Polydrug use among urban adolescent cigarette smokers

Publication date: March 2017
Source:Addictive Behaviors, Volume 66
Author(s): Karma L. McKelvey, Danielle E. Ramo, Kevin Delucchi, Mark L. Rubinstein
PurposeAdolescent smokers are at increased risk for polydrug use, which is associated with more consequences than use of a single drug. Here we classified subgroups of polydrug use among urban adolescent cigarette-smokers; described the sociodemographic, smoking, and depression correlates; and identified three-year outcomes associated with subgroup membership.MethodsAdolescent cigarette smokers (N=176; Mage=16.1; 35% male; 27% white) completed surveys assessing drug use, smoking characteristics, demographics, and depressive symptoms at baseline and 12, 24, and 36months follow-up.ResultsAlmost all participants (96%) reported using, on average, two (SD=0.97) substances (including other tobacco products) in addition to cigarettes. Latent class analysis revealed two distinct classes of polydrug users. "Limited Range Use" (84%) class members reported current use of other tobacco, alcohol, and marijuana, as did "Extended Range Use" class members (16%) who also reported current use of "harder drugs" (i.e., cocaine/crack, hallucinogens, ecstasy, and misused prescriptions). The classes did not differ on demographics or baseline likelihood of marijuana (χ²=0.25; p<0.62) or alcohol use (χ²=3.3; p<0.07). At baseline, a larger proportion of Extended Range Use class members reported both smoking the entire cigarette and symptoms of clinical depression. Extended Range Use class membership at baseline predicted higher mean depression scores at 24 and 36months.ConclusionAdolescent cigarette-smokers who reported extended range use (18%) also reported symptoms of clinical depression at baseline and follow-up. These findings indicate a need for early monitoring of depression symptoms and prevention and cessation interventions targeting this high-risk group.



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Editorial Board

Publication date: March 2017
Source:Addictive Behaviors, Volume 66





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Altered visual contrast gain control is sensitive for idiopathic generalized epilepsies

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): Daehan Won, Wonsuk Kim, W. Art Chaovalitwongse, Jeffrey J. Tsai
ObjectiveVisual hyperexcitability in the form of abnormal contrast gain control has been shown in photosensitive epilepsy and idiopathic generalized epilepsies. We assessed the accuracy and reliability of measures of visual contrast gain control in discerning individuals with idiopathic generalized epilepsies from healthy controls.MethodsTwenty-four adult patients with idiopathic generalized epilepsy and 32 neurotypical control subjects from two study sites participated in a prospective, cross-sectional study. We recorded steady-state visual evoked potentials to a wide range of contrasts of a flickering grating stimulus. The resultant response magnitude vs. contrast curves were fitted to a standard model of contrast response function, and the model parameters were used as input features to a linear classifier to separate patients from controls. Additionally we compared the relative contribution of model parameters towards the classification using a sparse feature-selection approach.ResultsClassification accuracy was 80% or better. Sensitivity and specificity both were 80-85%. Cross validation confirmed robust classifier performance generalizable across the data from the two samples. Patients' relative lack of gain control at high contrasts was the most important information distinguishing patients from controls.ConclusionsIndividuals with idiopathic generalized epilepsy were distinguishable from the neurotypical with a high degree of accuracy and reliability by a reduction in gain control at high contrasts.SignificanceGain control is an essential neural operation that regulates neuronal sensitivity to stimuli and may represent a novel biomarker of hyperexcitability.



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Congenital Zika virus infection: the tropical Asian perspective

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): Beuy Joob, Viroj Wiwanitkit




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Clinical implication of cervical vestibular evoked myogenic potentials in benign paroxysmal positional vertigo

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): Mun Young Chang, Ji Ho Shin, Kyung Hyun Oh, Young Ho Hong, Seog-Kyun Mun
ObjectivesTo evaluate the value of cervical vestibular evoked myogenic potential (cVEMP) as a prognostic factor for benign paroxysmal positional vertigo (BPPV).MethodsWe reviewed 65 patients with BPPV who underwent cVEMP. Patients were divided into two groups according to resistance to the repositioning maneuver. Univariable and multivariable analyses were performed with age, gender, affected semicircular canal, affected side and cVEMP parameters to find the associated factors for resistance to the repositioning maneuver.ResultsFrom univariable analysis, cVEMP interaural amplitude difference (IAD) ratio, the affected semicircular canal and the affected side showed a better association (p<0.10) with resistance to the repositioning maneuver. With multivariable analysis, decreased cVEMP IAD ratio at the affected side (⩽-25%) (p=0.043, OR=4.934) and the posterior semicircular canal (p=0.049, OR=3.780) remained as associated factors.ConclusionsDecreased cVEMP IAD ratio at the affected side is associated with resistance to the repositioning maneuver. BPPV patients with decreased cVEMP IAD ratio at the affected side have a higher likelihood of their BPPV persisting after a single repositioning maneuver.SignificancecVEMP test may provide a prognosis of BPPV. A decreased cVEMP IAD ratio at the affected side may be prognostic of BPPV not resolving after a single repositioning maneuver.



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Inhibitory control in euthymic bipolar disorder: event related potentials during a Go/NoGo task

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): A.M. Morsel, M. Dhar, W. Hulstijn, A. Temmerman, M. Morrens, B. Sabbe
ObjectivesPatients with bipolar disorder (BD) are reported to have difficulties with inhibition, even in a euthymic state. However, the literature on cortical activity associated with response inhibition in BD remains ambiguous. This study investigates inhibition in euthymic BD using electrophysiological measures, while controlling for effects of specific medications.MethodsTwenty patients with BD were compared with eighteen healthy controls on a Go/NoGo task while electroencephalogram was recorded. Behavioral and event-related potential (ERP) measurements were analyzed for the two groups. Medication effects were controlled for in the analysis.ResultsPatients with BD had marginally reduced NoGo N2 amplitudes and increased NoGo P3 amplitudes compared with healthy controls when patients using benzodiazepines were excluded from the study. No behavioural differences between the groups were found.ConclusionsReduced NoGo N2 amplitudes in BD reflect aberrant conflict detection, an early stage of the inhibition process. In addition, increased NoGo P3 amplitudes in BD despite normal task performance reflect an overactive cortical system during a simple inhibition task.SignificanceDifficulties in early stages of inhibition in BD appear to have been compensated by increased cortical activation. This study extends current knowledge regarding cortical activations relating to inhibition in BD.



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Motor Unit Number Index (MUNIX) detects motor neuron loss in pre-symptomatic muscles in Amyotrophic lateral sclerosis

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): Christoph Neuwirth, Paul E. Barkhaus, Christian Burkhardt, José Castro, David Czell, Mamede de Carvalho, Sanjeev Nandedkar, Erik Stålberg, Markus Weber
ObjectiveMotor Unit Number Index (MUNIX) is a quantitative neurophysiological measure that provides an index of the number of lower motor neurons supplying a muscle. It reflects the loss of motor neurons in patients with Amyotrophic Lateral Sclerosis (ALS). However, it is unclear whether MUNIX also detects motor unit loss in strong, non-wasted muscles.MethodsThree centres measured MUNIX in 49 ALS patients every three months in six different muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor digitorum brevis, abductor hallucis) on the less affected side. The decline of MUNIX in initially non-wasted, clinically strong muscles (manual muscle testing, MMT grade 5) was analysed before and after onset of weakness.ResultsIn 49 subjects, 151 clinically strong muscles developed weakness and were included for analysis. The average monthly relative loss of MUNIX was 5.0% before and 5.6% after onset of weakness. This rate of change was significantly higher compared to ALS functional rating scale (ALSFRS-R) and compound muscle action potential (CMAP) change over 12 months prior to the onset of muscle weakness (p=0.024).ConclusionMUNIX is an electrophysiological marker that detects lower motor neuron loss in ALS, before clinical weakness becomes apparent by manual muscle testing.SignificanceThis makes MUNIX a good biomarker candidate for disease progression



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Auditory brainstem responses to stop consonants predict literacy

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): Nicole E. Neef, Gesa Schaadt, Angela D. Friederici
ObjectivePrecise temporal coding of speech plays a pivotal role for sound processing throughout the central auditory system which in turn influences literacy acquisition. The current study tests whether an electrophysiological measure of this precision predicts literacy skills.MethodsComplex auditory brainstem responses were analyzed from 62 native-German speaking children aged 11-13 years. We employed the cross-phaseogram approach to compute the quality of the electrophysiological stimulus contrast [da] and [ba]. Phase shifts were expected to vary with literacy.ResultsReceiver operating curves demonstrated a feasible sensitivity and specificity of the electrophysiological measure. A multiple regression analysis resulted in a significant prediction of literacy by delta cross-phase as well as phonological awareness. A further commonality analysis separated a unique variance explained by the physiological measure from a unique variance explained by the behavioral measure, and common effects of both.ConclusionsDespite multicollinearities between literacy, phonological awareness, and subcortical differentiation of stop consonants, a combined assessment of behavior and physiology strongly increases the ability to predict literacy skills.SignificanceThe strong link between the neurophysiological signature of sound encoding and literacy outcome suggests that the delta cross-phase could indicate the risk of dyslexia and thereby complement subjective psychometric measures for early diagnoses.



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Aberrant temporal behavior of mismatch negativity generators in schizophrenia patients and subjects at clinical high risk for psychosis

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): Minah Kim, Kang Ik Kevin Cho, Youngwoo Bryan Yoon, Tae Young Lee, Jun Soo Kwon
ObjectiveAlthough disconnection syndrome has been considered a core pathophysiologic mechanism of schizophrenia, little is known about the temporal behavior of mismatch negativity (MMN) generators in individuals with schizophrenia or clinical high risk (CHR) for psychosis.MethodsMMN was assessed in 29 schizophrenia patients, 40 CHR subjects, and 47 healthy controls (HCs). Individual realistic head models and the minimum L2 norm algorithm were used to generate a current source density (CSD) model of MMN. The strength and time course of MMN CSD activity were calculated separately for the frontal and temporal cortices and were compared across brain regions and groups.ResultsSchizophrenia patients and CHR subjects displayed lower MMN CSD strength than HCs in both the temporal and frontal cortices. We found a significant time delay in MMN generator activity in the frontal cortex relative to that in the temporal cortex in HCs. However, the sequential temporo-frontal activities of MMN generators were disrupted in both the schizophrenia and CHR groups.ConclusionsImpairments and altered temporal behavior of MMN multiple generators were observed even in individuals at risk for psychosis.SignificanceThese findings suggest that aberrant MMN generator activity might be helpful in revealing the pathophysiology of schizophrenia.



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Co-occurrence of high-frequency oscillations and delayed responses evoked by intracranial electrical stimulation in stereo-EEG studies

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): Cristian Donos, Ioana Mîndruţă, Mihai Dragoş Malîia, Alin Raşină, Jean Ciurea, Andrei Barborica
ObjectiveTo perform a side-by-side comparison of two epileptogenicity biomarkers, high frequency oscillations (HFOs) and delayed responses (DRs), as a result of single-pulse electrical stimulation.MethodsWe have recorded stimulation-evoked HFOs and DRs in 16 epileptic patients undergoing presurgical evaluation using the stereoelectroencephalographic method. To evaluate converging and complementary information provided by the biomarkers, we analyzed them individually and for logical "and"/"or" combinations between them. 3D maps of the biomarkers' distributions by recording location (inbound maps) and by stimulation location (outbound maps) were created to analyze their relationship with the epileptogenic structures.ResultsHFOs occur less frequently than DRs, by 18.7%, when counting by recording contacts, and more frequently, by 7.4%, when counting by stimulation contacts. 40.6% of the contacts exhibiting HFOs also exhibit DRs, and 44.1% of the contacts exhibiting DRs also exhibit HFOs. When combining biomarkers, there was a tradeoff between increased seizure onset zone (SOZ) sensitivity, from 21.3% to 73%, and decreased specificity, from 87.2% to 34.3%.ConclusionsThere is a moderate similarity in the information provided by the DRs and HFOs.SignificanceThe biomarkers complement each other, but there is a tradeoff between different metrics for SOZ localization.



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Saccades abnormalities in posterior cortical atrophy - A case report

Publication date: Available online 18 December 2016
Source:Clinical Neurophysiology
Author(s): Yasuo Terao, Fukuda Hideki, Shin-ichi Tokushige, Satomi Inomata-Terada, Masashi Hamada, Yoshikazu Ugawa




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Utility of Deep inspiration breath-hold for left sided breast radiation therapy in preventing early cardiac perfusion defects - A Prospective Study

Publication date: Available online 18 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Timothy Zagar, Orit Kaidar - Person, Xiaoli Tang, Ellen Jones, Jason Matney, Shiva Das, Rebecca L. Green, Arif Sheikh, Amir H. Khandani, William H. McCartney, Jorge Daniel Oldan, Terence Z. Wong, Lawrence Bruce Marks
PurposeTo evaluate early cardiac single photon computed tomography (SPECT) findings after left breast/chest wall postoperative radiation therapy (RT) in the setting of deep inspiration breath hold (DIBH).MethodsWe performed a prospective single-institution- single arm study of patients who were planned for tangential RT with DIBH to the left breast/chest wall (+/- internal mammary nodes). Deep inspiration breath hold was done utilizing a controlled surface monitoring technique (AlignRT, Vision RT Ltd., London, UK). Radiation therapy was given with tangential fields and a heart block. Radiation-induced cardiac perfusion and wall-motion changes were assessed using pre-RT and 6 month post-RT SPECT scans. A cumulative SPECT summed-rest score (SRS) was used to quantify perfusion in predefined left ventricle segments. The incidence of wall-motion abnormalities was assessed in each of these same segments.ResultsA total of 20 patients with normal pre-RT scans were studied; median age 56 years (range, 39-72). Seven (35%) patients were also irradiated to left internal mammary chain, and 5 (25%) had an additional RT field to supraclavicular nodes. Median heart dose 94cGy (range, 56-200), median V25Gy was zero (range, 0-0.1). None of the patients had post-RT perfusion or wall motion abnormalities.ConclusionsOur results suggest that DIBH and conformal cardiac blocking for patients receiving tangential RT for left-sided breast cancer is an effective means to avoid early RT-associated cardiac perfusion defects.

Teaser

To evaluate radiation induced cardiac toxicity after left breast/chest wall adjuvant radiation in the setting of Vision RT-based deep inspiration breath hold. We performed a prospective single-institution- single arm study. Our results suggest that Vision RT-based deep inspiration breath hold for patients receiving adjuvant tangential radiation for left-sided breast cancer is an effective means to avoid radiation-associated cardiac perfusion and motion defects.


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Nationwide multicenter retrospective study on high-dose-rate brachytherapy as monotherapy for prostate cancer

Publication date: Available online 18 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yasuo Yoshioka, Tadayuki Kotsuma, Akira Komiya, Shinji Kariya, Koji Konishi, Norio Nonomura, Kazuhiko Ogawa, Eiichi Tanaka, Kensaku Nishimura, Yasuyoshi Fujiuchi, Hiroshi Kitamura, Takuji Yamagami, Ichiro Yamasaki, Kazuo Nishimura, Teruki Teshima, Katsumasa Nakamura, Jun Itami
PurposeTo present, analyze and discuss results of a nationwide multicenter retrospective study on high-dose-rate brachytherapy (HDR-BT) as monotherapy for low-, intermediate- and high-risk prostate cancer.Methods and materialsFrom 1995 through 2013, 524 patients, 73 (14%) with low-risk, 207 (40%) with intermediate-risk, and 244 (47%) with high-risk prostate cancer, were treated with HDR-BT as monotherapy at 5 institutions in XXXXX. Dose fractionations were 27 Gy/2 fractions for 69 patients (13%), 45.5 Gy/7 fractions for 168 (32%), 49 Gy/7 fractions for 149 (28%), 54 Gy/9 fractions for 130 (25%), and others for 8 (2%). Of these patients, 156 (30%) did not receive androgen deprivation therapy (ADT), 202 patients (39%) did receive ADT <1 year, 112 (21%) for 1-3 years, and 54 (10%) for >3 years. Median follow-up time was 5.9 years (range, 0.4-18.1 years), with a minimum of 2 years for surviving patients.ResultsAfter 5 years, respective actuarial rates of no biochemical evidence of disease (bNED), overall survival (OS), cause-specific survival (CSS), and metastasis-free survival (MFS) for all patients were 92%, 97%, 99%, and 94%. For low/intermediate/high-risk patients, the 5-year bNED rates were 95%/94%/89%, the 5-year OS rates were 98%/98%/94%, the 5-year CSS rates were 98%/100%/98%, and the 5-year MFS rates were 98%/95%/90%, respectively. The cumulative incidence of late Grade 2-3 genitourinary toxicity at 5 years was 19%, and that of late Grade 3 was 1%. The corresponding incidences of gastrointestinal toxicity were 3% and 0% (0.2%). No Grade 4 or 5 of either type of toxicity was detected.ConclusionsThe findings of this nationwide multicenter retrospective study demonstrate that HDR-BT as monotherapy was safe and effective for all patients with low-, intermediate- and high-risk prostate cancer.

Teaser

A nationwide multicenter retrospective study on high-dose-rate brachytherapy (HDR-BT) as monotherapy for prostate cancer was conducted. A total of 524 patients was treated at 5 institutions in Japan. Median follow-up time was 5.9 years. For low/intermediate/high-risk patients, 5-year rates for no biochemical evidence of disease were 95%/94%/89%, respectively. Late Grade 3 genitourinary/gastrointestinal toxicity rate was 1%/0.2% at 5 years. This study thus demonstrated that HDR-BT monotherapy was safe and effective for patients with prostate cancer.


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Single nucleotide polymorphism TGFβ1 R25P correlates with acute toxicity during neoadjuvant chemoradiotherapy in rectal cancer patients

Publication date: Available online 18 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): J. Joshua Smith, Isaac Wasserman, Sarah A. Milgrom, Oliver S. Chow, Chin-Tung Chen, Sujata Patil, Karyn A. Goodman, Julio Garcia-Aguilar
Purpose/Objective: Our group and others have identified an association between single nucleotide polymorphisms (SNPs) and toxicity during chemoradiotherapy (CRT) in rectal cancer patients. This study aimed to validate these findings in an independent population.Methods and MaterialsThe cohort consisted of 165 patients who received CRT for rectal cancer from 2006 to 2012. Prospectively recorded toxicity information, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, was retrieved from the medical record. Additionally, a subset of 52 patients recorded their gastrointestinal symptoms weekly during CRT, using the 7-item Bowel Problems Scale. DNA was extracted from normal tissue in the proctectomy specimens and screened for 3 SNPs: XRCC1 R399Q, XPD K751Q, and TGFβ1 R25P. Univariable and multivariable logistic regression models were constructed.ResultsThe median radiation dose was 50.4 Gy, and all patients received concurrent chemotherapy. Toxicities measured by CTCAE were closely associated with patients reported outcomes for the patients who completed the 7-item Bowel Problems Scale. Grade ≥ 3 toxicity occurred during CRT in 14 patients (8%). All 14 patients had either XRCC1 R399Q or TGFβ1 R25P polymorphisms. The TGFβ1 R25P polymorphism was significantly associated with grade ≥3 toxicity (OR 3.47, p = 0.04) and, in patients who completed the Bowel Problems Scale, with grade ≥4 toxicity (OR 5.61, p = 0.02). The latter finding persisted in a multivariable logistic regression model controlling for ethnicity, age, and gender (adjusted OR 1.83, p = 0.02).ConclusionsWe have validated the correlation between the TGFβ1 R25P SNP and acute toxicity during CRT in an independent cohort using both clinician- and patient-reported toxicity. The information from our study could be used as a basis to formulate a prospective trial testing its utility as a biomarker of acute toxicity during neoadjuvant treatment in locally advanced rectal cancer.

Teaser

Our group and others have identified an association between single nucleotide polymorphisms and acute toxicity in patients receiving neoadjuvant chemoradiotherapy for rectal cancer. The current study validated these correlations in an independent cohort of 165 patients.


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Low dose radiotherapy for benign painful skeletal disorders –The typical treatment for the elderly patient?

Publication date: Available online 18 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Oliver Micke, M. Heinrich Seegenschmiedt, Irenaeus A. Adamietz, Guenter Kundt, Khashayar Fakhrian, Ulrich Schaefer, Ralph Muecke
PurposeThe aim of this prospective analysis was to evaluate the short-term and long-term efficacy of low dose radiotherapy (RT) for calcaneodynia, achillodynia, painful gonarthrosis, and painful bursitis trochanterica in eldely patients with an age of => 70 years.MethodsBetween October 2011 and October 2013, patients with an age of => 70 years with painful degenerative disorders of joints were recruited for a prospective trial. Single doses of 0.5 - 1.0 Gy and a total dose of 6.0 Gy per series were used. Pain was measured before and right after RT (early response) with a 10 scale visual analogue scale (VAS. Additionally, pain relief was measured with the four-scale pain score according to "von Pannewitz" (VPS) immediately on completion of RT and during follow-up. We defined a good response as complete pain relief and markedly improved.Results166 evaluable patients with a mean age of 76.6 years (70-90) with calcaneodynia (n=51), achillodynia (n=8), painful gonarthrosis (n=80), and painful bursitis trochanterica (n=27) were recruited. The mean VAS value before treatment was 6.38 and immediately on completion of RT 4.49(p<0.001). Concerning the VPS immediately on completion of RT, 6 patients were free of pain, 56 were much improved, 47 reported slight improvement, and 57 experienced no change. After a median follow-up of 29 months, 109 patients could be reached for evaluation of follow up results.33 patients were free of pain, 21 had marked improvement, 18 had some improvement, and 37 experienced no change. Therefore, a good response immediately on completion of RT could be achieved in 62/166 patients, and with the follow up in 54/109 patients(p=0.001).ConclusionsLow dose RT is a very effective treatment for the management of painful degenerative disorders of joints in the elderly. Low dose radiotherapy offers a low-risk, genuinely conservative, non-invasive therapeutic alternative for elderly patients.

Teaser

Low dose RT is a very effective treatment for the management of painful degenerative skeletal disorders in the elderly. Due to the delayed onset of analgesic effects low dose RT results in a significantly improved long-term efficacy in comparison to the results immediately after RT. In view of the ageing population and the corresponding increase in painful degenerative disorders of joints, low dose radiotherapy offers a low-risk, genuinely conservative, non-invasive therapeutic alternative for elderly patients.


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A Comparison between Low Dose-Rate Brachytherapy +/- Androgen Deprivation, External Beam Radiotherapy +/- Androgen Deprivation, and Radical Prostatectomy +/- Adjuvant or Salvage Radiotherapy for High-Risk Prostate Cancer

Publication date: Available online 18 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jay P. Ciezki, Michael Weller, Chandana A. Reddy, Jeffrey Kittel, Harguneet Singh, Rahul Tendulkar, Kevin L. Stephans, James Ulchaker, Kenneth Angermeier, Andrew Stephenson, Steven Campbell, Georges-Pascal Haber, Eric A. Klein
PurposeWe compare the efficacy and toxicity among the three major modalities available used to treat high-risk prostate cancer (HRCaP).Methods and MaterialsFrom 1996-2012, 2557 HRCaP patients were treated: 734 external beam radiation (EBRT) +/- androgen deprivation therapy (ADT), 515 low-dose-rate prostate brachytherapy (LDR) +/- ADT, and 1308 radical prostatectomy (RP) +/- EBRT. Biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer-specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v4.03). The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray's test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM.ResultsThe median follow-up and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (p=0.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73% for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (p=0.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and 6.8% for RP (p=0.0004). The 10-year cumulative incidence of > grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (p<0.0001). The 10-year cumulative incidence of > grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, 1.0% for RP (p<0.0001).ConclusionHRCaP treated with EBRT, LDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR.

Teaser

There is no level I evidence defining a standard of care for patients with high-risk prostate cancer. Clinical trials comparing treatment variations within a modality exist but none compare outcomes among modalities. We present an inception cohort study in which we compare efficacy and toxicity among the three major therapeutic modalities for high-risk prostate cancer: radical prostatectomy plus/minus adjuvant or salvage radiotherapy, external beam radiotherapy plus/minus androgen deprivation, and low-dose-rate prostate brachytherapy plus/minus androgen deprivation therapy.


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The impact of prostate MR/ultrasound fusion-guided biopsy on radiation treatment recommendations.

Publication date: Available online 18 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Aaron Reed, Luca F. Valle, Uma Shankavaram, Andra Krauze, Aradhana Kaushal, Erica Schott, Theresa Cooley-Zgela, Bradford Wood, Peter Pinto, Peter Choyke, Baris Turkbey, Deborah E. Citrin
BackgroundTargeted magnetic resonance (MR)/ultrasound fusion prostate biopsy (MRI-Bx) has recently been compared to standard of care extended sextant ultrasound-guided prostate biopsy (SOC-Bx) and was associated with an increased rate of detection of clinically significant prostate cancer. This study sought to determine the influence of MRI-Bx on radiation and androgen deprivation therapy (ADT) treatment recommendations.Methods/Materials: All patients treated with radiotherapy that underwent SOC-Bx and MRI-Bx at our institution were included. Using clinical T stage, pretreatment PSA, and Gleason score, patients were categorized into NCCN risk groups and radiation/ADT treatment recommendations were assigned. Intensification of recommended treatment after multiparametric MRI, SOC-Bx, and MRI-Bx was evaluated.ResultsFrom January 2008 to January 2016, 73 patients received radiation therapy at our institution after undergoing a simultaneous SOC-Bx and MRI-Bx (n=47 with prior SOC-Bx). Repeat SOC-Bx and MRI-Bx resulted in frequent upgrading compared to prior SOC-Bx (Gleason 7: 6.7% vs. 44.6%, p<0.001; Gleason 8-10: 2.1% vs. 38%, p<0.001). MRI-Bx increased the proportion of patients classified as very-high risk from 24.7% to 41.1% (p=0.027). Compared to SOC-Bx alone, including MRI-Bx findings resulted in a higher percentage of pathologically positive cores (mean 37% vs. 44%). Incorporation of multiparametric MRI and MRI-Bx results increased the recommended use and duration of ADT (duration increased in 28/73 patients, addition in 8/73 patients).ConclusionIn patients referred for radiotherapy, MRI-Bx resulted in an increase in the percentage of positive cores, Gleason Score, and risk grouping. The benefit of treatment intensification based on MRI-Bx findings is unknown.

Teaser

Prostate MR/ultrasound fusion-guided biopsy has recently been shown to identify clinically significant prostate cancer at rates higher than standard extended sextant ultrasound guided biopsy. Targeted biopsy often results in an increase in tumor grade. As fusion biopsy becomes more prevalent, an understanding of how it may alter radiation recommendations as a result of risk group migration is important. This study demonstrates a general pattern of increasing risk group and treatment intensification when results of fusion biopsy are incorporated.


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Use of Point-of-Care Ultrasound for the Diagnosis of Ovarian Hyperstimulation Syndrome

Publication date: Available online 18 December 2016
Source:The Journal of Emergency Medicine
Author(s): Sowdhamani Bellapu, Joshua Guttman
BackgroundOvarian hyperstimulation syndrome (OHSS) occurs when ovaries are overstimulated and enlarged due to fertility treatments resulting in a shift of serum from the intravascular space to the third space, mainly the abdominal cavity. It is the most serious complication of ovarian hyperstimulation for assisted reproduction.Case ReportWe present the case of a 40-year-old woman who presented with abdominal bloating and nausea 2 weeks after undergoing in vitro fertilization (IVF); she was diagnosed by an outside radiology ultrasound as having a ruptured ovarian cyst. A point-of-care emergency ultrasound performed by the emergency physician made the diagnosis of ovarian hyperstimulation syndrome. This led to more expedient management and obstetrical consultation.Why Should an Emergency Physician Be Aware of This?Abdominal bloating and nausea are common presenting complaints in pregnant women. OHSS is a rare but potentially fatal complication of IVF. Recognition and early diagnosis by the emergency physician can lead to appropriate intervention and consultation.



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Transient Coagulopathy Due to Wasp Sting: A Case Report

Publication date: Available online 18 December 2016
Source:The Journal of Emergency Medicine
Author(s): Jeremy Shaowei Mong, Chee Kheong Ooi
BackgroundInsect venom anaphylaxis is a potentially life-threatening disorder. Transient coagulopathy in insect venom anaphylaxis is a rare phenomenon.Case ReportA 41-year-old man presented to the Emergency Department (ED) with hypotension after a run in a park. History and examination revealed signs of anaphylactic shock. A deranged coagulation profile with a normal platelet count led to the diagnosis of wasp sting anaphylaxis.Why Should an Emergency Physician Be Aware of This?Transient deranged coagulation profile with a normal platelet count may arise from insect venom anaphylaxis. This specific finding may aid the emergency physician in making a diagnosis of anaphylactic shock in an otherwise healthy patient presenting with shock with no apparent cause.



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Limitations in Prehospital Communication Between Trauma Helicopter, Ambulance Services, and Dispatch Centers

Publication date: Available online 18 December 2016
Source:The Journal of Emergency Medicine
Author(s): Annelieke Maria Karien Harmsen, Georgios Giannakopoulos, Gaby Franschman, Herman Christiaans, Frank Bloemers
BackgroundPrehospital communication with Emergency Medical Services (EMS) is carried out in hectic situations. Proper communication among all medical personal is required to enhance collaboration, to provide the best care and enable shared situational awareness.ObjectiveThe objective of this article was to give insight into current Dutch prehospital emergency care communication among all EMS and evaluate the usage of a new physician staffed helicopter EMS (P-HEMS) cancellation model.MethodsTrauma-related P-HEMS dispatches between November 1, 2014 and May 31, 2015 for the Lifeliner 1 were included; a random sample of 100 dispatches was generated. Tape recordings on all verbal prehospital communication between the dispatch center, EMS, and P-HEMS were transcribed and analyzed. Qualitative content analysis was performed, using open coding to code key messages.ResultsNinety-two tape recordings were analyzed. The most frequent reason for P-HEMS dispatch was suspicion of brain injury (24%). The cancellation model was followed in 66%, overruled in 9%, and not applicable in 25%. The main reason for not adhering to the model was hemodynamic stability. In 5% of P-HEMS dispatches, a complete ABCD (airway, breathing, circulation, disability) methodology was used for handover, in 9% a complete Situation-Background-Assessment-Recommendation technique, in 2% a complete Mechanism-Injuries-Signs-Treatment method was used. The other handovers were incomplete.ConclusionsPrehospital handover between EMS on-scene and P-HEMS often entails insufficient information. The cancellation model for P-HEMS is frequently used and promotes adequate information transfer. To increase joined decision-making, more patient and situational information needs to be handed over. Standardization of prehospital trauma handovers will facilitate this and improve trauma patient's outcome.



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Reply to Jansen et al.

Publication date: Available online 18 December 2016
Source:The Journal of Emergency Medicine
Author(s): Peter Jacobsen, Niels Erik Ebbehøj




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Predictors of Intrathoracic Injury after Blunt Torso Trauma in Children Presenting to an Emergency Department as Trauma Activations

Publication date: Available online 18 December 2016
Source:The Journal of Emergency Medicine
Author(s): Caitlin McNamara, Irina Mironova, Erik Lehman, Robert P. Olympia
BackgroundThoracic injuries are a major cause of death associated with blunt trauma in children. Screening for injury with chest x-ray study, compared with chest computed tomography (CT) scan, has been controversial, weighing the benefits of specificity with the detriment of radiation exposure.ObjectiveTo identify predictors of thoracic injury in children presenting as trauma activations to a Level I trauma center after blunt torso trauma, and to compare these predictors with those previously reported in the literature.MethodsWe performed a retrospective chart review of pediatric patients (<18 years of age) who presented to the Emergency Department of a Level I trauma center between June 2010 and June 2013 as a trauma activation after sustaining a blunt torso trauma and who received diagnostic imaging of the chest as part of their initial evaluation.ResultsData analysis was performed on 166 patients. There were 33 patients (20%) with 45 abnormalities detected on diagnostic imaging of the chest, with the most common abnormalities being lung contusion (36%), pneumothorax (22%), and rib fracture (13%). Statistically significant predictors of abnormal diagnostic imaging of the chest included Glasgow Coma Scale score (GCS) < 15 (27% with abnormality vs. 13% without abnormality), hypoxia (22% vs. 5%), syncope/loss of consciousness (55% vs. 35%), cervical spine tenderness (12% vs. 3%), thoraco-lumbar-sacral spine tenderness (41% vs. 17%), and abdominal/pelvic tenderness (12% vs. 3%).ConclusionsBased on our data, predictors of thoracic injury in children after blunt torso trauma include GCS < 15, hypoxia, syncope/dizziness, cervical spine tenderness, thoraco-lumbar-sacral spine tenderness, and abdominal/pelvic tenderness.



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Emergency Department Cardiopulmonary Evaluation of Low-Risk Chest Pain Patients with Self-Reported Stress and Anxiety

Publication date: Available online 18 December 2016
Source:The Journal of Emergency Medicine
Author(s): Paul I. Musey, Jeffrey A. Kline
BackgroundChest pain is a high-risk emergency department (ED) chief complaint; the majority of clinical resources are directed toward detecting and treating cardiopulmonary emergencies. However, at follow-up, 80%–95% of these patients have only a symptom-based diagnosis; a large number have undiagnosed anxiety disorders.ObjectiveOur aim was to measure the frequency of self-identified stress or anxiety among chest pain patients, and compare their pretest probabilities, care processes, and outcomes.MethodsPatients were divided into two groups: explicitly self-reported anxiety and stress or not at 90-day follow-up, then compared on several variables: ultralow (<2.5%) pretest probability, outcome rates for acute coronary syndrome (ACS) and pulmonary embolism (PE), radiation exposure, total costs at 30 days, and 90-day recidivism.ResultsEight hundred and forty-five patients were studied. Sixty-seven (8%) explicitly attributed their chest pain to "stress" or "anxiety"; their mean ACS pretest probability was 4% (95% confidence interval 2.9%–5.7%) and 49% (33/67) had ultralow pretest probability (0/33 with ACS or PE). None (0/67) were diagnosed with anxiety. Seven hundred and seventy-eight did not report stress or anxiety and, of these, 52% (403/778) had ultralow ACS pretest probability. Only one patient (0.2%; 1/403) was diagnosed with ACS and one patient (0.4%; 1/268) was diagnosed with PE. Patients with self-reported anxiety had similar radiation exposure, associated costs, and nearly identical (25.4% vs. 25.7%) ED recidivism to patients without reported anxiety.ConclusionsWithout prompting, 8% of patients self-identified "stress" or "anxiety" as the etiology for their chest pain. Most had low pretest probability, were over-investigated for ACS and PE, and not investigated for anxiety syndromes.



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Subject Index

Publication date: December 2016
Source:Clinical Therapeutics, Volume 38, Issue 12





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Editorial Board

Publication date: December 2016
Source:Clinical Therapeutics, Volume 38, Issue 12





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Table of Contents

Publication date: December 2016
Source:Clinical Therapeutics, Volume 38, Issue 12





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A Note of Thanks

Publication date: December 2016
Source:Clinical Therapeutics, Volume 38, Issue 12





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SGLT2 Inhibitor–associated Diabetic Ketoacidosis: Clinical Review and Recommendations for Prevention and Diagnosis

Publication date: December 2016
Source:Clinical Therapeutics, Volume 38, Issue 12
Author(s): Ronald M. Goldenberg, Lori D. Berard, Alice Y.Y. Cheng, Jeremy D. Gilbert, Subodh Verma, Vincent C. Woo, Jean-François Yale
PurposeSodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents available on the market. Regulator warnings and concerns regarding the risk of developing diabetic ketoacidosis (DKA), however, have dampened enthusiasm for the class despite the combined glycemic, blood pressure, and occasional weight benefits of SGLT2 inhibitors. With the goal of improving patient safety, a cross-Canada expert panel and writing group were convened to review the evidence to-date on reported SGLT2 inhibitor–related DKA incidents and to offer recommendations for preventing and recognizing patients with SGLT2 inhibitor–associated DKA.MethodsReports covering DKA events in subjects taking SGLT2 inhibitors that were published in PubMed, presented at professional conferences, or in the public domain from January 2013 to mid-August 2016 were reviewed by the group independently and collectively. Practical recommendations for diagnosis and prevention were established by the panel.FindingsDKA is rarely associated with SGLT2 inhibitor therapy. Patients with SGLT2 inhibitor–associated DKA may be euglycemic (plasma glucose level <14 mmol/L). DKA is more likely in patients with insulin-deficient diabetes, including those with type 2 diabetes, and is typically precipitated by insulin omission or dose reduction, severe acute illness, dehydration, extensive exercise, surgery, low-carbohydrate diets, or excessive alcohol intake. SGLT2 inhibitor–associated DKA may be prevented by withholding SGLT2 inhibitors when precipitants develop, avoiding insulin omission or inappropriate insulin dose reduction, and by following sick day protocols as recommended.ImplicationsPreventive strategies should help avoid SGLT2 inhibitor–associated DKA. All SGLT2 inhibitor–treated patients presenting with signs or symptoms of DKA should be suspected to have DKA and be investigated for DKA, especially euglycemic patients. If DKA is diagnosed, SGLT2 inhibitor treatment should be stopped, and the DKA should be treated with a traditional treatment protocol.



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Author Index

Publication date: December 2016
Source:Clinical Therapeutics, Volume 38, Issue 12





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Population Pharmacokinetic–Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects

Publication date: December 2016
Source:Clinical Therapeutics, Volume 38, Issue 12
Author(s): Hyang-Ki Choi, Jin Ah Jung, Tomoe Fujita, Hideki Amano, Jong-Lyul Ghim, Dong-Hwan Lee, Kenichi Tabata, Il-Dae Song, Mika Maeda, Yuji Kumagai, Boaz Mendzelevski, Jae-Gook Shin
PurposeThe goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences.MethodsThis multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic–pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method.FindingsA total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration–effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin's pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An Emax model (E[C]=[Emax⋅C]/[EC50+C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic–pharmacodynamic link model.ImplicationsThe drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316.



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The importance of TH22 and TC22 cells in the pathogenesis of Helicobacter pylori-associated gastric diseases

Abstract

Background

An association exists between Helicobacter pylori (H. pylori), peptic ulcers, gastritis, and sometimes gastric carcinomas. Th22 cells have protective and inflammatory roles in defense against microbes.

Aim

We investigated the frequencies of Th22, Tc22, Th22/17, and Tc22/17 cells in addition to the changes in levels of cytokines IL-22, IL-6, IL-23, TNF-α, IL-1β, and TGF-β in sera from patients with H. pylori-associated gastritis, and peptic ulcer, and in uninfected patients.

Methods

A total of 76 patients with H. pylori-associated disorders formed the studied group. Frequencies of T-cell subsets were determined by flow cytometry. Levels of cytokines IL-22, IL-6, IL-23, TNF-α, IL-1β, and TGF-β in the sera and supernatants of patients were measured by ELISA and flow cytometry.

Results

The study participants included 32 males and 44 females with a mean age of 38.5±15.3 years. We divided the infected group into peptic ulcer and gastritis (mild, moderate, active chronic, and chronic). The frequencies of Th22, Tc22, and Tc22/17 increased significantly in the peptic ulcer, moderate, active chronic, and chronic gastritis groups compared to the uninfected group. Th22/17 only increased significantly in the chronic gastritis group. We observed significant increases in IL-22 in the moderate and active chronic gastritis, IL-23 in the active chronic and chronic gastritis, and TNF-α in the peptic ulcer and moderate gastritis groups. Following in vitro antigenic stimulation, we observed significantly higher levels of IL-1β, IL-23, and IL-6 in the active chronic gastritis group, as well as IL-6 and IL-1β in the chronic gastritis group compared to the uninfected group.

Conclusion

Increased Th22, Tc22, and Tc22/17 cells and IL-22 levels appear to be influential in progression and severity of H. pylori infection. Th22/17 can be an interesting therapeutic target for chronic H. pylori infections where eradication is more difficult.

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The roles of oncogenic miRNAs and their therapeutic importance in breast cancer

Publication date: February 2017
Source:European Journal of Cancer, Volume 72
Author(s): Samia O'Bryan, Shengli Dong, J. Michael Mathis, Suresh K. Alahari
Since the discovery of tumour suppressive miRNA in 2002, the dysregulation of miRNAs was implicated in many cancers, exhibiting both tumour suppressive and oncogenic roles. Dysregulation of miRNAs was found to be involved in the initiation of oncogenesis, as well as the progression, invasion and metastasis of cancers. While normal miRNA inhibitory functions help regulate gene expression in the cell, oncogenic miRNA, when dysregulated can lead to suppression of critical pathways that control apoptosis, cell cycle progression, growth and proliferation. This suppression allows for the upregulation of pro-oncogenic factors that drive cell survival, growth and proliferation. Due to emerging discoveries, oncogenic miRNAs are proving to be a critical component in cancers, such as breast cancer, and may provide novel avenues for cancer treatment. In this article, we discuss the roles of the most studied oncogenic miRNAs in breast cancer including clusters and families involved as well as the less studied and recently discovered oncogenic miRNAs. These miRNAs provide valuable information into the complexity of regulatory elements affected by their overexpression and the overall impact in the progression of breast cancer. Also, identifying miRNAs causing or leading to resistance or sensitivity to current anti-cancer drugs prior to treatment may lead to an improvement in treatment selection and overall patient response. This review summarizes known and recently discovered miRNAs in literature found to have oncogenic roles in breast cancer initiation and the progression, invasion and metastasis of the disease.



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Transcriptional architecture of the mammalian circadian clock

Nature Reviews Genetics. doi:10.1038/nrg.2016.150

Author: Joseph S. Takahashi

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Genetic engineering: CREATE-ing genome-wide designed mutations

Nature Reviews Genetics. doi:10.1038/nrg.2016.163

Author: Darren J. Burgess

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Antiprotozoal glutathione derivatives with flagellar membrane binding activity against T. brucei rhodesiense

Publication date: Available online 18 December 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Sylvie Daunes, Vanessa Yardley, Simon.L. Croft, Claudius D'Silva
A new series of N-substituted S-(2,4-dinitrophenyl)glutathione dibutyl diesters were synthesized to improve in vitro anti-protozoal activity against the pathogenic parasites Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani. The results obtained indicate that N-substituents enhance the inhibitory properties of glutathione diesters whilst showing reduced toxicity against KB cells as in the cases of compounds 5, 9, 10, 16, 18 and 19. We suggest that the interaction of N-substituted S-(2,4-dinitrophenyl) glutathione dibutyl diesters with T. b. brucei occurs mainly by weak hydrophobic interactions such as London and van der Waals forces. A QSAR study indicated that the inhibitory activity of the peptide is associated negatively with the average number of C atoms, NC and positively to SZX, the ZX shadow a geometric descriptor related to molecular size and orientation of the compound. HPLC-UV studies in conjunction with optical microscopy indicate that the observed selectivity of inhibition of these compounds against bloodstream form T. b.brucei parasites in comparison to L. donovani under the same conditions is due to intracellular uptake via endocytosis in the flagellar pocket.

Graphical abstract

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New derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity

Publication date: Available online 18 December 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Johanna Faist, Clemens Hinteregger, Werner Seebacher, Robert Saf, Pascal Mäser, Marcel Kaiser, Robert Weis
Novel ω-aminoacyl and -alkyl derivatives of 7-chloroquinolin-4-amine were prepared and their structures confirmed by NMR spectroscopy. Their antiprotozoal activities were examined in vitro against the sensitive NF54 strain as well as against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). The results were compared with the activities of clinically used drugs. Their antitrypanosomal activities were only moderate whereas their antiplasmodial activities looked very promising. Some were equal or slightly more active than chloroquine against the sensitive strain. However, in comparison to chloroquine, the activity of the new compounds was decreased much less in the resistant strain. Several possessed activity against both strains in low nanomolar concentration.

Graphical abstract

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Lycopene pretreatment improves hepatotoxicity induced by acetaminophen in C57BL/6 mice

Publication date: Available online 18 December 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Ana Carla Balthar Bandeira, Rafaella Cecília da Silva, Joamyr Victor Rossoni Júnior, Vivian Paulino Figueiredo, André Talvani, Silvia Dantas Cangussú, Frank Silva Bezerra, Daniela Caldeira Costa
Acetaminophen (APAP) is an antipyretic and analgesic drug that, in high doses, leads to severe liver injury and potentially death. Oxidative stress is an important event in APAP overdose. Researchers are looking for natural antioxidants with the potential to mitigate the harmful effects of reactive oxygen species in different models. Lycopene has been widely studied for its antioxidant properties. The aim of this study was to evaluate the antioxidant potential of lycopene pretreatment in APAP-induced liver injury in C57BL/6 mice. C57BL/6 male mice were divided into the following groups: control (C); sunflower oil (CO); acetaminophen 500 mg/kg (APAP); acetaminophen 500 mg/kg + lycopene 10 mg/kg (APAP+L10), and acetaminophen 500 mg/kg + lycopene 100 mg/kg (APAP+L100). Mice were pretreated with lycopene for 14 consecutive days prior to APAP overdose. Analyses of blood serum and livers were performed. Lycopene was able to improve redox imbalance, decrease thiobarbituric acid reactive species level, and increase CAT and GSH levels. In addition, it decreased the IL-1β expression and the activity of MMP-2. This study revealed that preventive lycopene consumption in C57BL/6 mice can attenuate the effects of APAP-induced liver injury. Furthermore, by improving the redox state, and thus indicating its potential antioxidant effect, lycopene was also shown to have an influence on inflammatory events.

Graphical abstract

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Aqueous synthesis of Ag and Mn co-doped In2S3/ZnS quantum dots with tunable emission for dual-modal targeted imaging

Publication date: Available online 18 December 2016
Source:Acta Biomaterialia
Author(s): Pei-Yu Lai, Chih-Ching Huang, Tzung-Han Chou, Keng-Liang Ou, Jia-Yaw Chang
Here, we present the microwave-assisted synthesis of In2S3/ZnS core/shell quantum dots (QDs) co-doped with Ag⁺ and Mn²⁺ (referred to as AgMn:In2S3/ZnS). Ag⁺ altered the optical properties of the host QDs, whereas the spin magnetic moment (S = 5/2) of Mn²⁺ efficiently induced the longitudinal relaxation of water protons. To the best of our knowledge, this is the first report of the aqueous synthesis of color-tunable AgMn:In2S3/ZnS core/shell QDs with magnetic properties. The synthetic procedure is rapid, facile, reproducible, and scalable. The obtained QDs offered a satisfactory quantum yield (45%), high longitudinal relaxivity (6.84 s^–1 mM^–1), and robust photostability. In addition, they exhibited excellent stability over a wide pH range (5–12) and high ionic strength (0.15–2.0 M NaCl). As seen by confocal microscopy and magnetic resonance imaging, AgMn:In2S3/ZnS conjugated to hyaluronic acid (referred to as AgMn:In2S3/ZnS@HA) efficiently and specifically targeted cluster determinant 44, a receptor overexpressed on cancer cells. Moreover, AgMn:In2S3/ZnS@HA showed negligible cytotoxicity in vitro and in vivo, rendering it a promising diagnostic probe for dual-modal imaging in clinical applications.

Graphical abstract

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Injectable Hyaluronic Acid Down-regulates Interferon Signaling Molecules, IGFBP3 and IFIT3 in the Bovine Intervertebral Disc

Publication date: Available online 18 December 2016
Source:Acta Biomaterialia
Author(s): Zepur Kazezian, Zhen Li, Mauro Alini, Sibylle Grad, Abhay Pandit
Low back pain which is a major cause of disability for people aged between 20 and 50 years imposes a serious socio-economic burden. The current focus of regenerative medicine is on identifying molecular markers to facilitate the design of targeted therapeutics. Previously, we have demonstrated that expression of the anti-proliferative interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) and pro-apoptotic insulin-like growth factor-binding protein-3 (IGFBP3), are up-regulated as downstream targets of the inflammatory cytokine interferon α (IFNα) signaling pathway in the human annulus fibrosus (AF). Here, we hypothesized that injection of hyaluronic acid (HA) would have an anti-inflammatory and matrix modulatory effect on injured and IFNα2β inflamed bovine intervertebral discs (IVD). Discs with an AF defect and challenged with IFNα2β were used in a bovine IVD organ culture model to test the effect of HA on the IFNα2β pathway, as well as the matrix proteins aggrecan and collagen I. qRT-PCR was used to assess the gene expression of IFNα2β signaling molecules. Additionally, immunostaining was used to measure protein expression. Our results show that HA treatment significantly down-regulates IFNAR1, IFNAR2, STAT1/2, JAK1, IFIT3 and IGFBP3 mRNA expression in the inflamed groups. Protein analysis confirmed the PCR results. In the extracellular matrix, aggrecan and collagen I were up-regulated while ADAMTS4 was down-regulated upon treatment of the injured and inflamed discs with HA. Hence, HA demonstrates both an anti-inflammatory role, resulting in the down-regulation of IFIT3 and IGFBP3 in the AF, and a matrix modulatory effect by up-regulating aggrecan and collagen I expression.Statement of significanceThe pro-inflammatory environment of the degenerated IVD represents a challenge for regenerative therapies. The study demonstrates that hyaluronan acts as an anti-inflammatory molecule by down-regulating IFNAR1 and IFNAR2, the signalling molecules STAT1, STAT2, JAK1 and the downstream apoptotic targets IGFBP3 and IFIT3. We also demonstrated that hyaluronan modulates the disc matrix environment by increasing aggrecan and collagen I synthesis and down-regulating ADAMTS4 that degrades the matrix under inflammatory conditions. The significance of this work lies in the fact that hyaluronan acts as an anti-inflammatory molecule by shifting the disc environment towards a more anabolic state and by promoting native IVD matrix production.

Graphical abstract

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Self-assembled supramolecular polymers with tailorable properties that enhance cell attachment and proliferation

Publication date: Available online 18 December 2016
Source:Acta Biomaterialia
Author(s): Chih-Chia Cheng, Duu-Jong Lee, Jem-Kun Chen
Self-assembled supramolecular scaffolds, a combination of noncovalent interactions within a biocompatible polymer substrate, can be used for efficient construction of highly-controlled self-organizing hierarchical structures; these newly-developed biomaterials exhibit excellent mechanical properties, tunable surface hydrophilicity, low cytotoxicity and high biodegradability, making them highly attractive for tissue engineering and regenerative medicine applications. Herein, we demonstrate a novel supramolecular poly(ε-caprolactone) (PCL) containing self-complementary sextuple hydrogen-bonded uracil-diamidopyridine (U-DPy) moieties, which undergoes spontaneous self-assembly to form supramolecular polymer networks. Inclusion of various U-DPy contents enhanced the mechanical strength and viscosities of the resulting materials by up to two orders of magnitude compared to control PCL. Surface wettability and morphological studies confirmed physically-crosslinked films can be readily tailored to provide the desired surface properties. Cell viability assays indicated the excellent in vitro biocompatibility of U-DPy-functionalized substrates and indicate the potential of these materials for various biomedical applications. More importantly, mouse fibroblast NIH/3T3 cells cultured on these substrates displayed a more elongated cell morphology and had substantially higher cell densities than cells seeded on control PCL substrate, which indicates that introduction of U-DPy moieties into polymer matrixes could be used to create tissue culture surfaces that enhance cell attachment and proliferation. This new system is suggested as a potential route towards the practical realization of next-generation tissue-engineering scaffolds.Statement of SignificanceIn this study, we report a significant breakthrough in development of self-assembled supramolecular polymers to form well-defined scaffolds through self-complementary hydrogen-bonding interactions. These newly developed materials exhibited extremely good mechanical properties, fine-tunable hydrophilic characteristics and excellent biocompatibility due to hydrogen-bond-induced physical cross-linking. Importantly, cell adhesion and proliferation assays indicated that these substrates efficiently promoted the growth of mouse embryonic fibroblasts NIH/3T3 cells in vitro. Thus, this finding provides a simple and effective route for the development of next-generation tissue-engineering scaffolds that have improved mechanical properties, increased surface hydrophilicity and can enhance the growth and biological activity of adherent cells.

Graphical abstract

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A simple basis for determination of the Modulus and Hydraulic Conductivity of human ocular surface using nano-indentation

Publication date: Available online 18 December 2016
Source:Acta Biomaterialia
Author(s): M.V. Swain, J. Nohava, P. Eberwein
This paper presents a simple analysis based upon Darcy's Law and indentation contact mechanics to determine the effective hydraulic conductivity and elastic modulus of fluid filled tissues. The approach is illustrated with the mechanical response of the human ocular surface using a 500 μm radius spherical tipped indenter. Indentations of various regions of the ocular surface including the corneal stroma, limbal region and sclera have been conducted. Force-control indentations were made to a maximum force, which was maintained before unloading. Measurements of the indentation response of cornea at three different loading rates were also made. Elastic like response was observed during loading, which was followed by extensive creep prior to unloading.Statement of significanceThis manuscript attempts to provide a relatively simply model for the contact loading of fluid containing tissues and materials. It shows that the response of such materials provides a basis for determining the effective modulus and effective hydraulic conductivity (permeability) in much the same manner that hardness and modulus do for the indentation of elastic-plastic materials. Eye tissue with its anisotropic elastic and permeability properties is used to illustrate the approach.

Graphical abstract

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Sustained tobramycin release from polyphosphate double network hydrogels

Publication date: Available online 18 December 2016
Source:Acta Biomaterialia
Author(s): Dwight D. Lane, Amber K. Fessler, Seungah Goo, Dustin L. Williams, Russell J. Stewart
Sustained local delivery of antibiotics from a drug reservoir to treat or prevent bacterial infections can avoid many of the drawbacks of systemic administration of antibiotics. Prolonged local release of high concentrations of antibiotics may also be more effective at treating bacteria in established biofilm populations that are resistant to systemic antibiotics. A double network hydrogel comprising an organic polyphosphate pre-polymer network polymerized within a polyacrylamide network de-swelled to about 50% of its initial volume when the polyphosphate network was crosslinked with polycationic tobramycin, an aminoglycoside antibiotic. The antibiotic-loaded hydrogels contained approximately 200 mg/ml of tobramycin. The hydrogels continuously released daily amounts of tobramycin above the Pseudomonas aeruginosa minimal bactericidal concentration for greater than 50 days, over the pH range 6.0 to 8.0, and completely eradicated established P. aeruginosa biofilms within 72 h in a flow cell bioreactor. The presence of physiological concentrations of Mg²⁺ and Ca²⁺ ions doubled the cumulative release over 60 days. The polyphosphate hydrogels show promise as materials for sustained localized tobramycin delivery to prevent post-operative P. aeruginosa infections including infections established in biofilms.Statement of SignificancePolyphosphate hydrogels were loaded with high concentrations of tobramycin. The hydrogels provided sustained release of bactericidal concentrations of tobramycin for 50 days, and were capable of completely eradicating P. aeruginosa in established biofilms. The hydrogels have potential for localized prevention or treatment of P. aeruginosa infections.

Graphical abstract

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Controlling the selective and directional migration of hepatocytes by a complementary density gradient of glycosylated hyperbranched polymers and poly(ethylene glycol) molecules

Publication date: Available online 18 December 2016
Source:Acta Biomaterialia
Author(s): Su Liang, Shan Yu, Ning Zhou, Jun Deng, Changyou Gao
Repair and regeneration of defected tissues and organs depends strongly on the directional migration of targeted cells, for example, the enhancement of directional migration of hepatocytes could be helpful in liver regeneration and transplantation. Herein a complementary gradient of galactose-modified hyperbranched polymers (LA-HPMA) and poly(ethylene glycol) (PEG) molecules was designed and prepared on a same substrate. Characterizations of X-ray photoelectron spectrometry and quartz crystal microbalance with dissipation (QCM-d) demonstrated the unidirectional change in grafting density of LA-HPMA and PEG molecules, respectively. On the LA-HPMA/PEG complementary gradient surface, the human hepatoma (HepG2) cells showed preferential orientation and enhanced directional migration toward the region of lower PEG density and higher LA-HPMA density. By contrast, the mouse embryonic fibroblasts (NIH3T3) showed random migration irrelevant to the gradient. The success of the complementary gradient relies on the specific interaction between galactose and asialoglyco protein receptor (ASGPR) expressed on HepG2 cells.SignificanceA continuous complementary gradient of glycosylated hyperbranched polymers and PEG is fabricated to govern cell-substrate interaction.Selective and directional migration of hepatocytes over fibroblasts is achieved on the complementary gradient.A new perspective on designing complex biomaterials for desired tissue regeneration.

Graphical abstract

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Title page

Publication date: September–December 2016
Source:Current Problems in Cancer, Volume 40, Issues 5–6





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Table of Contents

Publication date: September–December 2016
Source:Current Problems in Cancer, Volume 40, Issues 5–6





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Amyloidosis: A rare disease with varied manifestations

Publication date: September–December 2016
Source:Current Problems in Cancer, Volume 40, Issues 5–6
Author(s): Beata Holkova




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Title page

Publication date: March–August 2016
Source:Current Problems in Cancer, Volume 40, Issues 2–4





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Table of Contents

Publication date: March–August 2016
Source:Current Problems in Cancer, Volume 40, Issues 2–4





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Adaptation to Leftward Shifting Prisms Alters Motor Interhemispheric Inhibition

Adaptation to rightward shifting prisms (rightward prism adaptation, RPA) ameliorates neglect symptoms in patients while adaptation to leftward shifting prisms (leftward prism adaptation, LPA) induces neglect-like behaviors in healthy subjects. It has been hypothesized that prism adaptation (PA) modulates interhemispheric balance between the parietal cortices by inhibiting the posterior parietal cortex (PPC) contralateral to the prismatic deviation, but PA's effects on interhemispheric inhibition (IHI) have not been directly investigated. Since there are hyper-excitable connections between the PPC and primary motor cortex (M1) in the left hemisphere of neglect patients, we reasoned that LPA might mimic right hemisphere lesions by reducing parietal IHI, hyper-exciting the left PPC and PPC-M1 connections, and in turn altering IHI at the motor level. Namely, we hypothesized that LPA would increase IHI from the left to the right M1. We examined changes in left-to-right and right-to-left IHI between the 2 M1s using the ipsilateral silent period (iSP) (Meyer et al. 1995) before and after either LPA or RPA. The iSP was significantly longer after LPA but only from left-to-right and it did not change at all after RPA. This is the first physiological demonstration that LPA alters IHI in the healthy brain.

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Parsing the Role of the Hippocampus in Approach-Avoidance Conflict

The hippocampus plays a central role in the approach–avoidance conflict that is central to the genesis of anxiety. However, its exact functional contribution has yet to be identified. We designed a novel gambling task that generated approach–avoidance conflict while controlling for spatial processing. We fit subjects' behavior using a model that quantified the subjective values of choice options, and recorded neural signals using functional magnetic resonance imaging (fMRI). Distinct functional signals were observed in anterior hippocampus, with inferior hippocampus selectively recruited when subjects rejected a gamble, to a degree that covaried with individual differences in anxiety. The superior anterior hippocampus, in contrast, uniquely demonstrated value signals that were potentiated in the context of approach–avoidance conflict. These results implicate the anterior hippocampus in behavioral avoidance and choice monitoring, in a manner relevant to understanding its role in anxiety. Our findings highlight interactions between subregions of the hippocampus as an important focus for future study.

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Genetic engineering: CREATE-ing genome-wide designed mutations

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Transcriptional architecture of the mammalian circadian clock

Next-generation sequencing approaches have yielded new insights into circadian function. Here, Takahashi reviews genome-wide analyses of the clock transcriptional feedback loop in mammals, which reveal a global circadian regulation of transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription and chromatin remodelling.

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Cutaneous Merkel cell carcinoma: multiple asynchronous primary lesions in a patient on immunosuppressive therapy

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New guidelines for management of febrile seizures in Japan

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Jun Natsume, Shin-ichiro Hamano, Kuniaki Iyoda, Hideaki Kanemura, Masaya Kubota, Masakazu Mimaki, Shinichi Niijima, Takuya Tanabe, Harumi Yoshinaga, Noriko Kojimahara, Hirohumi Komaki, Kenji Sugai, Tokiko Fukuda, Yoshihiro Maegaki, Hideo Sugie
In 2015, the Japanese Society of Child Neurology released new guidelines for the management of febrile seizures, the first update of such guidelines since 1996. In 1988, the Conference on Febrile Convulsions in Japan published "Guidelines for the Treatment of Febrile Seizures." The Task Committee of the Conference proposed a revised version of the guidelines in 1996; that version released in 1996 was used for the next 19years in Japan for the clinical management of children with febrile seizures. Although the guidelines were very helpful for many clinicians, new guidelines were needed to reflect changes in public health and the dissemination of new medical evidence. The Japanese Society of Child Neurology formed a working group in 2012, and published the new guidelines in March 2015. The guidelines include emergency care, application of electroencephalography, neuroimaging, prophylactic diazepam, antipyretics, drugs needing special attention, and vaccines. While the new guidelines contain updated clinical recommendations, many unsolved questions remain. These questions should be clarified by future clinical research.



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Prenatal irradiation–induced brain neuropathology and cognitive impairment

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Bo Yang, Bo Xu Ren, Feng Ru Tang
Embryo/fetus is much more radiosensitive than neonatal and adult human being. The main potential effects of pre-natal radiation exposure on the human brain include growth retardation, small head/brain size, mental retardation, neocortical ectopias, callosal agenesis and brain tumor which may result in a lifetime poor quality of life. The patterns of prenatal radiation-induced effects are dependent not only on the stages of fetal development, the sensitivity of tissues and organs, but also on radiation sources, doses, dose rates. With the increased use of low dose radiation for diagnostic or radiotherapeutic purposes in recent years, combined with postnatal negative health effect after prenatal radiation exposure to fallout of Chernobyl nuclear power plant accident, the great anxiety and unnecessary termination of pregnancies after the nuclear disaster, there is a growing concern about the health effect of radiological examinations or therapies in pregnant women. In this paper, we reviewed current research progresses on pre-natal ionizing irradiation–induced abnormal brain structure changes. Subsequent postnatal neuropsychological and neurological diseases were provided. Relationship between irradiation and brain aging was briefly mentioned. The relevant molecular mechanisms were also discussed. Future research directions were proposed at the end of this paper. With limited human data available, we hoped that systematical review of animal data could relight research interests on prenatal low dose/dose rate irradiation–induced brain microanatomical changes and subsequent neurological and neuropsychological disorders.



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The pathology of incipient polymicrogyria

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Phedias Diamandis, David Chitayat, Ants Toi, S. Blaser, Patrick Shannon
ObjectiveTo characterise the early tissue changes of post encephaloclastic polymicrogyria in the human fetus.MethodsWe identified and reviewed the clinical histories and autopsy pathology of post ischemic fetal cerebral cortical injury at less than 30weeks gestational age (GA). The histology of local cortical abnormalities was examined with neuronal, glial, microglial and vascular immunohistochemical markers.ResultsWe identified eight cases ranging from 18 to 29weeks GA: 5 cases show full thickness cortical infarcts and 3 show periSylvian post-ischemic necrosis of the cerebral cortex. The maximal age is less than 10weeks after injury. There are abnormalities in gross fissuration as early as one month after injury. Disruption of the pia limitans was associated with a microglial and glial response and full thickness cortical injury. Macrophages were often seen accumulating deep to abnormal cortex. Hyperplasia of the subpial granular cell layer was universal in perilesional cortex. Cajal Retzius neuron hyperplasia, aggregation, and both superficial and deep displacement were noted. Where there was loss and dispersal of early cortical pyramidal neurons there was usually no pseudolaminar necrosis. Radial glia by 18weeks GA showed altered growth patterns and lateral branching. Altered migration of primitive elements was often prominent. Particularly prior to 20weeks GA subadjacent subplate neurons showed striking hypertrophy.ConclusionsThe array of histological changes encompasses all tissue elements of the affected brains, early in the evolution polymicrogyria. Although subpial alterations were ubiquitous, not all changes are referable to alterations in the pia limitans. The role of the necroinflammatory response in the genesis of abnormal cytoarchitecture deserves further study.



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Longitudinal change in white matter in preterm infants without magnetic resonance imaging abnormalities: Assessment of serial diffusion tensor imaging and their relationship to neurodevelopmental outcomes

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Satoshi Kidowaki, Masafumi Morimoto, Kei Yamada, Koji Sakai, Masashi Zuiki, Hiroshi Maeda, Satoshi Yamashita, Takashi Morita, Tatsuji Hasegawa, Tomohiro Chiyonobu, Sachiko Tokuda, Hajime Hosoi
PurposeWe used diffusion tensor imaging (DTI) to evaluate longitudinal changes in fractional anisotropy (FA) of white matter tracts in preterm infants without abnormal magnetic resonance imaging (MRI) findings. Imaging was conducted at term equivalent age (TEA) and 1year of corrected age. Furthermore, we assessed correlations between FA and neurodevelopmental outcomes at 3years of corrected age to investigate brain prematurity of preterm infants without MRI abnormalities.MethodsPreterm infants underwent serial MRI at TEA and 1year of corrected age. Of these, 13 infants entered a retrospective study, undergoing neurodevelopmental assessment at 3years of corrected age. These infants were divided into two groups depending on gestational age (GA): <26weeks and ⩾26weeks. DTI-based tractography was performed to obtain the FA of the motor tract, sensory tract, superior cerebellar peduncle, middle cerebellar peduncle, and corpus callosum. FA was compared between two groups, and correlations between FA and neurodevelopmental outcomes were assessed.ResultsFA of the splenium at TEA was significantly different between the two groups divided according to GA. However, this difference was no longer observed at 1year of corrected age. There was no correlation between FA of the splenium at TEA and neurodevelopmental assessment scores at 3years of corrected age.ConclusionsAt TEA, FA of the splenium was lower in younger GA infants without MRI abnormalities, but this may not affect subsequent neurodevelopmental outcomes.



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Editorial Board

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1





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Efficacy of bezafibrate on fibroblasts of glutaric acidemia type II patients evaluated using an in vitro probe acylcarnitine assay

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Kenji Yamada, Hironori Kobayashi, Ryosuke Bo, Jamiyan Purevsuren, Yuichi Mushimoto, Tomoo Takahashi, Yuki Hasegawa, Takeshi Taketani, Seiji Fukuda, Seiji Yamaguchi
IntroductionWe evaluated the effects of bezafibrate (BEZ) on β-oxidation in fibroblasts obtained from patients with glutaric acidemia type II (GA2) of various clinical severities using an in vitro probe (IVP) assay.MethodsCultured fibroblasts from 12 patients with GA2, including cases of the neonatal-onset type both with and without congenital anomalies (the prenatal- and neonatal-onset forms, respectively), the infantile-onset, and the myopathic forms, were studied. The IVP assay was performed by measuring acylcarnitines (ACs) in the cell culture medium of fibroblasts incubated with palmitic acid for 96h in the presence of 0–800μM BEZ using tandem mass spectrometry.ResultsThe IVP assay showed that 100μM BEZ markedly reduced the level of palmitoylcarnitine (C16) in the neonatal-onset, infantile-onset, and myopathic forms of GA2, either increasing or maintaining a high level of acetylcarnitine (C2), which serves as an index of energy production via β-oxidation. In the prenatal-onset form, although a small reduction of C16 was also observed in the presence of 100μM BEZ, the level of C2 remained low. At concentrations higher than 100μM, BEZ further decreased the level of ACs including C16, but a concentration over 400μM decreased the level of C2 in most cases.DiscussionBEZ at 100μM was effective for all GA2 phenotypes except for the prenatal-onset form, as a reduction of C16 without deterioration of C2 is considered to indicate improvement of β-oxidation. The effects of higher doses BEZ could not be estimated by the IVP assay but might be small or nonexistent.



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A Japanese case of β-ureidopropionase deficiency with dysmorphic features

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Tomoyuki Akiyama, Takashi Shibata, Harumi Yoshinaga, Tomiko Kuhara, Yoko Nakajima, Takema Kato, Yasuhiro Maeda, Morimasa Ohse, Makio Oka, Misao Kageyama, Katsuhiro Kobayashi
β-Ureidopropionase deficiency is a rare autosomal recessive disease affecting the last step of pyrimidine degradation, and it is caused by a mutation in the UPB1 gene. Approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. Non-neurological symptoms have been rarely reported. We describe a case of this disease with developmental delay and dysmorphic features. Gas chromatography–mass spectrometry-based urine metabolomics demonstrated significant (⩾+4.5 standard deviation after logarithmic transformation) elevations of β-ureidopropionic acid and β-ureidoisobutyric acid, strongly suggesting a diagnosis of β-ureidopropionase deficiency. Subsequent quantitative analysis of pyrimidines by liquid chromatography–tandem mass spectrometry supported this finding. Genetic testing of the UPB1 gene confirmed compound heterozygosity of a novel mutation (c.976C>T) and a previously-reported mutation (c.977G>A) that is common in East Asians. β-Ureidopropionase deficiency is probably underdiagnosed, considering a wide phenotypical variability, non-specific neurological presentations, and an estimated prevalence of 1/5000–6000. Urine metabolomics should be considered for patients with unexplained neurological symptoms.



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Cerebral arteriopathy associated with heterozygous Arg179Cys mutation in the ACTA2 gene: Report in 2 newborn siblings

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Jose de Grazia, Ignacio Delgado, Angel Sanchez-Montanez, Susana Boronat, Miguel del Campo, Elida Vazquez
Mutations in the ACTA2 gene lead to a multisystemic smooth muscle dysfunction syndrome that causes vascular disease, congenital mydriasis, and variable presentation of urinary and gastrointestinal problems. The heterozygous Arg179 mutation is associated with a distinctive cerebrovascular phenotype. We report the cases of two newborn siblings with heterozygous ACTA2 Arg179Cys substitution and provide neuroimaging exams that demonstrate the distinctive cerebrovascular phenotype, also associated with variable degree of hypoplasia of the vertebro-basilar circulation as well as hypoxic-ischemic lesions.



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Epileptic phenotype of FGFR3-related bilateral medial temporal lobe dysgenesis

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Tetsuya Okazaki, Yoshiaki Saito, Riyo Ueda, Takeya Awashima, Yoko Nishimura, Isao Yuasa, Yuki Shinohara, Kaori Adachi, Masayuki Sasaki, Eiji Nanba, Yoshihiro Maegaki
Hypochondroplasia (HCH) is a skeletal dysplasia, characterized by short stature and macrocephaly. Clinical symptoms and radiological and histopathological features of HCH are similar, but milder than those seen in achondroplasia. Particularly, HCH patients with Asn540Lys mutation in the FGFR3 gene are reported to have medial temporal lobe dysgenesis and epilepsy.We report a 3-year-old girl who developed recurrent epileptic apnea, which started immediately after birth. The apneic seizures were refractory to antiepileptic medications; ictal electroencephalography showed rhythmic activity originating from the left or right temporal areas and rarely from the right frontal area. Macrocephaly was noted since birth. Neuroimaging revealed bilateral dysgenesis and hypometabolism of the medial temporal structures as well as perfusion changes in the left lateral temporofrontal areas during the ictal period. Clonazepam was initiated and acetazolamide dosage was increased at 6months, resulting in complete seizure control after 8months of age. Genetic analysis identified an Asn540Lys (c.1620 C>A) mutation in the FGFR3 gene. Characteristic bone findings on the lumbar spine, iliac bone, and femur were retrospectively confirmed on X-rays during infancy.This was the first report that delineated the epilepsy phenotype in FGFR3-related bilateral medial temporal lobe dysgenesis; such findings would lead to an early diagnosis and better epilepsy management.



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Two mild cases of Dravet syndrome with truncating mutation of SCN1A

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Toru Takaori, Akira Kumakura, Atsushi Ishii, Shinichi Hirose, Daisuke Hata
BackgroundSCN1A is the gene that codes for the neuronal voltage-gated sodium-channel alpha-subunit 1. It is generally considered that an SCN1A truncating mutation causes the severe phenotype of Dravet syndrome.PatientsWe describe 11- and 4-year-old male patients presenting with mild Dravet syndrome with a truncating mutation of SCN1A. The former patient showed moderate mental retardation; however, seizure was controlled to almost one incident a year by levetiracetam and topiramate. Carbamazepine was also effective, which is atypical of Dravet syndrome. The latter patient showed a borderline developmental quotient and did not have episodes of afebrile seizure.ConclusionTwo patients presented with mild Dravet syndrome, even though they had a truncating mutation of SCN1A. Not all truncating mutations of SCN1A cause the severe phenotype of Dravet syndrome.



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A case of Dravet syndrome with cortical myoclonus indicated by jerk-locked back-averaging of electroencephalogram data

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Yoshinori Kobayashi, Yoshiyuki Hanaoka, Tomoyuki Akiayma, Iori Ohmori, Mamoru Ouchida, Toshiyuki Yamamoto, Makio Oka, Harumi Yoshinaga, Katsuhiro Kobayashi
We report a female patient with Dravet syndrome (DS) with erratic segmental myoclonus, the origin of which was first identified in the cerebral cortex by the detection of myoclonus-associated cortical discharges. The discharges were disclosed through jerk-locked back-averaging of electroencephalogram (EEG) data using the muscle activity of myoclonus as triggers. The detected spikes on the contralateral parieto-central region preceded myoclonic muscle activity in the forearms by 28–46ms. The patient was six months old at the time of examination, and was developing normally before seizure onset at two months of age. She suffered from recurrent afebrile or febrile generalized tonic–clonic seizures that often developed into status epilepticus. Interictal EEG and brain magnetic resonance imaging (MRI) showed no significant findings. The amplitudes of the somatosensory-evoked potentials were not extremely large. She has a chromosomal microdeletion involving SCN1A and adjacent genes.



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Quinidine therapy for West syndrome with KCNTI mutation: A case report

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Masataka Fukuoka, Ichiro Kuki, Hisashi Kawawaki, Shin Okazaki, Kiyohiro Kim, Yuka Hattori, Hitomi Tsuji, Megumi Nukui, Takeshi Inoue, Yoko Yoshida, Takehiro Uda, Sadami Kimura, Yukiko Mogami, Yasuhiro Suzuki, Nobuhiko Okamoto, Hirotomo Saitsu, Naomichi Matsumoto
The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried. However, the epileptic spasms were intractable. Whole exome sequencing identified a KCNT1 mutation (c.1955G>T; p.G652V). At 2years and 6months, the patient had daily epileptic spasms despite valproate and lamotrigine treatment, and was therefore admitted for quinidine therapy. With quinidine therapy, decreased epileptic spasms and decreased epileptiform paroxysmal activity were observed by interictal EEG. Regarding development, babbling, responsiveness, oral feeding and muscle tone were ameliorated. Only transient diarrhea was observed as an adverse effect. Thus, quinidine therapy should be attempted in patients with West syndrome caused by KCNT1 mutations, as reported for MPSI.



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A case of acute encephalopathy with biphasic seizures and late reduced diffusion: Utility of arterial spin labeling sequence

Publication date: January 2017
Source:Brain and Development, Volume 39, Issue 1
Author(s): Keita Kuya, Shinya Fujii, Fuminori Miyoshi, Koyo Ohno, Yuki Shinohara, Yoshihiro Maegaki, Toshihide Ogawa
A 1-year-old boy was admitted because of febrile status epilepticus (FSE). A secondary cluster of seizures was seen on day 5 after onset, and the patient eventually displayed developmental delay. Conventional magnetic resonance imaging (MRI) showed no abnormal findings on day 1 after onset, but showed reduced diffusion in the subcortical regions of bilateral frontal lobes on day 5 after onset. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was diagnosed. Arterial spin labeling (ASL) revealed reduced cerebral blood flow (CBF) in bilateral frontal lobes on day 1 after onset and showed increased CBF in the corresponding region in the subacute phase. Outcomes after prolonged febrile seizures are usually good, but mental deficit and/or epilepsy often remain in AESD. Discriminating between these syndromes is difficult, because no useful biomarkers have been identified. Reduced CBF in bilateral frontal lobes was observed on ASL on day 1 of FSE in the present case, and this finding may be predictive of developing AESD.



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