Does Risk of Brain Cancer Increase with Intracranial Volume? A Population-Based Case-Control Study

Abstract

Background

Glioma is the most common primary brain tumor and is believed to arise from glial stem cells. Despite large efforts there are limited established risk factors. It has been suggested that tissue with more stem cells may exhibit higher risk of cancer due to chance alone. Assuming a positive correlation between the number of stem cell divisions in an organ and size of the same organ, we hypothesized that variation in intracranial volume, as a proxy for brain size may be linked to risk of high-grade glioma.

Methods

Intracranial volume was calculated from pre-treatment 3D T1-weighted MRI brain scans from 124 patients with high-grade glioma and 995 general population based controls. Binomial logistic regression analyses were performed to ascertain the effect of intracranial volume and sex on the likelihood that participants have high-grade glioma.

Results

An increase in intracranial volume of 100 mL was associated with an odds ratio (OR) of high-grade glioma of 1.69 (95 % CI 1.44 to 1.98; P < 0.001). After adjusting for intracranial volume, female sex emerged as a risk factor for high-grade glioma (OR for male sex = 0.56, 95 % CI 0.33 to 0.93; P = 0.026).

Conclusions

Intracranial volume is strongly associated with risk of high-grade glioma. After correcting for intracranial volume, risk of high-grade glioma was higher in women. The development of glioma is correlated to brain size and may to a large extent be a stochastic event related to the number of cells at risk.

Antibody therapy targeting CD19 for B-cell non-Hodgkin lymphoma

Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients

Abstract

BACKGROUND

Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects.

PATIENTS AND METHODS

In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m² was administered one week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating PBMCs and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing.

RESULTS

Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+immunotherapy. No objective responses were observed, while nine patients presented stable disease (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting stable disease (SD). IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD.

CONCLUSIONS

This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

Detection of somatic RAS mutations in circulating tumor DNA from metastatic colorectal cancer patients: are we ready for clinical use?

Associations Between Maternal Obesity and Pregnancy Hyperglycemia and Timing of Pubertal Onset in Adolescent Girls: A Population-Based Study

Abstract

Early puberty is associated with adverse health outcomes. We investigated whether in utero exposure to maternal obesity is associated with daughters' pubertal timing using 15,267 racially/ethnically diverse Kaiser Permanente Northern California members age 6-11 years with pediatrician-assessed Tanner staging (2003-2017). We extracted maternal body mass index (BMI) during pregnancy from the electronic health record. Using a proportional hazards model with interval censoring we examined the associations between maternal obesity and girl's pubertal timing, and effect modification by race/ethnicity and mediation by pre-pubertal BMI. Maternal obesity (BMI ≥30 kg/m²) or overweight (BMI 25-29.9 kg/m²) was associated with earlier breast onset in girls [hazard ratio (HR) = 1.39, 95% confidence interval (CI): 1.30, 1.49; HR = 1.21, 95% CI: 1.13, 1.29, respectively], adjusting for girls' race/ethnicity, maternal age, education, parity and smoking during pregnancy. There was interaction by race/ethnicity for associations between maternal obesity and girls' pubic hair onset: associations were strongest among Asian and white girls [HR = 1.53, 95% CI: 1.24, 1.90; HR = 1.34, 95% CI: 1.18, 1.52, respectively] and absent for African-American girls. Adjustment for girls' pre-pubertal BMI only slightly attenuated associations. Our results suggest the importance of maternal metabolic factors during pregnancy on girls' pubertal timing and potential differences in the associations by race/ethnicity.

The Association of Arsenic Exposure and Arsenic Metabolism with the Metabolic Syndrome and its Individual Components: Prospective Evidence from the Strong Heart Family Study

Abstract

Inorganic arsenic exposure is ubiquitous and both exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. The association between arsenic exposure and arsenic metabolism with metabolic syndrome and its individual components, however, is relatively unknown. We used poisson regression with robust variance to evaluate the association between baseline arsenic exposure (urine arsenic levels) and metabolism (relative percentage of arsenic species over their sum) with incident metabolic syndrome and its individual components (elevated waist circumference, elevated triglycerides, reduced HDL, hypertension, elevated fasting plasma glucose) in 1,047 participants from the Strong Heart Family Study, a prospective family-based cohort in American Indian communities (baseline visits in 1998-1999 and 2001-2003, follow-up visits in 2001-2003 and 2006-2009). 32% of participants developed metabolic syndrome over follow-up. An IQR increase in arsenic exposure was associated with 1.19 (95% CI: 1.01, 1.41) greater risk for elevated fasting plasma glucose but not with other individual components or overall metabolic syndrome. Arsenic metabolism, specifically lower MMA% and higher DMA% was associated with higher risk of overall metabolic syndrome and elevated waist circumference, but not with any other component. These findings support there is a contrasting and independent association between arsenic exposure and arsenic metabolism with metabolic outcomes which may contribute to overall diabetes risk.

RE: “PROSPECTIVE COHORT STUDY OF UTERINE FIBROIDS AND MISCARRIAGE RISK”

THE AUTHORS REPLY

Impact of dynamical and microphysical schemes on black carbon prediction in a regional climate model over India

Abstract

Aerosol concentrations and their properties strongly depend on dynamics of atmosphere. Effects of physical and dynamical parameterizations on meteorology and black carbon (BC) mass in Weather Research and Forecasting model coupled with Chemistry (WRF-CHEM) are investigated over India. Simulations are performed in ten experiments considering two boundary layer, three cumulus parameterization, and five microphysics schemes during winter and monsoon of 2008. Morrison double-moment physical parameterization, Yonsei University boundary layer parameterization with Kain-Fritsch and Grell-Freitas cumulus parameterization schemes are found suitable to simulate meteorology and BC mass over India. BC mass is found to be underestimated in almost all experiments during winter; while, BC mass is overestimated in monsoon over Ahmedabad, Delhi, and Kanpur, which suggests inefficient wet scavenging of BC in monsoon, while lower emission rate may cause differences in winter. The results will be useful in understanding parameterizations and their impact on aerosols.

On valuing impairment

Abstract

In The Minority Body, Elizabeth Barnes rejects prevailing social constructionist accounts of disability for two reasons. First, because they understand disability in terms of oppressive social responses to bodily impairment, they cannot make sense of disability pride. Second, they maintain a problematic distinction between impairment and disability. In response to these challenges, this paper defends a version of the social model of disability, which we call the Social Exclusion Model. On our account, to be disabled is to be in a bodily or psychological state that is represented as an impairment in the prevailing ideology of one's society, and to be excluded from valuable activities on the basis of this representation. While this model refers to a distinction between disability and impairment, it makes no presuppositions about which bodies function 'normally' and which do not. It is the ideology of impairment rather than impairment itself that does any work to determine whether a person is disabled. We argue that this model answers some of the important objections that Barnes raises against prevailing social constructionist accounts of disability, and that it's focus on the oppressive social positioning of disabled people gives it explanatory power that Barnes's own account lacks.

Vitamin D Status and Cardiovascular Risk in Obesity: Effect of Physical Activity in Nonvitamin D Supplemented Adolescents

Metabolic Syndrome and Related Disorders, Ahead of Print.

Untangling Waist Circumference and Hip Circumference from Body Mass Index with a Body Shape Index, Hip Index, and Anthropometric Risk Indicator

Metabolic Syndrome and Related Disorders, Ahead of Print.

Sexual Coercion and Women's Education: A Pilot Study

Violence and Gender, Ahead of Print.

Addressing Onset and Desistance of Bullying Behavior: Surveying Perpetrators

Violence and Gender, Ahead of Print.

Erratum to: Perioperative Corticosteroids Reduce Short-Term Edema and Ecchymosis in Rhinoplasty: A Meta-Analysis

Coroneos CJ, Voineskos SH, Cook DJ, Farrokhyar F, Thoma A. Perioperative Corticosteroids Reduce Short-Term Edema and Ecchymosis in Rhinoplasty: A Meta-Analysis. Aesthet Surg J. 2016; 36(2):136–146; DOI: https://doi.org/10.1093/asj/sjv138

Response to “The Importance of Clinically Relevant Research When Making Comparisons”

We thank you for the opportunity to respond to this Letter to the Editor entitled "The Importance of Clinically Relevant Research When Making Comparisons"¹ which attempts to critique our recent publication "Hypochlorous Acid vs Povidone-Iodine Containing Irrigants: Which Antiseptic is More Effective for Breast Implant Pocket Irrigation?"²

The Importance of Clinically Relevant Research When Making Comparisons

We wish to thank the authors for their efforts in Australia to acquire and evaluate this product "PhaseOne" which is a form of pure hypochlorous acid (HOCl) not available in their country and that has never been marketed there.¹ The authors of this study have previously published quite interesting and significant findings regarding dried biofilms on hard surfaces in the healthcare environment.^2-4 In this particular study, though, standard methods that might be considered directly applicable to disinfection of soiled hard surfaces and equipment⁵ – involving addition of 5% bovine calf serum (BCS) to simulate surface "soiling" – were inappropriately applied to the evaluation of the potential performance of antiseptics in the surgical breast pocket at time of implant placement. Based on actual protein measurements of pocket fluid taken at the time of breast implant surgery (as noted below), the use of the 5% bovine serum in the experiments in this study, and the excessively high relative resultant levels of protein in relation to the amount of antiseptic tested, has produced invalid findings that have no relevance to the actual clinical setting.

Decadal changes in surface ozone at the tropical station Thiruvananthapuram (8.542° N, 76.858° E), India: effects of anthropogenic activities and meteorological variability

Abstract

This paper presents the first observational results from an Indian station on the long-term changes in surface ozone (O₃)—a major environmental pollutant and green house gas—over a period of about 40 years. It is based on the in situ measurements carried out during 1973–1975, 1983–1985, 1997–1998 and 2004–2014 at the tropical coastal station, Thiruvananthapuram. From 1973 to 1997, surface O₃ shows a slow increase of ~ 0.1 ppb year⁻¹ and a faster increase of 0.4 ppb year⁻¹ afterwards till 2009 after which it showed a levelling off till 2012 followed by a minor decrease. The highest rate of increase is observed during 2005 to 2009 (2 ppb year⁻¹), and the overall increase from 1973 to 2012 is ~ 10 ppb. The increase in day time O₃ (peak O₃) is estimated as 0.42 ppb year⁻¹ during 1997–2012 and 2.93 ppb year⁻¹ during 2006–2012. Interestingly, the long-term trend in O₃ showed seasonal dependence which is more pronounced during O₃ peaking seasons (winter/summer). The observed trends were analysed in the light of the changes in NO₂, a major outcome of anthropogenic activities and methane which has both natural and anthropogenic sources and also meteorological parameters. Surface O₃ and NO_x exhibited positive association, but with varying rate of increase of O₃ for NO_x < 4 and > 4 ppb. Methane, a precursor of O₃ also showed increase in tune with O₃. Unlike many other high-latitude locations, meteorology plays a significant role in the long-term trends in O₃ at this tropical site with water vapour abundance and strong solar irradiance which favour photochemistry. A comparison with the corresponding changes in the satellite-retrieved tropospheric column O₃ (TCO) also showed an increase of 0.03 DU year⁻¹ during 1996–2005 which enhanced to 0.12 DU year⁻¹ after 2005. Both surface O₃ and satellite-retrieved TCO were positively correlated with daily maximum temperature, increasing at the rate of 1.54 ppb °C⁻¹ and 1.9 DU °C⁻¹, respectively, on yearly basis. Surface O₃ is found to be negatively correlated with water vapour content (ρ_v) at this tropical site, but at higher levels of ρ_v, O₃ shows a positive trend.

Effects of silver nanoparticles on stress biomarkers of Channa striatus : immuno-protective or toxic?

Abstract

Nanotechnology is a novel arena with promising applications in the field of medicine, industry, and agriculture including fisheries. Cross-disciplinary interactions and the application of this technology in biological systems have led to the innovation of novel nanoparticle antioxidants, which are the subject of our study. In context with above background, we designed an experiment on nano-silver to elucidate its role for mitigation of abiotic and biotic stress. Three diets were formulated viz. silver nanoparticles (Ag-NPs) incorporated at 0.5 and 1 mg/kg diet and control diet (Ag-NPs at 0 mg/kg). Fish were exposed to sublethal level of 1/25th of LC₅₀ (4 ppm) of lead (Pb) and temperature at 34 °C. The effect of Ag-NPs on productive performance (weight gain %, feed conversion ratio, protein efficiency ratio, and specific growth rate), stress biomarkers (catalase, super oxide dismutase, glutathione-s-transferase, acetylcholine esterase, cortisol, heat shock protein), biochemical and immunological response (protein and carbohydrate metabolic enzymes, phagocytic activity, serum total protein and albumin: globulin ratio), histopathology alterations in the liver and gill as well as survival of Channa striatus, following challenge with pathogenic bacteria were evaluated. Dietary Ag-NPs at 0.5-mg supplementation improved growth performance, immunity, survival, and reduced stress biomarker such as HSP 70, cortisol, and blood glucose in various fish tissues. Exposure to Pb and high temperature and group fed with Ag-NPs (1 mg/kg diet) demonstrated remarkable changes in the histo-architect of liver such as pyknotic nuclei, pyknosis, leucocyte infiltration, hemorrhage and karyokinesis, blood vessels with nucleated, lipid vacuoles in the liver tissue. Histology of gill displayed hyperplasia, aneurism, blood congestion, severe telengiectiasis, epithelial lifting, curling of secondary lamella, hyperplasia of epithelial cell of secondary lamella in the group exposed to lead and high temperature and supplemented with Ag-NPs at 1 mg/kg diet. In addition to histopathology, feeding with Ag-NPs at 1 mg/kg diet deteriorated and altered all studied parameters including reduced growth performance. Results obtained in the present study suggest that supplementation of Ag-NPs at 0.5 mg/kg diet has a definitive role to play in the mitigation of abiotic and biotic stress in C. striatus.

Management of Pediatric Urticaria with Review of the Literature on Chronic Spontaneous Urticaria in Children

Publication date: Available online 14 March 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Moshe Ben-Shoshan, Clive E. Grattan
There are substantial knowledge gaps related to diagnosis and management of pediatric cases of chronic urticaria, and in particular chronic spontaneous urticaria (CSU). In this article we aimed to review the diagnosis and management of chronic urticaria in children and CSU in particular. We conducted a systematic review of articles published in English and French on pediatric CSU management in the last 10 years. We included experimental studies (eg, randomized controlled trials), other experimental designs (eg, nonrandomized methods of assignment, controlled before-after studies, and interrupted time series), and observational studies (eg, prospective or retrospective cohort studies, cross-sectional studies, case-control studies, and case reports). Our findings highlight the efficacy of second-generation antihistamines for the treatment of CSU in children and supports the use of omalizumab for more severe cases. However, our study also reveals severe knowledge gaps related to the best management strategy in children with more severe/refractory cases of CSU. Future studies are required to establish the beneficial effect of high doses of second-generation antihistamines as well as the effectiveness and safety of omalizumab and other biologics in young children.

FR-Novedades en la terapia adyuvante del melanoma cutáneo avanzado

Publication date: Available online 13 March 2018
Source:Actas Dermo-Sifiliográficas
Author(s): D. Morgado-Carrasco, F. Terc, S.S. Ertekin, L. Ferrandiz

Milia, una reacción infrecuente tras terapia fotodinámica

Publication date: Available online 13 March 2018
Source:Actas Dermo-Sifiliográficas
Author(s): V. Flores-Climente, J. Dalmau, L. Puig

Validación de una adaptación transcultural al idioma español de la escala Hair Specific Skindex-29

Publication date: Available online 13 March 2018
Source:Actas Dermo-Sifiliográficas
Author(s): A. Guerra-Tapia, A. Buendía-Eisman, J. Ferrando
Introducción y objetivoLa alopecia femenina tiene un impacto importante sobre la calidad de vida. Analizadas las escalas publicadas para medir este impacto, hemos considerado que la escala Hair Specific Skindex 29 (HSS29) es la más adecuada para el objetivo del proyecto: obtener una herramienta en español para el seguimiento en el tratamiento de la alopecia androgenética femenina, que permita medir la evolución del impacto en la calidad de vida y adaptar e individualizar el tratamiento a las necesidades de la mujer. La escala HSS29 puntúa entre 0 (nula afectación) y 100 (total afectación) y discrimina 3dominios (emociones, síntomas y función), siendo una escala útil en la práctica clínica diaria, autocumplimentada en menos de 5 min.Materiales y métodosSe realizó el proceso metodológico establecido para la validación transcultural de una escala, a través de la traducción y retrotraducción por 2traductores nativos en la lengua original de la escala (inglés), con el consenso de un comité de 3dermatólogos expertos cuando fuera necesario. La versión consensuada se sometió a un pretest con pacientes para comprobar la correcta comprensión. Posteriormente, se determinaron las características psicométricas de la escala, la fiabilidad y su validez de constructo (sensibilidad y especificidad mediante curva ROC, fiabilidad por alfa de Cronbach, constructo por análisis factorial con rotación Varimax), de apariencia y la validez test-retest (correlación intraclase).ResultadosCiento setenta mujeres con alopecia y 30 controles respondieron a la escala. Un subgrupo de 15 pacientes realizó el test-retest y respondieron a la escala tras 1-2 días de la valoración inicial. La escala presentó una excelente sensibilidad y especificidad medida por la curva ROC 0,98 (intervalo de confianza del 95%, 0,97-0,99) y una muy elevada fiabilidad con alfa de Cronbach de 0,96. El análisis factorial mostró que los ítems se distribuyeron en las 3dimensiones (funcional, emociones y síntomas) como en la escala original. No se encontraron diferencias significativas entre los valores del test y del retest (23,05 ± 16,42 vs. 22,01 ± 17,72, p = ns) y el coeficiente de correlación intraclase fue excelente (superior a 0,9).ConclusionesLa versión española de la escala HSS29 presenta unas características psicométricas similares a la escala original y es una herramienta útil para la evaluación de la calidad de vida en alopecia femenina.Background and objectiveFemale androgenetic alopecia (FAA) has considerable impact on quality of life. Our analysis of the clinical scales available in the literature to measure the impact of FAA led us to choose the Hair Specific Skindex 29 (HSS29) as the most appropriate for adaptation to Spanish as a tool for following patients in treatment for FAA. This tool assesses disease impact on quality of life over time so that treatments can be tailored to patients' needs. The HSS29 score reflects impact in 3 domains (emotions, symptoms, and functioning) on a scale of 0 (no effect) to 100 (maximum effect). The scale is useful in routine clinical practice, and patients can respond to all items in 5minutes.Materials and methodsWe followed recommended procedures to produce a cross-cultural adaptation of the scale. The process involved forward translation of the questionnaire to Spanish followed by back translation by 2 native speakers of the original language (English) and revision as needed after discussion and consensus by a committee of 3 expert dermatologists. The comprehensibility of the resulting translation was assessed in a test–retest step. Next, the psychometric properties, reliability, and construct validity were assessed. Sensitivity and specificity were evaluated with the area under the receiver operating characteristic (ROC) curve, reliability with Cronbach's α, and construct validity by factor analysis using a Varimax rotation. Face validity was also assessed during the process. The intraclass correlation coefficient (ICC) was calculated in the test–retest step.ResultsA total of 170 women with FAA and 30 control subjects completed the cross-culturally adapted Spanish questionnaire. A subgroup of 15 subjects responded a second time between 1 and 2 days after their first session (test–retest). Sensitivity and specificity were excellent according to the area under the ROC curve (0.98; 95% CI, 0.97–0.99), and high reliability was reflected by a Cronbach's α of 0.96. Factor analysis showed that the items were grouped in the same 3 domains (functioning, emotions, and symptoms) as in the original version of the scale. There were no significant differences in the mean (SD) scores on the test and the retest (23.05 [16.42] vs. 22.01 [17.72], respectively). The ICC of over 0.9 indicated excellent correlation between responses to the adapted Spanish version.ConclusionsThe psychometric properties of the Spanish version of the HSS29 are similar to those of the original scale. The Spanish HSS29 is a useful tool for assessing quality of life in FAA.

Graphical abstract

Disseminated Asymptomatic Papules Over the Body

A woman in her 30s had a 15-year history of generalized asymptomatic papules on her arms, trunk, legs, neck, and face; examination revealed skin-colored to red-brown papules distributed over her trunk, extremities, neck, forehead, and periocular regions. What is your diagnosis?

JAMA Dermatology—The Year in Review, 2017

JAMA Dermatology continues to enhance our digital presence, which serves to inform physicians and the public about advances in treatment of skin conditions. The journal content is available online ahead of print, and we connect with our readers via the electronic table of contents and through social media. Each weekly online issue of the journal offers an article free to be downloaded for 1 week; thus, the public has free access to selected articles. Our reach extended to 3.4 million people in 2017 with full-text downloads. Our online presence is international, with more than 100 000 users in Canada, India, the United Kingdom, and the United States.

Spinal Dysraphism Presenting as a Translucent Papule in a Man

This case report describes a man with spinal dysraphism presenting as a translucent papule.

Sun Protection Use and Sunburn Among US Adults

This cross-sectional study using National Health Interview Survey data examined the prevalence of sun protection use and sunburn and the association between sunburn and demographic characteristics and health behaviors in the US population.

JAMA Dermatology Peer Reviewers in 2017

Extracellular vesicle-carried Jagged-1 inhibits HUVEC sprouting in a 3D microenvironment

Abstract

NOTCH signalling is an evolutionarily conserved juxtacrine signalling pathway that is essential in development. Jagged1 (JAG1) and Delta-like ligand 4 (DLL4) are transmembrane NOTCH ligands that regulate angiogenesis by controlling endothelial cell (EC) differentiation, vascular development and maturation. In addition, DLL4 could bypass its canonical cell–cell contact-dependent signalling to influence NOTCH signalling and angiogenesis at a distance when it is packaged into extracellular vesicles (EVs). However, it is not clear whether JAG1 could also be packaged into EVs to influence NOTCH signalling and angiogenesis. In this work, we demonstrate that JAG1 is also packaged into EVs. We present evidence that JAG1-EVs inhibit NOTCH signalling and regulate EC behaviour and function. JAG1-EVs inhibited VEGF-induced HUVEC proliferation and migration in 2D culture condition and suppressed sprouting in a 3D microfluidic microenvironment. JAG1-EV treatment of HUVECs leads to a reduction of Notch1 intracellular domain (N1-ICD), and the proteasome and the intracellular domain of JAG1 (JAG1-ICD) are both required for this reduction to occur. These findings reveal a novel mechanism of JAG1 function in NOTCH signalling and ECs through EVs.

A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors

Hyperekplexia, an inherited neuronal disorder characterized by exaggerated startle responses with unexpected sensory stimuli, is caused by dysfunction of glycinergic inhibitory transmission. From analysis of newly identified human hyperekplexia mutations in the glycine receptor (GlyR) α1 subunit, we found that an alanine-to-proline missense mutation (A384P) resulted in substantially higher desensitization level and lower agonist sensitivity of homomeric α1 GlyRs when expressed in HEK cells. The incorporation of the β subunit fully reversed the reduction in agonist sensitivity and partially reversed the desensitization of α1^A384P. The heteromeric α1^A384Pβ GlyRs showed enhanced desensitization but unchanged agonist-induced maximum responses, surface expression, main channel conductance, and voltage dependence compared with that of the wild-type α1β (α1^WTβ) GlyRs. Coexpression of the R392H and A384P mutant α1 subunits, which mimic the expression of the compound heterozygous mutation in a hyperekplexia patient, resulted in channel properties similar to those with α1^A384P subunit expression alone. In comparison, another human hyperekplexia mutation α1^P250T, which was previously reported to enhance desensitization, caused a strong reduction in maximum currents in addition to the altered desensitization. These results were further confirmed by overexpression of α1^P250T or α1^A384P subunits in cultured neurons isolated from SD rats of either sex. Moreover, the IPSC-like responses of cells expressing α1^A384Pβ induced by repeated glycine pulses showed a stronger frequency-dependent reduction than those expressing α1^WTβ. Together, our findings demonstrate that A384 is associated with the desensitization site of the α1 subunit and its proline mutation produced enhanced desensitization of GlyRs, which contributes to the pathogenesis of human hyperekplexia.

SIGNIFICANCE STATEMENT Human startle disease is caused by impaired synaptic inhibition in the brainstem and spinal cord, which is due to either direct loss of GlyR channel function or reduced number of synaptic GlyRs. Considering that fast decay kinetics of GlyR-mediated inhibitory synaptic responses, the question was raised whether altered desensitization of GlyRs will cause dysfunction of glycine transmission and disease phenotypes. Here, we found that the α1 subunit mutation A384P, identified from startle disease patients, results in enhanced desensitization and leads to rapidly decreasing responses in the mutant GlyRs when they are activated repeatedly by the synaptic-like simulation. These observations suggest that the enhanced desensitization of postsynaptic GlyRs could be the primary pathogenic mechanism of human startle disease.

Linking the Neuropsychiatric Disease Gene TCF4 to Neuronal Activity-Dependent Regulatory Networks

The Primacy of Spatial Context in the Neural Representation of Events

Some theories of episodic memory hypothesize that spatial context plays a fundamental role in episodic memory, acting as a scaffold on which episodes are constructed. A prediction based on this hypothesis is that spatial context should play a primary role in the neural representation of an event. To test this hypothesis in humans, male and female participants imagined events, composed of familiar locations, people, and objects, during an fMRI scan. We used multivoxel pattern analysis to determine the neural areas in which events could be discriminated based on each feature. We found that events could be discriminated according to their location in areas throughout the autobiographical memory network, including the parahippocampal cortex and posterior hippocampus, retrosplenial cortex, posterior cingulate cortex, precuneus, and medial prefrontal cortex. Events were also discriminable based on person and object features, but in fewer regions. Comparing classifier performance in regions involved in memory for scenes and events demonstrated that the location of an event was more accurately classified than the person or object involved. These results support theories that suggest that spatial context is a prominent defining feature of episodic memory.

SIGNIFICANCE STATEMENT Remembered and imagined events are complex, consisting of many elements, including people, objects, and locations. In this study, we sought to determine how these types of elements differentially contribute to how the brain represents an event. Participants imagined events consisting of familiar locations, people, and objects (e.g., kitchen, mom, umbrella) while their brain activity was recorded with fMRI. We found that the neural patterns of activity in brain regions associated with spatial and episodic memory could distinguish events based on their location, and to some extent, based on the people and objects involved. These results suggest that the spatial context of an event plays an important role in how an event is represented in the brain.

Control of Homeostatic Synaptic Plasticity by AKAP-Anchored Kinase and Phosphatase Regulation of Ca2+-Permeable AMPA Receptors

Neuronal information processing requires multiple forms of synaptic plasticity mediated by NMDARs and AMPA-type glutamate receptors (AMPARs). These plasticity mechanisms include long-term potentiation (LTP) and long-term depression (LTD), which are Hebbian, homosynaptic mechanisms locally regulating synaptic strength of specific inputs, and homeostatic synaptic scaling, which is a heterosynaptic mechanism globally regulating synaptic strength across all inputs. In many cases, LTP and homeostatic scaling regulate AMPAR subunit composition to increase synaptic strength via incorporation of Ca²⁺-permeable receptors (CP-AMPAR) containing GluA1, but lacking GluA2, subunits. Previous work by our group and others demonstrated that anchoring of the kinase PKA and the phosphatase calcineurin (CaN) to A-kinase anchoring protein (AKAP) 150 play opposing roles in regulation of GluA1 Ser845 phosphorylation and CP-AMPAR synaptic incorporation during hippocampal LTP and LTD. Here, using both male and female knock-in mice that are deficient in PKA or CaN anchoring, we show that AKAP150-anchored PKA and CaN also play novel roles in controlling CP-AMPAR synaptic incorporation during homeostatic plasticity in hippocampal neurons. We found that genetic disruption of AKAP-PKA anchoring prevented increases in Ser845 phosphorylation and CP-AMPAR synaptic recruitment during rapid homeostatic synaptic scaling-up induced by combined blockade of action potential firing and NMDAR activity. In contrast, genetic disruption of AKAP-CaN anchoring resulted in basal increases in Ser845 phosphorylation and CP-AMPAR synaptic activity that blocked subsequent scaling-up by preventing additional CP-AMPAR recruitment. Thus, the balanced, opposing phospho-regulation provided by AKAP-anchored PKA and CaN is essential for control of both Hebbian and homeostatic plasticity mechanisms that require CP-AMPARs.

SIGNIFICANCE STATEMENT Neuronal circuit function is shaped by multiple forms of activity-dependent plasticity that control excitatory synaptic strength, including LTP/LTD that adjusts strength of individual synapses and homeostatic plasticity that adjusts overall strength of all synapses. Mechanisms controlling LTP/LTD and homeostatic plasticity were originally thought to be distinct; however, recent studies suggest that CP-AMPAR phosphorylation regulation is important during both LTP/LTD and homeostatic plasticity. Here we show that CP-AMPAR regulation by the kinase PKA and phosphatase CaN coanchored to the scaffold protein AKAP150, a mechanism previously implicated in LTP/LTD, is also crucial for controlling synaptic strength during homeostatic plasticity. These novel findings significantly expand our understanding of homeostatic plasticity mechanisms and further emphasize how intertwined they are with LTP and LTD.

Enhanced Operant Extinction and Prefrontal Excitability in a Mouse Model of Angelman Syndrome

Angelman syndrome (AS), a neurodevelopmental disorder associated with intellectual disability, is caused by loss of maternal allele expression of UBE3A in neurons. Mouse models of AS faithfully recapitulate disease phenotypes across multiple domains, including behavior. Yet in AS, there has been only limited study of behaviors encoded by the prefrontal cortex, a region broadly involved in executive function and cognition. Because cognitive impairment is a core feature of AS, it is critical to develop behavioral readouts of prefrontal circuit function in AS mouse models. One such readout is behavioral extinction, which has been well described mechanistically and relies upon prefrontal circuits in rodents. Here we report exaggerated operant extinction in male AS model mice, concomitant with enhanced excitability in medial prefrontal neurons from male and female AS model mice. Abnormal behavior was specific to operant extinction, as two other prefrontally dependent tasks (cued fear extinction and visuospatial discrimination) were largely normal in AS model mice. Inducible deletion of Ube3a during adulthood was not sufficient to drive abnormal extinction, supporting the hypothesis that there is an early critical period for development of cognitive phenotypes in AS. This work represents the first formal experimental analysis of prefrontal circuit function in AS, and identifies operant extinction as a useful experimental paradigm for modeling cognitive aspects of AS in mice.

SIGNIFICANCE STATEMENT Prefrontal cortex encodes "high-level" cognitive processes. Thus, understanding prefrontal function is critical in neurodevelopmental disorders where cognitive impairment is highly penetrant. Angelman syndrome is a neurodevelopmental disorder associated with speech and motor impairments, an outwardly happy demeanor, and intellectual disability. We describe a behavioral phenotype in a mouse model of Angelman syndrome and related abnormalities in prefrontal cortex function. We hypothesize that robust and reliable prefrontally encoded behavior may be used to model cognitive impairments in Angelman syndrome.

Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving

Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies ("incubates") during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneurosomes prepared after >47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2α (eIF2α) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2α dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving.

SIGNIFICANCE STATEMENT Cue-induced cocaine craving progressively intensifies (incubates) during withdrawal in both humans and rats. This may contribute to persistent vulnerability to relapse. We previously demonstrated a role for protein translation in synaptic adaptations in the NAc closely linked to incubation. Here, we tested the hypothesis that translation is dysregulated during cocaine withdrawal, and this contributes to incubated craving. Analysis of signaling pathways regulating translation suggested that translation is enhanced when "incubated" rats undergo a cue-induced seeking test. Furthermore, intra-NAc infusions of drugs that inhibit protein translation through different mechanisms reduced expression of incubated cue-induced cocaine seeking. These results demonstrate that the expression of incubation depends on an acute increase in translation that may result from dysregulation of several pathways.

Basolateral Amygdala Inputs to the Medial Entorhinal Cortex Selectively Modulate the Consolidation of Spatial and Contextual Learning

Although evidence suggests that the basolateral amygdala (BLA) and dorsal hippocampus (DH) work together to influence the consolidation of spatial/contextual learning, the circuit mechanism by which the BLA selectively modulates spatial/contextual memory consolidation is not clear. The medial entorhinal cortex (mEC) is a critical region in the hippocampus-based system for processing spatial information. As an efferent target of the BLA, the mEC is a candidate by which the BLA influences the consolidation of such learning. To address several questions regarding this issue, male Sprague Dawley rats received optogenetic manipulations of different BLA afferents immediately after training in different learning tasks. Optogenetic stimulation of the BLA–mEC pathway using ChR2(E123A) after spatial and cued-response Barnes maze training enhanced and impaired retention, respectively, whereas optical inhibition of the pathway using eNpHR3.0 produced trends in the opposite direction. Similar stimulation of the BLA-posterior dorsal striatum pathway had no effect. BLA–mEC stimulation also selectively enhanced retention for the contextual, but not foot shock, component of a modified contextual fear-conditioning procedure. In both sets of experiments, only stimulation using bursts of 8 Hz light pulses significantly enhanced retention, suggesting the importance of driving activity in this frequency range. An 8 Hz stimulation of the BLA–mEC pathway increased local field potential power in the same frequency range in the mEC and in the DH. Together, the present findings suggest that the BLA modulates the consolidation of spatial/contextual memory via projections to the mEC and that activity within the 8 Hz range is critical for this modulation.

SIGNIFICANCE STATEMENT The mechanism by which the basolateral amygdala (BLA) influences the consolidation of spatial/contextual memory is unknown. Using an optogenetic approach with multiple behavioral procedures, we found that immediate posttraining 8 Hz stimulation of BLA projections to the medial entorhinal cortex (mEC) enhanced retention for spatial/contextual memory, impaired retention for cued-response memory, and had no effect on foot shock learning for contextual fear conditioning. Electrophysiological recordings confirmed that 8 Hz stimulation of this pathway increased activity in the 8 Hz range in the mEC and in the dorsal hippocampus, a region critical for spatial memory consolidation. This suggests that coordinated BLA activity with downstream regions in the 8 Hz activity range immediately after training is important for consolidation of multiple memory forms.

Combinatorial Effects of Alpha- and Gamma-Protocadherins on Neuronal Survival and Dendritic Self-Avoidance

The clustered protocadherins (Pcdhs) comprise 58 cadherin-related proteins encoded by three tandemly arrayed gene clusters, Pcdh-α, Pcdh-β, and Pcdh- (Pcdha, Pcdhb, and Pcdhg, respectively). Pcdh isoforms from different clusters are combinatorially expressed in neurons. They form multimers that interact homophilically and mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, axonal tiling, and dendritic self-avoidance. Most studies have analyzed clusters individually. Here, we assessed functional interactions between Pcdha and Pcdhg clusters. To circumvent neonatal lethality associated with deletion of Pcdhgs, we used Crispr-Cas9 genome editing in mice to combine a constitutive Pcdha mutant allele with a conditional Pcdhg allele. We analyzed roles of Pcdhas and Pcdhgs in the retina and cerebellum from mice (both sexes) lacking one or both clusters. In retina, Pcdhgs are essential for survival of inner retinal neurons and dendritic self-avoidance of starburst amacrine cells, whereas Pcdhas are dispensable for both processes. Deletion of both Pcdha and Pcdhg clusters led to far more dramatic defects in survival and self-avoidance than Pcdhg deletion alone. Comparisons of an allelic series of mutants support the conclusion that Pcdhas and Pcdhgs function together in a dose-dependent and cell-type-specific manner to provide a critical threshold of Pcdh activity. In the cerebellum, Pcdhas and Pcdhgs also cooperate to mediate self-avoidance of Purkinje cell dendrites, with modest but significant defects in either single mutant and dramatic defects in the double mutant. Together, our results demonstrate complex patterns of redundancy between Pcdh clusters and the importance of Pcdh cluster diversity in postnatal CNS development.

SIGNIFICANCE STATEMENT The formation of neural circuits requires diversification and combinatorial actions of cell surface proteins. Prominent among them are the clustered protocadherins (Pcdhs), a family of ~60 neuronal recognition molecules. Pcdhs are encoded by three closely linked gene clusters called Pcdh-α, Pcdh-β, and Pcdh-. The Pcdhs mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, and spatial patterning of axons and dendrites. Most studies to date have been limited to single clusters. Here, we used genome editing to assess interactions between Pcdh-α and Pcdh- gene clusters. We examined two regions of the CNS, the retina and cerebellum and show that the 14 α-Pcdhs and 22 -Pcdhs act synergistically to mediate neuronal survival and dendrite patterning.

The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies As a Function of Age and Is Associated with Changes in Episodic Memory and Processing Speed

The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimer's pathology. Little is known, however, about the longitudinal trajectory of this network's intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49–87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans (n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age x time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50–66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults.

SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity.

Large Visual Stimuli Induce Two Distinct Gamma Oscillations in Primate Visual Cortex

Recent studies have shown the existence of two gamma rhythms in the hippocampus subserving different functions but, to date, primate studies in primary visual cortex have reported a single gamma rhythm. Here, we show that large visual stimuli induce a slow gamma (25–45 Hz) in area V1 of two awake adult female bonnet monkeys and in the EEG of 15 human subjects (7 males and 8 females), in addition to the traditionally known fast gamma (45–70 Hz). The two rhythms had different tuning characteristics for stimulus orientation, contrast, drift speed, and size. Further, fast gamma had short latency, strongly entrained spikes and was coherent over short distances, reflecting short-range processing, whereas slow gamma appeared to reflect long-range processing. Together, two gamma rhythms can potentially provide better coding or communication mechanisms and a more comprehensive biomarker for diagnosis of mental disorders.

SIGNIFICANCE STATEMENT Gamma rhythm has been associated with high-level cognitive functions such as attention and feature binding and has been reported to be abnormal in brain disorders such as autism and schizophrenia. Unlike previous studies that have shown a single gamma rhythm in the primate visual cortex, we found that large visual gratings induce two distinct gamma oscillations in both monkey LFP and human EEG. These rhythms, termed slow (25–45 Hz) and fast (45–70 Hz), exhibited distinct tuning preferences, latencies, and coherence profiles, potentially reflecting processing at two different ranges. Multiple gamma oscillations in visual cortex may provide a richer representation of external visual stimuli and could be used for developing brain–machine interfacing applications and screening tests for neuropsychiatric disorders.

Mind-Wandering in People with Hippocampal Damage

Subjective inner experiences, such as mind-wandering, represent the fundaments of human cognition. Although the precise function of mind-wandering is still debated, it is increasingly acknowledged to have influence across cognition on processes such as future planning, creative thinking, and problem-solving and even on depressive rumination and other mental health disorders. Recently, there has been important progress in characterizing mind-wandering and identifying the associated neural networks. Two prominent features of mind-wandering are mental time travel and visuospatial imagery, which are often linked with the hippocampus. People with selective bilateral hippocampal damage cannot vividly recall events from their past, envision their future, or imagine fictitious scenes. This raises the question of whether the hippocampus plays a causal role in mind-wandering and, if so, in what way. Leveraging a unique opportunity to shadow people (all males) with bilateral hippocampal damage for several days, we examined, for the first time, what they thought about spontaneously, without direct task demands. We found that they engaged in as much mind-wandering as control participants. However, whereas controls thought about the past, present, and future, imagining vivid visual scenes, hippocampal damage resulted in thoughts primarily about the present comprising verbally mediated semantic knowledge. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and also reveal its impact beyond episodic memory, placing it at the heart of our mental life.

SIGNIFICANCE STATEMENT Humans tend to mind-wander ~30–50% of their waking time. Two prominent features of this pervasive form of thought are mental time travel and visuospatial imagery, which are often associated with the hippocampus. To examine whether the hippocampus plays a causal role in mind-wandering, we examined the frequency and phenomenology of mind-wandering in patients with selective bilateral hippocampal damage. We found that they engaged in as much mind-wandering as controls. However, hippocampal damage changed the form and content of mind-wandering from flexible, episodic, and scene based to abstract, semanticized, and verbal. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and reveal its impact beyond episodic memory, placing it at the heart of our mental life.

Visual Information Present in Infragranular Layers of Mouse Auditory Cortex

The cerebral cortex is a major hub for the convergence and integration of signals from across the sensory modalities; sensory cortices, including primary regions, are no exception. Here we show that visual stimuli influence neural firing in the auditory cortex of awake male and female mice, using multisite probes to sample single units across multiple cortical layers. We demonstrate that visual stimuli influence firing in both primary and secondary auditory cortex. We then determine the laminar location of recording sites through electrode track tracing with fluorescent dye and optogenetic identification using layer-specific markers. Spiking responses to visual stimulation occur deep in auditory cortex and are particularly prominent in layer 6. Visual modulation of firing rate occurs more frequently at areas with secondary-like auditory responses than those with primary-like responses. Auditory cortical responses to drifting visual gratings are not orientation-tuned, unlike visual cortex responses. The deepest cortical layers thus appear to be an important locus for cross-modal integration in auditory cortex.

SIGNIFICANCE STATEMENT The deepest layers of the auditory cortex are often considered its most enigmatic, possessing a wide range of cell morphologies and atypical sensory responses. Here we show that, in mouse auditory cortex, these layers represent a locus of cross-modal convergence, containing many units responsive to visual stimuli. Our results suggest that this visual signal conveys the presence and timing of a stimulus rather than specifics about that stimulus, such as its orientation. These results shed light on both how and what types of cross-modal information is integrated at the earliest stages of sensory cortical processing.

Maternal Immune Activation During the Third Trimester Is Associated with Neonatal Functional Connectivity of the Salience Network and Fetal to Toddler Behavior

Prenatal maternal immune activation (MIA) is associated with altered brain development and risk of psychiatric disorders in offspring. Translational human studies of MIA are few in number. Alterations of the salience network have been implicated in the pathogenesis of the same psychiatric disorders associated with MIA. If MIA is pathogenic, then associated abnormalities in the salience network should be detectable in neonates immediately after birth. We tested the hypothesis that third trimester MIA of adolescent women who are at risk for high stress and inflammation is associated with the strength of functional connectivity in the salience network of their neonate. Thirty-six women underwent blood draws to measure interleukin-6 (IL-6) and C-reactive protein (CRP) and electrocardiograms to measure fetal heart rate variability (FHRV) at 34–37 weeks gestation. Resting-state imaging data were acquired in the infants at 40–44 weeks postmenstrual age (PMA). Functional connectivity was measured from seeds placed in the anterior cingulate cortex and insula. Measures of cognitive development were obtained at 14 months PMA using the Bayley Scales of Infant and Toddler Development–Third Edition (BSID-III). Both sexes were studied. Regions in which the strength of the salience network correlated with maternal IL-6 or CRP levels included the medial prefrontal cortex, temporoparietal junction, and basal ganglia. Maternal CRP level correlated inversely with FHRV acquired at the same gestational age. Maternal CRP and IL-6 levels correlated positively with measures of cognitive development on the BSID-III. These results suggest that MIA is associated with short- and long-term influences on offspring brain and behavior.

SIGNIFICANCE STATEMENT Preclinical studies in rodents and nonhuman primates and epidemiological studies in humans suggest that maternal immune activation (MIA) alters the development of brain circuitry and associated behaviors, placing offspring at risk for psychiatric illness. Consistent with preclinical findings, we show that maternal third trimester interleukin-6 and C-reactive protein levels are associated with neonatal functional connectivity and with both fetal and toddler behavior. MIA-related functional connectivity was localized to the salience, default mode, and frontoparietal networks, which have been implicated in the pathogenesis of psychiatric disorders. Our results suggest that MIA alters functional connectivity in the neonatal brain, that those alterations have consequences for cognition, and that these findings may provide pathogenetic links between preclinical and epidemiological studies associating MIA with psychiatric risk in offspring.

A suppository kit for metronomic photodynamic therapy: The elimination of rectal cancer in situ

Publication date: Available online 13 March 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): X.F. Shi, W.D. Jin, H. Gao, H.J. Yin, Y.X. Li, H. Huang, H. Ma, H.J. Dong
Metronomic photodynamic therapy (mPDT) was developed to improve tumor-specific responses through cell death by apoptosis. We developed an mPDT suppository kit including ALA and LED suppositories and analyzed its killing effect on rectal tumors in rabbits. Methods: The ALA (10 wt%) suppository was prepared using ALA powder, type 36 semi-synthetic fatty acid glyceride, and azone. The LED suppository was constructed by encapsulating LED units and a circuit in transparent epoxy resin. VX2 cells were injected into the rectal submucosa of rabbits to establish a carcinoma model in situ. The ALA suppository was inserted into the rectal cavity for 30 min of uptake and activated for 1 h by the LED suppository at a power density of 20 mW/cm². The mPDT process was repeated three times once a day. MRI was used to monitor tumor growth, histopathology and TUNEL staining were performed at 14 days after mPDT. Results: The overall response rate was 60% in the mPDT group using the kit in which the tumor size was decreased up to about 50% at 7 days post-mPDT and almost eliminated at 14 days. HE staining showed that only 6.16% of the tumor tissue remained after mPDT treatment. TUNEL detection showed that the apoptosis rate was 18.9%. Conclusion: We verified the killing effect of the mPDT suppository kit on rectal tumors in rabbits based on mPDT that induced tumor cell apoptosis.

Sunlight-induced genotoxicity and damage in keratin structures decrease tadpole performance

Publication date: Available online 14 March 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Caroline Peripolli dos Santos, James Eduardo Lago Londero, Maurício Beux dos Santos, Rayana dos Santos Feltrin, Luiza Loebens, Livia Bataioli Moura, Sonia Zanini Cechin, André Passaglia Schuch
The increased incidence of solar ultraviolet (UV) radiation, an environmental genotoxic agent, due to ozone depletion or deforestation may help to explain the enigmatic decline of amphibian populations in specific localities. In this work, we evaluated the importance of DNA repair performed by photolyases to maintain the performance of treefrog tadpoles after acute and chronic treatments with environmental-simulated doses of solar UVB and UVA radiation. Immediately after UV treatments, tadpoles were exposed to a visible light source to activate photolyases or kept in dark containers. The biological effects of UV treatments were evaluated through morphological, histological, locomotor and survival analyzes of Boana pulchella tadpoles (Anura: Hylidae). The results indicate that tadpole body weight suffered influence after both UVB and UVA treatments, although the body length was bit affected. The locomotor performance of UVB-exposed tadpoles was significantly reduced. In addition, UVB radiation induced a severe impact on tadpole skin, as well as on keratinized structures of mouth (tooth rows and jaw), indicating that these should be important effects of solar UV radiation in the reduction of tadpole performance. Furthermore, photolyases activation was fundamental for the maintenance of tadpole performance after chronic UVB exposures, but it was relatively inefficient after acute exposures to UVB, but not to UVA radiation. Therefore, this work demonstrates how the UV-induced genotoxicity and structural alterations in the skin and oral apparatus affect tadpole performance and survival.

Graphical abstract

Human serum albumin binding to the biologically active labdane diterpene “leoheterin”: Spectroscopic and in silico analysis

Publication date: Available online 13 March 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Mohd. Sajid Ali, Musarat Amina, Hamad A. Al-Lohedan, Nawal M. Al Musayeib
Labdane diterpenes are important substances due to their remarkable biological activities such as, antibacterial, antiprotozoal, antifungal and cytostatic and cytotoxic effects against human cancer cells. We have isolated a labdane diterpene named "leoheterin" from the aerial parts of the Otostegia fruticosa Forssk (Briq) obtained from south west Arabian mountains of Saudi Arabia. The isolated compound was characterized by ¹HNMR, ¹³CNMR, IR and UV–visible spectroscopies. Due to the pharmaceutical importance of this class of compounds we have studied the interaction of HSA with leoheterin by using several spectroscopic methods. The change in the UV spectrum of HSA in presence of leoheterin is comprises the interaction between them. Congruently, leoheterin quenches the fluorescence of HSA with a prominent blue shift of 5 nm, reminiscent of involvement of hydrophobic interactions. There was 1:1 binding between leoheterin and albumin which was taken place via static quenching mechanism. From CD it was revealed that leoheterin induces the secondary structure of HSA which is further supported by 3-d fluorescence measurements which shows a decrease in the size of the HSA-leoheterin complex as compared to the HSA alone. Molecular docking simulations presented that among the first three conformers which have been arranged according to the least binding energies and are also in good corroboration with the free energies of binding obtained experimentally, the first two conformers shown the binding in hemin binding site of subdomain IB while in third conformer the binding site was near to the drug binding site 1 located in subdomain IIA. All conformers exhibited the involvement of hydrogen bonding as well as hydrophobic interactions.

Monroe’s Mark

For most of human history, beauty marks have not always considered to be beautiful. In Ancient Rome, the standard of beauty was fair and spotless skin. In medieval Europe, pigmented lesions were one of several cutaneous signs associated with "evil" or demonic connection, the so-called Devil's mark. The attitude toward beauty marks improved in the 18th century, when moles became popular among the royal courts of Europe. Artificial beauty marks, known as mouches, were created from silk, velvet, or taffeta and were worn by both men and women. After a several-centuries–long period of quiescence, however, the beauty mark reemerged in the 1950s in association with the era's greatest sex symbol, Marilyn Monroe. She quickly became known for the off-center mole above her left upper lip, and with it she appealed to generations of women for many years to come.

Generalized Lichen Nitidus Following Anti–PD-1 Antibody Treatment

This case report describes the occurrence of generalized lichen nitidus following anti–PD-1 antibody treatment.

US Food and Drug Administration Approach for Safe Medical Devices

With the increased awareness of skin conditions and demand for aesthetic treatments requiring the expertise of dermatologists, there has been a growth in the associated medical device industry. Dermatology medical devices include point-of-care diagnostics, ablative technologies, skin imaging devices, dermal fillers, lasers, and wound dressings. Many new devices in dermatology offer practitioners and patients additional options for a variety of conditions including diabetic wound care, skin lesion screening, and alopecia treatment.

Comorbidities in Autoimmune Skin Diseases

Alvan Feinstein, both a clinician and an epidemiologist, introduced the concept of comorbidity as a peculiar and important feature of chronic diseases almost 50 years ago. This concept may still require a more precise definition and a deeper understanding, but there is no doubt that better knowledge about comorbidities will always be conducive to improvements in clinical care, epidemiology, and health services planning and financing. Also, as noted by Tinetti and Fried nearly 15 years ago, awareness of existing comorbidities of a given chronic disease will facilitate "The End of the Disease Era," as they titled their article, and ultimately bring about the essential paradigm shift in clinical medicine from the "disease-oriented" model to a more "integrated individually tailored model" in which clinical decision making can be "focused primarily on the priorities and preferences of individual patients,"^(p181) and health conditions are recognized as a complex interplay of genetic, environmental, psychological, social, and other factors.

Evaluating Industry Payments Among Dermatology Clinical Practice Guideline Authors

To the Editor The article by Checketts et al regarding industry payments among dermatology clinical practice guideline (CPG) authors was accompanied by an editorial by Katz highlighting some of the problems with the study's methodology. We have significant additional concerns regarding its conclusions.

Dermatologic Device Approval by the US Food and Drug Administration

This cross-sectional database study characterizes the postapproval changes to Class III dermatologic devices and evaluates inconsistencies in the use of the premarket approval pathway.

Sun Safety

This Patient Page provides information on sun protection and safety.

Association Between Pemphigus and Neurologic Diseases

This population-based cross-sectional study estimates the association between pemphigus and 4 neurologic conditions using one of the largest cohorts of patients with pemphigus.

Rituximab as Single Long-term Maintenance Therapy in Difficult-to-Treat Pemphigus

This case-series study of 11 patients with severe, difficult-to-treat pemphigus examines whether rituximab alone can be used long-term as maintenance therapy for prevention of relapse.

Comorbidity Development in Children With Psoriasis

This cohort study examines the risk ocomorbidities in children with and without psoriasis, after accounting for obesity.

Sir James Paget—Contributions of a Surgeon and Pathologist

Sir James Paget is remembered as one of the greatest English surgeons and fathers of pathology. After passing the College of Surgeon's Examination in 1836, he struggled to find a job practicing medicine and spent 7 years doing various odd jobs for minimal compensation.

Rapid Repigmentation of Vitiligo-Affected Skin After Tofacitinib Plus UV-B

This case report describes 2 patients who experienced rapid repigmentation of vitiligo-affected skin after tofacitinib plus low-dose, narrowband UV-B therapy.

Skin Microbiome and Gene Mutations in Adult Atopic Dermatitis

This case-control study examines skin and nasal microbiome diversity and composition in patients with atopic dermatitis.

Congenital Syphilis and The Inheritance by Edvard Munch

This Notable Note provides an example of how an artistic work may unexpectedly provide information about the history of a disease.

Follicular and Epidermal Cell Suspension for Vitiligo Treatment

This randomized clinical trial compares the effects of combined epidermal cell suspension and follicular cell suspension with those of epidermal cell suspension alone in treatment of vitiligo.

Characteristics and health risk assessment of volatile organic compounds emitted from interior materials in vehicles: a case study from Nanjing, China

Abstract

It has become a great habit for driving to work in people's daily life in China. In order to understand the concentration of volatile organic compounds (VOCs) in vehicles and the health risks related to inhalation exposure to VOCs, this study investigated the pollution characteristics and health risks posed by VOCs emitted from interior materials in vehicles. A total of 47 of 62 VOCs were studied, using 23 randomly selected vehicles of different brands in Nanjing city, China. The potential cancer and non-cancer health risks associated with VOC inhalation were assessed based on conventional approaches proposed by the United States Environmental Protection Agency (USEPA). The mean concentration of total VOCs was 1126.85 μg/m³, with a range of 321.29 to 2321.94 μg/m³. Of these, halohydrocarbons and aromatic hydrocarbons were the dominant components of the detected VOCs. The concentrations of several individual VOC exceeded more than 100 μg/m³. The individual mean cancer risks for the 17 health-related VOCs ranged from 4.64 × 10⁻¹⁰ to 1.09 × 10⁻⁴, with a cumulative risk of 1.61 × 10⁻⁴. The mean cancer risks associated with naphthalene, chloroform, 1,4-dichlorobenzene, and 1,2-dibromoethylene were 1.09 × 10⁻⁴, 1.61 × 10⁻⁵, 1.11 × 10⁻⁵, and 1.07 × 10⁻⁵, respectively. These risks are higher than the acceptable risk levels defined by the USEPA and the World Health Organization (WHO). Of these, naphthalene was regarded as having a "definite risk"; chloroform, 1,4-dichlorobenzene, and 1,2-dibromoethylene were regarded as having a "probable risk"; and 1,2-dichloroethane and carbon tetrachloride were regarded as having "possible risk." The individual mean non-cancer risks associated with 28 health-related VOCs and total VOCs were within acceptable ranges; naphthalene was the dominant pollutant.

Expression Changes in Lactate and Glucose Metabolism and Associated Transporters in Basal Ganglia following Hypoxic-Ischemic Reperfusion Injury in Piglets [PEDIATRICS]

BACKGROUND AND PURPOSE:

The neonatal brain has active energy metabolism, and glucose oxidation is the major energy source of brain tissue. Lactate is produced by astrocytes and released to neurons. In the central nervous system, lactate is transported between neurons and astrocytes via the astrocyte-neuron lactate shuttle. The aim of this study was to investigate the regulatory mechanisms of energy metabolism in neurons and astrocytes in the basal ganglia of a neonatal hypoxic-ischemic brain injury piglet model.

MATERIALS AND METHODS:

A total of 35 healthy piglets (3–5 days of age; 1.0–1.5 kg) were assigned to a control group (n = 5) or a hypoxic-ischemic model group (n = 30). The hypoxic-ischemic model group was further divided into 6 groups according to the ¹H-MR spectroscopy and PET/CT scan times after hypoxia-ischemia (0–2, 2–6, 6–12, 12–24, 24–48, and 48–72 hours; n = 5/group). ¹H-MR spectroscopy data were processed with LCModel software. Maximum standard uptake values refer to the maximum standard uptake values for glucose (or FDG). The maximum standard uptake values of the basal ganglia–to-occipital cortex ratio were analyzed. The expression levels of glucose transporters and monocarboxylate transporters were detected by immunohistochemical analysis.

RESULTS:

Lactate levels decreased after an initial increase, with the maximal level occurring around 2–6 hours following hypoxia-ischemia. After hypoxia-ischemia, the maximum standard uptake values of the basal ganglia and basal ganglia/occipital cortex initially increased then decreased, with the maximum occurring at approximately 6–12 hours. The lactate and glucose uptake (basal ganglia/occipital cortex maximum standard uptake values) levels were positively correlated. The expression levels of glucose transporter-1 and glucose transporter-3 were positively correlated with the basal ganglia/occipital cortex. The expression levels of monocarboxylic acid transporter-2 and monocarboxylic acid transporter-4 were positively correlated with lactate content.

CONCLUSIONS:

The results indicate that lactate and glucose transporters have a synergistic effect on the energy metabolism of neurons and astrocytes following hypoxic-ischemic reperfusion brain injury.

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High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Comparison between Gadobutrol and Linear Gadolinium-Based Contrast Agents [PATIENT SAFETY]

BACKGROUND AND PURPOSE:

In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents.

MATERIALS AND METHODS:

This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups.

RESULTS:

The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group (t = 4.215, P < .001), while no significant increase was seen in the gadobutrol group (t = –1.422, P = .08). The globus pallidus/pons ratios followed similarly, with an increase in the linear gadolinium-based contrast agent group (t = 2.931, P < .0001) and no significant change in those receiving gadobutrol (t = 0.684, P = .25).

CONCLUSIONS:

Successive doses of gadobutrol do not result in T1 shortening compared with changes seen in linear gadolinium-based contrast agents.

MR Imaging Criteria for the Detection of Nasopharyngeal Carcinoma: Discrimination of Early-Stage Primary Tumors from Benign Hyperplasia [HEAD & NECK]

BACKGROUND AND PURPOSE:

MR imaging can detect nasopharyngeal carcinoma that is hidden from endoscopic view, but for accurate detection carcinoma confined within the nasopharynx (stage T1) must be distinguished from benign hyperplasia of the nasopharynx. This study aimed to document the MR imaging features of stage T1 nasopharyngeal carcinoma and to attempt to identify features distinguishing it from benign hyperplasia.

MATERIALS AND METHODS:

MR images of 189 patients with nasopharyngeal carcinoma confined to the nasopharynx and those of 144 patients with benign hyperplasia were reviewed and compared in this retrospective study. The center, volume, size asymmetry (maximum percentage difference in area between the right and left nasopharyngeal halves), signal intensity asymmetry, deep mucosal white line (greater contrast enhancement along the deep tumor margin), and absence/distortion of the adenoidal septa were evaluated. Differences were assessed with logistic regression and the ² test.

RESULTS:

The nasopharyngeal carcinoma center was lateral, central, or diffuse in 134/189 (70.9%), 25/189 (13.2%), and 30/189 (15.9%) cases, respectively. Nasopharyngeal carcinomas involving the walls showed that a deep mucosal white line was present in 180/183 (98.4%), with a focal loss of this line in 153/180 (85%) cases. Adenoidal septa were absent or distorted in 111/111 (100%) nasopharyngeal carcinomas involving the adenoid. Compared with benign hyperplasia, nasopharyngeal carcinoma had a significantly greater volume, size asymmetry, signal asymmetry, focal loss of the deep mucosal white line, and absence/distortion of the adenoidal septa (P < .001). Although size asymmetry was the most accurate criterion (89.5%) for nasopharyngeal carcinoma detection, use of this parameter alone would have missed 11.9% of early-stage T1 nasopharyngeal carcinomas.

CONCLUSIONS:

MR imaging features can help distinguish stage T1 nasopharyngeal carcinoma from benign hyperplasia in most cases.

Spinal Angiogram: A Treacherous Criterion Standard... [letter]

Quantitative Analysis of Conebeam CT for Delineating Stents in Stent-Assisted Coil Embolization [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Innovative techniques and device-related advances have improved the outcomes of neuroendovascular treatment. 3D imaging has previously used 2 x 2 binning, but 1 x 1 binning has recently been made available. The aim of this study was to evaluate the quantitative ability of conebeam CT for stent delineation and to investigate its effectiveness in the clinical environment.

MATERIALS AND METHODS:

Four acquisition groups of 3D MIP images acquired using conebeam CT with varying conditions (acquisition time, 10 or 20 seconds and binning, 1 x 1 or 2 x 2) were compared. Two methods of analysis were performed, a phantom study and an analysis of 28 randomly selected patients. The phantom study assessed the contrast-to-noise ratio and full width at half maximum values in conebeam CT images of intracranial stent struts. In the clinical subjects, we assessed contrast-to-noise ratio, full width at half maximum, and dose-area product.

RESULTS:

In the phantom study, the contrast-to-noise ratio was not considerably different between 10- and 20-second acquisition times at equivalent binning settings. Additionally, the contrast-to-noise ratio at equivalent acquisition times did not differ considerably by binning setting. For the full width at half maximum results, equivalent acquisition times differed significantly by binning setting. In the clinical analyses, the 10-second/1 x 1 group (versus 20 second/2 x 2) showed a higher contrast-to-noise ratio (P < .05) and a dose-area product reduced by approximately 70% (P < .05), but the difference in full width at half maximum was not significant (P = .20).

CONCLUSIONS:

For stent-assisted coil embolization, quantitative assessment of conebeam CT showed that 10 second/1 x 1 was equivalent to 20 second/2 x 2 for imaging deployed intracranial stents. Furthermore, the 10-second/1 x 1 settings resulted in a much smaller DAP.

Beware of Multiphase CTA Interpretation [letter]

Imaging of Anaplastic Thyroid Carcinoma [HEAD & NECK]

SUMMARY:

Anaplastic thyroid carcinoma is fatal if unresectable. However, improved survival has been reported after gross total resection and multimodality therapy. In this report, we describe the contrast-enhanced high-resolution CT characteristics of anaplastic thyroid carcinoma in 57 patients. Anaplastic thyroid carcinoma presented as a large neck mass with necrosis in 82% of cases. The tumors demonstrated common extrathyroidal extension (91%). Sixty-two percent of tumors demonstrated calcification. Visceral space invasion involved the esophagus (62%), trachea (57%), and larynx (29%). Carotid artery encasement was present in 42%, and 43% involved the internal jugular vein. Sixty-three percent had lateral compartment lymphadenopathy; 58% of these nodes were necrotic, and 11% were cystic. No metastatic nodes had calcification. Central compartment lymphadenopathy was seen in 56% of cases, and lateral retropharyngeal lymphadenopathy was detected in 12%. Knowledge of these imaging features aids in guiding the approach to the initial tissue diagnosis with either fine-needle aspiration or core biopsy, assessing the feasibility of surgical resection, and determining prognosis.

Reply: [reply]

Spinal Arteriovenous Vascular Malformations in Patients with Neural Tube Defects [SPINE]

BACKGROUND AND PURPOSE:

Neural tube defects, such as tethered cord, intradural lipoma, or myelomeningocele may coexist with spinal vascular malformations. The coexistence of these 2 rare entities is suggestive of a causal relationship between them, which may lead to further understanding of their pathogenesis. We present a series of 6 patients with epidural spinal arteriovenous fistulas associated with neural tube defects.

MATERIALS AND METHODS:

We retrieved cases of spinal vascular malformations associated with neural tube defects seen at our institution. The clinical presentation, MR imaging/MRA and angiographic imaging, treatment outcomes, and long-term neurologic outcomes were analyzed. Descriptive statistical analyses are reported.

RESULTS:

Six patients with epidural arteriovenous fistulas and neural tube defects were included in this study. The mean age at presentation was 42 years, and the most common presenting symptoms were lower extremity weakness followed by sensory disturbances and bladder/bowel dysfunction. In most cases (5/6), the fistulas were located at the sacral level. All cases were fed by the lateral sacral artery (6/6). Four patients had prior spine surgery, but the fistula was in the operative bed in 2 cases. All fistulas were extradural with secondary intradural venous drainage. Five patients underwent transarterial embolization with Onyx, and 1 patient had a treatment-related complication.

CONCLUSIONS:

It is conceivable that there is a pathophysiologic link between neural tube defects and development of spinal vascular malformations. Delayed neurologic deterioration or high conus signal in a patient with a neural tube defect should suggest the possibility of such an association.

Nonsphericity Index and Size Ratio Identify Morphologic Differences between Growing and Stable Aneurysms in a Longitudinal Study of 93 Cases [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Recent studies have strongly associated intracranial aneurysm growth with increased risk of rupture. Identifying aneurysms that are likely to grow would be beneficial to plan more effective monitoring and intervention strategies. Our hypothesis is that for unruptured intracranial aneurysms of similar size, morphologic characteristics differ between aneurysms that continue to grow and those that do not.

MATERIALS AND METHODS:

From aneurysms in our medical center with follow-up imaging dates in 2015, ninety-three intracranial aneurysms (23 growing, 70 stable) were selected. All CTA images for the aneurysm diagnosis and follow-up were collected, a total of 348 3D imaging studies. Aneurysm 3D geometry for each imaging study was reconstructed, and morphologic characteristics, including volume, surface area, nonsphericity index, aspect ratio, and size ratio were calculated.

RESULTS:

Morphologic characteristics were found to differ between growing and stable groups. For aneurysms of <3 mm, nonsphericity index (P < .001); 3–5 mm, nonsphericity index (P < .001); 5–7 mm, size ratio (P = .003); >7 mm, volume (P < .001); surface area (P < .001); and nonsphericity index (P = .002) were significant. Within the anterior communicating artery, the nonsphericity index (P = .008) and, within the posterior communicating artery, size ratio (P = .004) were significant. The nonsphericity index receiver operating characteristic area under the curve was 0.721 for discriminating growing and stable cases on the basis of initial images.

CONCLUSIONS:

Among aneurysms with similar sizes, morphologic characteristics appear to differ between those that are growing and those that are stable. The nonsphericity index, in particular, was found to be higher among growing aneurysms. The size ratio was found to be the second most significant parameter associated with growth.

Blunt Cerebrovascular Injuries: Advances in Screening, Imaging, and Management Trends [review-article]

SUMMARY:

Blunt cerebrovascular injury is a relatively uncommon but sometimes life-threatening injury, particularly in patients presenting with ischemic symptoms in that vascular territory. The decision to pursue vascular imaging (generally CT angiography) is based on clinical and imaging findings. Several grading scales or screening criteria have been developed to guide the decision to pursue vascular imaging, as well as to recommend different treatment options for various injuries. The data supporting many of these guidelines and options are limited however. The purpose of this article is to review and compare these scales and criteria and the data supporting clinical efficacy and to make recommendations for future research in this area.

MR Imaging-Based Evaluations of Olfactory Bulb Atrophy in Patients with Olfactory Dysfunction [HEAD & NECK]

BACKGROUND AND PURPOSE:

Although the olfactory bulb volume as assessed with MR imaging is known to reflect olfactory function, it is not always measured during olfactory pathway assessments in clinical settings. We aimed to evaluate the utility of visual olfactory bulb atrophy and neuropathy analyses using MR imaging in patients with olfactory dysfunction.

MATERIALS AND METHODS:

Thirty-four patients who presented with subjective olfactory loss between March 2016 and February 2017 were included. Patients underwent a nasal endoscopic examination, olfactory testing with the Korean Version of the Sniffin' Sticks test, and MR imaging. All patients completed the Sino-Nasal Outcome Test and Questionnaire of Olfactory Disorders. Olfactory bulb atrophy and neuropathy were evaluated on MR images by 2 head and neck radiologists.

RESULTS:

The etiology of olfactory loss was chronic rhinosinusitis with/without nasal polyps in 15 (44.1%) patients, respiratory viral infection in 7 (20.6%), trauma in 2 (5.9%), and idiopathic in 10 (29.4%) patients. Although 10 (29.4%) of the 34 patients were normosmic according to the Sniffin' Sticks test, their scores on the other tests were like those of patients who were hyposmic/anosmic according to the Sniffin' Sticks test. However, the detection rate of olfactory bulb atrophy was significantly higher in patients with hyposmia/anosmia than it was in patients with normosmia (P = .002). No difference in olfactory bulb neuropathy was identified among patients with normosmia and hyposmia/anosmia (P = .395).

CONCLUSIONS:

MR imaging evaluations of olfactory bulb atrophy can be used to objectively diagnose olfactory dysfunction in patients with subjective olfactory loss.

Development of High Signal Intensity within the Globus Pallidus and Dentate Nucleus following Multiple Administrations of Gadobenate Dimeglumine [PATIENT SAFETY]

BACKGROUND AND PURPOSE:

Previous studies have evaluated various gadolinium based contrast agents and their association with gadolinium retention, however, there is a discrepancy in the literature concerning the linear agent gadobenate dimeglumine. Our aim was to determine whether an association exists between the administration of gadobenate dimeglumine and the development of intrinsic T1-weighted signal in the dentate nucleus and globus pallidus.

MATERIALS AND METHODS:

In this single-center, retrospective study, the signal intensity of the globus pallidus, dentate nucleus, thalamus, and middle cerebellar peduncle was measured on unenhanced T1-weighted images in 29 adult patients who had undergone multiple contrast MRIs using exclusively gadobenate dimeglumine (mean, 10.1 ± 3.23 doses; range, 6–18 doses). Two neuroradiologists, blinded to the number of prior gadolinium-based contrast agent administrations, separately placed ROIs within the globi pallidi, thalami, dentate nuclei, and middle cerebellar peduncles on the last MR imaging examinations. The correlations between the globus pallidus:thalamus and the dentate nucleus:middle cerebellar peduncle signal intensity ratios with the number of gadolinium-based contrast agent administrations and cumulative dose were tested with either 1-tailed Pearson or Spearman correlations. A priori, P < .05 was considered statistically significant.

RESULTS:

Both the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the number of gadolinium-based contrast agent administrations (r = 0.39, P = .017, and r = 0.58, P = .001, respectively). Additionally, the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the cumulative dose of gadobenate dimeglumine (r = 0.48, P = .004, and r = 0.43, P = .009, respectively). Dentate nucleus hyperintensity was qualitatively present on the last MR imaging in 79.3%–86.2% of patients and in all patients who had received >10 doses.

CONCLUSIONS:

At high cumulative doses (commonly experienced by patients, for example, with neoplastic disease), gadobenate dimeglumine is associated with an increase in the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncles signal intensity ratios.

Prenatal Factors Associated with Postnatal Brain Injury in Infants with Congenital Diaphragmatic Hernia [PEDIATRICS]

BACKGROUND AND PURPOSE:

Approximately 60% of infants with congenital diaphragmatic hernia have evidence of brain injury on postnatal MR imaging. It is unclear whether any brain injury is present before birth. In this study, we evaluated fetal MR imaging findings of brain injury and the association of congenital diaphragmatic hernia severity with postnatal brain injury.

MATERIALS AND METHODS:

Fetal MR imaging and postnatal brain MR imaging were retrospectively evaluated in 36 cases of congenital diaphragmatic hernia (from 2009 to 2014) by 2 pediatric neuroradiologists. Brain injury on postnatal MR imaging and brain injury and congenital diaphragmatic hernia severity on fetal MR imaging were recorded. Correlations between brain abnormalities on fetal and postnatal brain MR imaging were analyzed. Postnatal brain injury findings correlating with the severity of congenital diaphragmatic hernia were also assessed.

RESULTS:

On fetal MR imaging, enlarged extra-axial spaces (61%), venous sinus distention (21%), and ventriculomegaly (6%) were identified. No maturational delay, intracranial hemorrhage, or brain parenchymal injury was identified on fetal MR imaging. On postnatal MR imaging, 67% of infants had evidence of abnormality, commonly, enlarged extra-axial spaces (44%). Right-sided congenital diaphragmatic hernia was associated with a greater postnatal brain injury score (P = .05). Low observed-to-expected lung volume was associated with postnatal white matter injury (P = .005) and a greater postnatal brain injury score (P = .008). Lack of liver herniation was associated with normal postnatal brain MR imaging findings (P = .03).

CONCLUSIONS:

Fetal lung hypoplasia is associated with postnatal brain injury in congenital diaphragmatic hernia, suggesting that the severity of lung disease and associated treatments affect brain health as well. We found no evidence of prenatal brain parenchymal injury or maturational delay.

Looking Deep into the Eye-of-the-Tiger in Pantothenate Kinase-Associated Neurodegeneration [PEDIATRICS]

BACKGROUND AND PURPOSE:

A detailed delineation of the MR imaging changes in the globus pallidus in pantothenate kinase–associated neurodegeneration will be helpful for diagnosis and monitoring of patients. The aim of this study was to determine the morphologic spectrum of the "eye-of-the-tiger" sign and the topographic pattern of iron deposition in a group of patients with pantothenate kinase–associated neurodegeneration.

MATERIALS AND METHODS:

Seventy-four MR imaging scans from 54 individuals with PANK2 mutations were analyzed for signal patterns in the globus pallidus. Sixteen SWI data from 15 patients who underwent 1.5T (n = 7), 3T (n = 7), and 7T (n = 2) MR imaging were included to visualize the iron topography.

RESULTS:

The linear hyperintensity alongside the medial border of the globus pallidus was the earliest T2 signal change. This finding was evident before SWI changes from iron deposition became visible. T2WI performed in early childhood mostly showed isolated hyperintense signal. In adult patients, marked signal reduction within an earlier hyperintense center resulting from iron accumulation led to the loss of signal difference between the central and surrounding areas. Signal hypointensity on SWI progressed from the medial to the lateral portion of the globus pallidus with increasing age. The fiber connections between the medial globus pallidus and the anteromedial aspect of the substantia nigra and subthalamic nucleus were markedly hypointense on SWI.

CONCLUSIONS:

In pantothenate kinase–associated neurodegeneration, the globus pallidus MR imaging changes using SWI develop as region-specific and age-dependent phenomena. Signal inhomogeneity was observed across the globus pallidus in pantothenate kinase–associated neurodegeneration and should be considered when determining the concentration of iron.

Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology.

MATERIALS AND METHODS:

Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient.

RESULTS:

All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed.

CONCLUSIONS:

Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.

Concerns about a New Preterm MR Imaging Scoring System [letter]

Cerebellar Hypoperfusion in Migraine Attack: Incidence and Significance [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Patients diagnosed with migraine with aura have an increased lifetime risk of ischemic stroke. It is not yet clear whether prolonged cortical hypoperfusion during an aura increases the immediate risk of cerebellar infarction because it may induce crossed cerebellar diaschisis and subsequent tissue damage. To address this question, we retrospectively analyzed potential relationships between cortical oligemia and cerebellar hypoperfusion in patients with migraine with aura and their potential relation to small infarct-like cerebellar lesions.

MATERIALS AND METHODS:

One hundred six migraineurs who underwent MR imaging, including DSC perfusion, were included in the study. In patients with apparent perfusion asymmetry, we used ROI analysis encompassing 18 infra- and supratentorial ROIs to account for differences in regional cerebral blood flow and volume. The presence of cerebellar hypoperfusion was calculated using an asymmetry index, with values of >10% being considered significant.

RESULTS:

We observed perfusion asymmetries in 23/106 patients, 22 in patients with migraine with aura (20.8%). Cerebellar hypoperfusion was observed in 12/23 patients (52.2%), and crossed cerebellar diaschisis, in 9/23 patients (39.1%) with abnormal perfusion. In none of the 106 patients were DWI restrictions observed during migraine with aura.

CONCLUSIONS:

Cerebellar hypoperfusion and crossed cerebellar diaschisis are common in patients with migraine with aura and cortical perfusion abnormalities. Crossed cerebellar diaschisis in migraine with aura may be considered a benign phenomenon because we observed no association with DWI restriction or manifest cerebellar infarctions, even in patients with prolonged symptom-related perfusion abnormalities persisting for up to 24 hours.

PACAP and migraine headache: immunomodulation of neural circuits in autonomic ganglia and brain parenchyma

The discovery that intravenous (IV) infusions of the neuropeptide PACAP-38 (pituitary adenylyl cyclase activating peptide-38) induced delayed migraine-like headaches in a large majority of migraine patients ha...

Bacterial community structure and diversity responses to the direct revegetation of an artisanal zinc smelting slag after 5 years

Abstract

This comparative field study examined the responses of bacterial community structure and diversity to the revegetation of zinc (Zn) smelting waste slag with eight plant species after 5 years. The microbial community structure of waste slag with and without vegetation was evaluated using high-throughput sequencing. The physiochemical properties of Zn smelting slag after revegetation with eight plant rhizospheres for 5 years were improved compared to those of bulk slag. Revegetation significantly increased the microbial community diversity in plant rhizospheres, and at the phylum level, Proteobacteria, Acidobacteria, and Bacteroidetes were notably more abundant in rhizosphere slags than those in bulk waste slag. Additionally, revegetation increased the relative abundance of plant growth-promoting rhizobacteria such as Flavobacterium, Streptomyces, and Arthrobacter as well as symbiotic N₂ fixers such as Bradyrhizobium. Three dominant native plant species (Arundo donax, Broussonetia papyrifera, and Robinia pseudoacacia) greatly increased the quality of the rhizosphere slags. Canonical correspondence analysis showed that the differences in bacterial community structure between the bulk and rhizosphere slags were explained by slag properties, i.e., pH, available copper (Cu) and lead (Pb), moisture, available nitrogen (N), phosphorus (P), and potassium (K), and organic matter (OM); however, available Zn and cadmium (Cd) contents were the slag parameters that best explained the differences between the rhizosphere communities of the eight plant species. The results suggested that revegetation plays an important role in enhancing bacterial community abundance and diversity in rhizosphere slags and that revegetation may also regulate microbiological properties and diversity mainly through changes in heavy metal bioavailability and physiochemical slag characteristics.

Large inserts for big data: artificial chromosomes in the genomic era

Abstract

The exponential increase in available microbial genome sequences coupled with predictive bioinformatic tools are underscoring the genetic capacity of bacteria to produce an unexpected large number of specialized bioactive compounds. Since most of the biosynthetic gene clusters (BGCs) present in microbial genomes are cryptic, i.e. not expressed under laboratory conditions, a variety of cloning systems and vectors have been devised to harbor DNA fragments large enough to carry entire BGCs and to allow their transfer in suitable heterologous hosts. This mini review provides an overview of the vectors and approaches that have been developed for cloning large BGCs, and successful examples of heterologous expression.

The consistent differential expression of genetic pathways following exposure of an industrial Pseudomonas aeruginosa strain to preservatives and a laundry detergent formulation

Abstract

Pseudomonas aeruginosa (P. aeruginosa) is a common contaminant associated with product recalls in the home and personal care (HPC) industry. Preservation systems are used to prevent spoilage and protect consumers, but greater knowledge is needed of preservative resistance mechanisms used by P. aeruginosa contaminants. We aimed to identify genetic pathways associated with preservative exposure by using an industrial P. aeruginosa strain and implementing RNA-Seq to understand gene expression changes in response to industry relevant conditions. The consistent differential expression of five genetic pathways during exposure to multiple industrial growth conditions associated with benzisothiazolone (BIT) and phenoxyethanol (POE) preservatives, and a laundry detergent (LD) formulation, was observed. A MexPQ-OpmE Resistance Nodulation Division (RND) efflux pump system was commonly up-regulated in response to POE, a combination of BIT and POE, and LD together with BIT. In response to all industry conditions, a putative sialic acid transporter and isoprenoid biosynthesis gnyRDBHAL operon demonstrated consistent up-regulation. Two operons phnBA and pqsEDCBA involved in PQS production and quorum-sensing, were also consistently down-regulated during exposure to all the industry conditions. The ability to identify consistently differentially expressed genetic pathways in P. aeruginosa can inform the development of future targeted preservation systems that maintain product safety and minimise resistance development.