomas, and the sensitivity and specificity of these strategies were compared. PCR-sequencing and IHC staining are reliable for retrospective assessment of IDH1 mutation in gliomas, but both methods usually take 1-2 days, which hinders their application for rapid diagnosis. GC-MS-based methods can detect 2-HG qualitatively and quantitatively, offering information on the IDH1 mutation status in gliomas with the sensitivity and specificity being 100%. Further optimization of the GC-MS based methodology (so called as the mini-column method) enabled us to determine 2-HG within 40 min in glioma samples without complex or time-consuming preparation. Most importantly, the ratio of 2-HG/glutamic acid was shown to be a reliable parameter for determination of mutation status. The mini-column method enables rapid identification of 2-HG, providing a promising strategy for intraoperative diagnosis of IDH1-mutated gliomas in the future.

PMID: 30573870 [PubMed - as supplied by publisher]



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Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma.

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Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma.

Blood. 2018 Dec 20;:

Authors: Opstal-van Winden AWJ, de Haan HG, Hauptmann M, Schmidt MK, Broeks A, Russell NS, Janus CPM, Krol ADG, van der Baan FH, De Bruin ML, van Eggermond AM, Dennis J, Anton Culver H, Haiman CA, Sawyer EJ, Cox A, Devilee P, Hooning MJ, Peto J, Couch FJ, Pharoah P, Orr N, Easton DF, Aleman BMP, Strong LC, Bhatia S, Cooke R, Robison LL, Swerdlow AJ, van Leeuwen FE

Abstract
Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211,155 germline single nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4,671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate <20%), of which one SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a 4-fold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.

PMID: 30573632 [PubMed - as supplied by publisher]



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Incidence of cirrhosis in young birth cohorts in Canada from 1997 to 2016: a retrospective population-based study.

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Incidence of cirrhosis in young birth cohorts in Canada from 1997 to 2016: a retrospective population-based study.

Lancet Gastroenterol Hepatol. 2018 Dec 17;:

Authors: Flemming JA, Dewit Y, Mah JM, Saperia J, Groome PA, Booth CM

Abstract
BACKGROUND: Recent data show that the prevalence of chronic liver disease and cirrhosis is increasing in adolescents and young adults in the USA. We aimed to describe the epidemiology of cirrhosis using an age-period-cohort approach to define birth-cohort effects on the incidence of cirrhosis in Ontario, Canada.
METHODS: We did a retrospective population-based cohort study in Ontario, Canada, using linked administrative health data from the databases of ICES, formerly the Institute for Clinical Evaluative Sciences. Patients aged at least 18 years with cirrhosis were identified by use of a validated case definition (defined as at least one inpatient or outpatient visit with a diagnosis of cirrhosis or oesophageal varices without bleeding). We calculated annual standardised incidence and prevalence in the general population. We used an age-period-cohort approach to assess the independent association between birth cohort and incidence of cirrhosis in men and women.
FINDINGS: Between Jan 1, 1997, and Dec 31, 2016, 165 979 individuals with cirrhosis were identified. The age-standardised incidence increased over the study (from 70·6 per 100 000 person-years in 1997 to 89·6 per 100 000 person-years in 2016) as did the prevalence (from 0·42% in 1997 to 0·84% in 2016). Using age-period-cohort modelling and the median birth year as the reference, the incidence of cirrhosis was higher in participants born in 1980 (incidence rate ratio 1·55, 95% CI 1·50-1·59, p<0·0001); and in participants born in 1990 (2·16, 95% CI 2·06-2·27, p<0·0001) compared with a person of the same age born in 1951. The increase in incidence of cirrhosis was greater in women than in men (eg, women born in 1990: 2·60, 95% CI 2·41-2·79; men born in 1990: 1·98, 1·85-2·12).
INTERPRETATION: The incidence of cirrhosis has increased over the past two decades, and more so in younger birth cohorts and in women. Future studies to define the cause and natural history of cirrhosis in these groups are essential to develop strategies that could reverse these trends for future generations.
FUNDING: Southeastern Ontario Academic Medical Association New Clinician Scientist Award; American Association for the Study of Liver Disease (AASLD) Foundation Clinical, Translational and Outcomes Research Award in Liver Disease (JAF).

PMID: 30573390 [PubMed - as supplied by publisher]



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Pelvic Complications After Prostate Cancer Radiation Therapy and Their Management: An International Collaborative Narrative Review.

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Pelvic Complications After Prostate Cancer Radiation Therapy and Their Management: An International Collaborative Narrative Review.

Eur Urol. 2018 Dec 17;:

Authors: Matta R, Chapple CR, Fisch M, Heidenreich A, Herschorn S, Kodama RT, Koontz BF, Murphy DG, Nguyen PL, Nam RK

Abstract
CONTEXT: Radiotherapy used for treating localized prostate cancer is effective at prolonging cancer-specific and overall survival. Still, acute and late pelvic toxicities are a concern, with gastrointestinal (GI) and genitourinary (GU) sequelae being most common as well as other pelvic complications.
OBJECTIVE: To present a critical review of the literature regarding the incidence and risk factors of pelvic toxicity following primary radiotherapy for prostate cancer and to provide a narrative review regarding its management.
EVIDENCE ACQUISITION: A collaborative narrative review of the literature from 2010 to present was conducted.
EVIDENCE SYNTHESIS: Regardless of the modality used, the incidence of acute high-grade pelvic toxicity is low following conventionally fractionated external beam radiotherapy (EBRT). After moderate hypofractionation, the crude cumulative incidences for late grade 3 or higher (G3+) GI and GU complications are as high as 6% and 7%, respectively. After extreme hypofractionation, the 5-yr incidences of G2+ GU and GI toxicities are 3-9% and 0-4%, respectively. Following brachytherapy monotherapy, crude rates of late G3+ GU toxicity range from 6% to 8%, while late GI toxicity is rare. With combination therapy (EBRT and brachytherapy), the cumulative incidence of late GU toxicity is high, between 18% and 31%; however, the prevalence is lower at 4-14%. Whole pelvic radiotherapy remains a controversial treatment option as there is increased G3+ GI toxicity compared with prostate-only treatment, with no overall survival benefit. Proton beam therapy appears to have similar toxicity to photon therapies currently in use. With respect to specific complications, urinary obstruction and urethral stricture are the most common severe urinary toxicities. Rectal and urinary bleeding can be recurrent long-term toxicities. The risk of hip fracture is also increased following prostate radiotherapy. The literature is mixed on the risk of in-field secondary pelvic malignancies following prostate radiotherapy. Urinary and GI fistulas are rare complications. Management of these toxicities may require invasive treatment and reconstructive surgery for refractory and severe symptoms.
CONCLUSIONS: There has been progress in the delivery of radiotherapy, enabling the administration of higher doses with minimal tradeoff in terms of slightly increased or equal toxicity. There is a need to focus future improvements in radiotherapy on sparing critical structures to reduce GU and GI morbidities. While complications such as fistulae, bone toxicity, and secondary malignancy are rare, there is a need for higher-quality studies assessing these outcomes and their management.
PATIENT SUMMARY: In this report, we review the literature regarding pelvic complications following modern primary prostate cancer radiotherapy and their management. Modern radiotherapy technologies have enabled the administration of higher doses with minimal increases in toxicity. Overall, high-grade long-term toxicity following prostate radiotherapy is uncommon. Management of late high-grade pelvic toxicities can be challenging, with patients often requiring invasive therapies for refractory cases.

PMID: 30573316 [PubMed - as supplied by publisher]



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The value of MR textural analysis in prostate cancer.

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The value of MR textural analysis in prostate cancer.

Clin Radiol. 2018 Dec 17;:

Authors: Patel N, Henry A, Scarsbrook A

Abstract
Current diagnosis and treatment stratification of patients with suspected prostate cancer relies on a combination of histological and magnetic resonance imaging (MRI) findings. The aim of this article is to provide a brief overview of prostate pathological grading as well as the relevant aspects of multiparametric (MRI) mpMRI, before indicating the potential that magnetic resonance textural analysis (MRTA) offers within prostate cancer. A review of the evidence base on MRTA in prostate cancer will enable discussion of the utility of this field while also indicating recommendations to future research. Radiomic textural analysis allows the assessment of spatial inter-relationships between pixels within an image by use of mathematical methods. First-order textural analysis is better understood and may have more clinical validity than higher-order textural features. Textural features extracted from apparent diffusion coefficient maps have shown the most potential for clinical utility in MRTA of prostate cancers. Future studies should aim to integrate machine learning techniques to better represent the role of MRTA in prostate cancer clinical practice. Nomenclature should be used to reduce misidentification between first-order and second-order energy and entropy. Automated methods of segmentation should be encouraged in order to reduce problems associated with inclusion of normal tissue within regions of interest. The retrospective and small-scale nature of most published studies, make it difficult to draw meaningful conclusions. Future larger prospective studies are required to validate the textural features indicated to have potential in characterisation and/or diagnosis of prostate cancer before translation into routine clinical practice.

PMID: 30573283 [PubMed - as supplied by publisher]



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Prospective validation of the NCI Breast Cancer Risk Assessment Tool (Gail Model) on 40,000 Australian women.

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Prospective validation of the NCI Breast Cancer Risk Assessment Tool (Gail Model) on 40,000 Australian women.

Breast Cancer Res. 2018 Dec 20;20(1):155

Authors: Nickson C, Procopio P, Velentzis LS, Carr S, Devereux L, Mann GB, James P, Lee G, Wellard C, Campbell I

Abstract
BACKGROUND: There is a growing interest in delivering more personalised, risk-based breast cancer screening protocols. This requires population-level validation of practical models that can stratify women into breast cancer risk groups. Few studies have evaluated the Gail model (NCI Breast Cancer Risk Assessment Tool) in a population screening setting; we validated this tool in a large, screened population.
METHODS: We used data from 40,158 women aged 50-69 years (via the lifepool cohort) participating in Australia's BreastScreen programme. We investigated the association between Gail scores and future invasive breast cancer, comparing observed and expected outcomes by Gail score ranked groups. We also used machine learning to rank Gail model input variables by importance and then assessed the incremental benefit in risk prediction obtained by adding variables in order of diminishing importance.
RESULTS: Over a median of 4.3 years, the Gail model predicted 612 invasive breast cancers compared with 564 observed cancers (expected/observed (E/O) = 1.09, 95% confidence interval (CI) 1.00-1.18). There was good agreement across decile groups of Gail scores (χ2 = 7.1, p = 0.6) although there was some overestimation of cancer risk in the top decile of our study group (E/O = 1.65, 95% CI 1.33-2.07). Women in the highest quintile (Q5) of Gail scores had a 2.28-fold increased risk of breast cancer (95% CI 1.73-3.02, p < 0.0001) compared with the lowest quintile (Q1). Compared with the median quintile, women in Q5 had a 34% increased risk (95% CI 1.06-1.70, p = 0.014) and those in Q1 had a 41% reduced risk (95% CI 0.44-0.79, p < 0.0001). Similar patterns were observed separately for women aged 50-59 and 60-69 years. The model's overall discrimination was modest (area under the curve (AUC) 0.59, 95% CI 0.56-0.61). A reduced Gail model excluding information on ethnicity and hyperplasia was comparable to the full Gail model in terms of correctly stratifying women into risk groups.
CONCLUSIONS: This study confirms that the Gail model (or a reduced model excluding information on hyperplasia and ethnicity) can effectively stratify a screened population aged 50-69 years according to the risk of future invasive breast cancer. This information has the potential to enable more personalised, risk-based screening strategies that aim to improve the balance of the benefits and harms of screening.

PMID: 30572910 [PubMed - in process]



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A Clickable Oxysterol Photolabel Retains NMDA Receptor Activity and Accumulates in Neurons.

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A Clickable Oxysterol Photolabel Retains NMDA Receptor Activity and Accumulates in Neurons.

Front Neurosci. 2018;12:923

Authors: Chen DM, Ziolkowski L, Benz A, Qian M, Zorumski CF, Covey DF, Mennerick S

Abstract
Oxysterol analogs that modulate NMDA receptor function are candidates for therapeutic development to treat neuropsychiatric disorders. However, the cellular actions of these compounds are still unclear. For instance, how these compounds are compartmentalized or trafficked in neurons is unknown. In this study, we utilized a chemical biology approach combining photolabeling and click chemistry. We introduce a biologically active oxysterol analog that contains: (1) a diazirine group, allowing for the permanent labeling of cellular targets, and (2) an alkyne group, allowing for subsequent in situ visualization using Cu2+ catalyzed cycloaddition of an azide-conjugated fluorophore. The physiological properties of this analog at NMDA receptors resemble those of other oxysterols, including occlusion with other oxysterol-like compounds. Fluorescent imaging reveals that the analog accumulates diffusely in the cytoplasm of neurons through an energy-independent mechanism. Overall, this work introduces a novel chemical biology approach to investigate oxysterol actions and introduces a tool useful for further cell biological and biochemical studies of oxysterols.

PMID: 30574068 [PubMed]



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Propofol Inhibits Cerebellar Parallel Fiber-Purkinje Cell Synaptic Transmission via Activation of Presynaptic GABAB Receptors in vitro in Mice.

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Propofol Inhibits Cerebellar Parallel Fiber-Purkinje Cell Synaptic Transmission via Activation of Presynaptic GABAB Receptors in vitro in Mice.

Front Neurosci. 2018;12:922

Authors: Xuan FL, Wang HW, Cao LX, Bing YH, Chu CP, Jin R, Qiu DL

Abstract
Propofol is a widely used intravenous sedative-hypnotic agent, which causes rapid and reliable loss of consciousness via activation of γ -aminobutyric acid A (GABAA) receptors. We previously found that propofol inhibited cerebellar Purkinje cells (PC) activity via both GABAA and glycine receptors in vivo in mice. We here examined the effect of propofol on the cerebellar parallel fiber (PF)-PC synaptic transmission in mouse cerebellar slices by whole-cell recording technique and pharmacological methods. We found that following blockade of GABAA and glycine receptors activity, propofol reversely decreased the amplitude of PF-PC excitatory postsynaptic currents (PF-PC EPSCs), and significantly increased paired-pulse ratio (PPR). The propofol-induced decrease in amplitude of PF-PC EPSCs was concentration-dependent. The half-inhibitory concentration (IC50) of propofol for inhibiting PF-PC EPSCs was 4.7 μM. Notably, the propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by GABAB receptor antagonist, saclofen (10 μM), but not blocked by N-methyl-D-aspartate receptor (NMDA) receptor antagonist, D-APV (50 μM). Application of the GABAB receptor agonist baclofen induced a decrease in amplitude and an increase in PPR of PF-PC EPSCs, as well masked the propofol-induced changes in PF-PC EPSCs. Moreover, the propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by a specific protein kinase A (PKA) inhibitor, KT5720. These results indicate that application of propofol facilitates presynaptic GABAB receptors, resulting in a depression of PF-PC synaptic transmission via PKA signaling pathway in mouse cerebellar cortex. The results suggest that the interaction with GABAB receptors may contribute to the general anesthetic action of propofol.

PMID: 30574067 [PubMed]



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Autophagy Induction by HIV-Tat and Methamphetamine in Primary Midbrain Neuronal Cells of Tree Shrews via the mTOR Signaling and ATG5/ATG7 Pathway.

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Autophagy Induction by HIV-Tat and Methamphetamine in Primary Midbrain Neuronal Cells of Tree Shrews via the mTOR Signaling and ATG5/ATG7 Pathway.

Front Neurosci. 2018;12:921

Authors: Li J, Wang W, Tong P, Leung CK, Yang G, Li Z, Li N, Sun X, Han Y, Lu C, Kuang D, Dai J, Zeng X

Abstract
Background: Addictive stimulant drugs, such as methamphetamine (METH), increase the risk of exposure to the human immunodeficiency virus-1 (HIV-1) infection and thus predispose individuals to the development of HIV-associated neurocognitive disorders (HANDs). Previous studies have indicated that HIV-Tat (the transactivator of transcription) and METH can synergistically induce autophagy in SH-SY5Y neuroblastoma cells and that autophagy plays a pivotal role in the neuronal dysfunction in HANDs. However, the underlying mechanism of METH-and HIV-Tat-induced neuronal autophagy remains unclear. Methods: We cultured primary midbrain neuronal cells of tree shrews and treated them with METH and HIV-Tat to study the role of METH and HIV-Tat in inducing autophagy. We evaluated the effects of the single or combined treatment of METH and HIV-Tat on the protein expressions of the autophagy-related genes, including Beclin-1 and LC3B, ATG5, and ATG7 in METH and HIV-Tat-induced autophagy. In addition, the presence of autophagosomes in the METH and/or HIV-Tat treatment was revealed using transmission electron microscopy. Results: The results indicated that METH increased the protein levels of LC3B and Beclin-1, and these effects were significantly enhanced by HIV-Tat. Moreover, the results suggested that ATG5 and ATG7 were involved in the METH and HIV-Tat-induced autophagy. In addition, it was found that mTOR inhibition via pharmacological intervention could trigger autophagy and promote METH and HIV-Tat-induced autophagy. Discussion: Overall, this study contributes to the knowledge of the molecular underpinnings of METH and HIV-Tat-induced autophagy in primary midbrain neuronal cells. Our findings may facilitate the development of therapeutic strategies for METH-and HIV-Tat-induced autophagy in HANDs.

PMID: 30574066 [PubMed]



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Altered Default Mode and Sensorimotor Network Connectivity With Striatal Subregions in Primary Insomnia: A Resting-State Multi-Band fMRI Study.

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Altered Default Mode and Sensorimotor Network Connectivity With Striatal Subregions in Primary Insomnia: A Resting-State Multi-Band fMRI Study.

Front Neurosci. 2018;12:917

Authors: Wang L, Wang K, Liu JH, Wang YP

Abstract
Background: Primary insomnia is a high prevalent sleep disorder. Disturbed brain activity during reward, emotional, and cognitive processing have been observed in insomnia patients. Studies have implicated a critical role of the striatum in these dysfunctions. However, there have been no direct investigations on the whole-brain functional connectivity (FC) of the striatum in insomnia. Methods: We analyzed the group differences in the FC images of 6 predefined striatal subregions based on the multi-band resting-state fMRI data of 18 insomnia patients and 16 healthy controls. Results: We found increased positive FC in the bilateral medial frontal gyrus for bilateral dorsal caudate (DC) and left inferior ventral striatum (VS) subregions, but increased negative FC in the bilateral inferior parietal lobe for the left inferior VSi and right dorsal caudal putamen (DCP) subregions, and in the lateral temporal, occipital, and primary sensorimotor areas for the bilateral DC and left superior VS subregions. The FC between the right DCP and right inferior parietal lobe showed significant positive correlation with Pittsburgh Sleep Quality Index (PSQI). Conclusion: The findings indicate disturbed striatal FC with the default mode network (DMN), the visual and somatosensory areas in insomnia, which likely reflects an inappropriate reward or emotional significance attribute to self-reflection, episodic memory, sensory-perception processes. The altered striatal FC might increase the risk of insomnia patients to develop depression and anxiety.

PMID: 30574065 [PubMed]



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A Comparative Atlas-Based Recognition of Mild Cognitive Impairment With Voxel-Based Morphometry.

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A Comparative Atlas-Based Recognition of Mild Cognitive Impairment With Voxel-Based Morphometry.

Front Neurosci. 2018;12:916

Authors: Long Z, Huang J, Li B, Li Z, Li Z, Chen H, Jing B

Abstract
An accurate and reliable brain partition atlas is vital to quantitatively investigate the structural and functional abnormalities in mild cognitive impairment (MCI), generally considered to be a prodromal phase of Alzheimer's disease. In this paper, we proposed an automated structural classification method to identify MCI from healthy controls (HC) and investigated whether the classification performance was dependent on the brain parcellation schemes, including Automated Anatomical Labeling (AAL-90) atlas, Brainnetome (BN-246) atlas, and AAL-1024 atlas. In detail, structural magnetic resonance imaging (sMRI) data of 69 MCI patients and 63 HC matched well on gender, age, and education level were collected and analyzed with voxel-based morphometry method first, then the volume features of every region of interest (ROI) belonging to the above-mentioned three atlases were calculated and compared between MCI and HC groups, respectively. At last, the abnormal volume features were selected as the classification features for a proposed support vector machine based identification method. After the leave-one-out cross-validation to estimate the classification performance, our results reported accuracies of 83, 92, and 89% with AAL-90, BN-246, and AAL-1024 atlas, respectively, suggesting that future studies should pay more attention to the selection of brain partition schemes in the atlas-based studies. Furthermore, the consistent atrophic brain regions among three atlases were predominately located at bilateral hippocampus, bilateral parahippocampal, bilateral amygdala, bilateral cingulate gyrus, left angular gyrus, right superior frontal gyrus, right middle frontal gyrus, left inferior frontal gyrus, and left precentral gyrus.

PMID: 30574064 [PubMed]



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Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons.

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Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons.

Front Neurosci. 2018;12:914

Authors: Pozner T, Schray A, Regensburger M, Lie DC, Schlötzer-Schrehardt U, Winkler J, Turan S, Winner B

Abstract
Mutations in SPG11 cause a complicated autosomal recessive form of hereditary spastic paraplegia (HSP). Mechanistically, there are indications for the dysregulation of the GSK3β/βCat signaling pathway in SPG11. In this study, we tested the therapeutic potential of the GSK3β inhibitor, tideglusib, to rescue neurodegeneration associated characteristics in an induced pluripotent stem cells (iPSCs) derived neuronal model from SPG11 patients and matched healthy controls as well as a CRISPR-Cas9 mediated SPG11 knock-out line and respective control. SPG11-iPSC derived cortical neurons, as well as the genome edited neurons exhibited shorter and less complex neurites than controls. Administration of tideglusib to these lines led to the rescue of neuritic impairments. Moreover, the treatment restored increased cell death and ameliorated the membranous inclusions in iPSC derived SPG11 neurons. Our results provide a first evidence for the rescue of neurite pathology in SPG11-HSP by tideglusib. The current lack of disease-modifying treatments for SPG11 and related types of complicated HSP renders tideglusib a candidate compound for future clinical application.

PMID: 30574063 [PubMed]



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Regional Homogeneity and Multivariate Pattern Analysis of Cervical Spondylosis Neck Pain and the Modulation Effect of Treatment.

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Regional Homogeneity and Multivariate Pattern Analysis of Cervical Spondylosis Neck Pain and the Modulation Effect of Treatment.

Front Neurosci. 2018;12:900

Authors: Chen J, Wang Z, Tu Y, Liu X, Jorgenson K, Ye G, Lin C, Liu J, Park J, Lang C, Liu B, Kong J

Abstract
Objects: We investigated brain functional alteration in patients with chronic cervical spondylosis neck pain (CSNP) compared to healthy controls (HCs) and the effect of intervention. Methods: 104 CSNP patients and 96 matched HCs were recruited. Patients received 4 weeks of treatment. Resting-state fMRI and Northwick Park Neck Pain Questionnaire (NPQ) were collected before and after treatment. Resting state regional homogeneity (rs-ReHo) and multivariate pattern analysis (MVPA) were applied to (1) investigate rs-ReHo differences between CSNP patients and controls and the effect of longitudinal treatment and (2) classify CSNP patients from HCs and predict clinical outcomes before treatment using MVPA. Results: We found that (1) CSNP patients showed decreased rs-ReHo in the left sensorimotor cortex and right temporo-parietal junction (rTPJ), and rs-ReHo at the rTPJ significantly increased after treatment; (2) rs-ReHo at rTPJ was associated with NPQ at baseline, and pre- and post-treatment rs-ReHo changes at rTPJ were associated with NPQ changes in CSNP patients; and (3) MVPA could discriminate CSNP patients from HCs with 72% accuracy and predict clinical outcomes with a mean absolute error of 19.6%. Conclusion: CSNP patients are associated with dysfunction of the rTPJ and sensorimotor area. Significance: rTPJ plays on important role in the pathophysiology and development of CSNP.

PMID: 30574062 [PubMed]



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Language-Eloquent White Matter Pathway Tractography and the Course of Language Function in Glioma Patients.

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Language-Eloquent White Matter Pathway Tractography and the Course of Language Function in Glioma Patients.

Front Oncol. 2018;8:572

Authors: Ille S, Engel L, Kelm A, Meyer B, Krieg SM

Abstract
Object: As various recent studies show, damage to white matter pathways leads to permanent functional deficits in a high percentage of patients. Particularly the subcortical language network is complex, and its visualization has a tremendous relevance for neurosurgeons. This pilot study aims to correlate language-eloquent white matter pathways with the course of language function after the resection of left-sided perisylvian gliomas. Methods: We included 10 patients who underwent resection of highly language-eloquent high- (9 pts) and low-grade gliomas (1 pts). We performed navigated repetitive transcranial magnetic stimulation (nrTMS)-based tractography via diffusion tensor imaging fiber trackings (DTI FT) preoperatively (PRE-1), postoperatively (POST-1), and at long-term follow up or tumor recurrence (PRE-2). We separately tracked the inferior fronto-occipital fascicle (IFOF), the frontal aslant tract (FAT), and the superior longitudinal (SLF), and arcuate fascicle (AF), and correlated the amount of visualized fibers to the patients' language function at each date. Results: The changes of nrTMS-based DTI FTs of single white matter pathways correlated with the according status of language function for any of the pathways in 80% of patients and in 19 of 30 (63%) single pathway comparisons between PRE-1 and POST-1. Between POST-1 and PRE-2 the nrTMS-based DTI FTs correlated with the status of language function for any of the pathways in all patients and in 24 of 30 (80%) single pathway comparisons. Single FT results correlated with the according status of language function at POST-1 in 60, 70, and 60% of cases, and with the according status of language function at PRE-2 in 60, 90, and 90% of cases for the tracking of the IFOF, FAT, and SLF/AF, respectively. Conclusion: By the present results we were able to show that nrTMS-based DTI FT of the IFOF, FAT, and SLF/AF mainly correlates with the according status of language function preoperatively, postoperatively, and at long-term follow up after the resection of left-sided perisylvian gliomas.

PMID: 30574455 [PubMed]



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The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia.

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The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia.

Front Oncol. 2018;8:555

Authors: Galimberti S, Grassi S, Baratè C, Guerrini F, Ciabatti E, Perutelli F, Ricci F, Del Genio G, Montali M, Barachini S, Giuliani C, Ferreri MI, Valetto A, Abruzzese E, Ippolito C, Iurlo A, Bocchia M, Sicuranza A, Martino B, Iovino L, Buda G, Salehzadeh S, Petrini M, Di Paolo A, Mattii L

Abstract
The Polycomb gene BMI1 expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, BMI1 is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a BCR-ABL1-independent way. Even if, it is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the BCR-ABL1 expression, but they summed up what previously observed about the BMI1 expression modulation. In this work we demonstrate for the first time that in CML the BMI1 protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.

PMID: 30574454 [PubMed]



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