Adult asthma scores - development and validation of multivariable scores to identify asthma in surveys

Publication date: Available online 18 July 2018

Source: The Journal of Allergy and Clinical Immunology: In Practice

Author(s): Ana Sá-Sousa, Ana Margarida Pereira, Rute Almeida, Luís Araújo, Mariana Couto, Tiago Jacinto, Alberto Freitas, Jean Bousquet, João A. Fonseca

Abstract

Background

One of the questions in epidemiology is the identification of adult asthma in studies.

Objective

We aim to 1) develop and validate multivariable scores for adult asthma identification in epidemiological studies; 2) explore cut-offs to rule-in/-out asthma, compared to asthma diagnosed by a physician after clinical examination and diagnostic tests, blinded to the self-administered questions.

Methods

We analyzed data (n=711 adults) from a nationwide population-based study. The predictors were self-administered questions identified in a literature review (A2-score) and from the GA2LEN questionnaire (GA2LEN-score). Scores were developed using exploratory factor analysis. Internal consistency, discriminative power and diagnostic accuracy were assessed.

Results

The A2-score comprises 8 questions (including "Did a physician confirm you had asthma?") and GA2LEN-score, 6 questions (including "Have you ever had asthma?"). Both had high Cronbach's alpha (0.89 and 0.85) and good AUC (90.4% and 89.0%). The scoring is the sum of positive answers. Asthma is present (rule-in) for scores≥4 (Specificity:99.2%; PPVs:93.3%, 91.7%; Accuracy:89.4%, 87.4%, respectively for A2-score and GA2LEN-score). Asthma is excluded (rule-out) for A2-scores of 0-1 and GA2LEN-score of 0 (Sensitivity:93.1%; NPV:98.2%, 98.0%; Accuracy:89.4%, 82.8%).

Conclusions

These practical scores can be used to rule-in/-out asthma in epidemiological studies and clinical screening/triage settings. They may help physicians in primary care or other specialties to screen asthmatics using a simple score with a high level of discrimination and to identify the best candidates to be referred for a diagnostic workup. Moreover, their use may contribute to reducing the inconsistencies of operational definitions of asthma across studies and surveys.

Investigating the efficacy of a new intravenous (IV) nanoemulsified sevoflurane/arginine formulation for maintenance of general anesthesia for embolization of cerebral aneurysm

Publication date: Available online 18 July 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Yu Liu, Yaoxian Zhang, Zihao Zheng, Xicheng Liu

Abstract

The aim of this research investigation was to profound analysis the mitigating impact of sevoflurane/arginine post-molding on cerebral ischemia-reperfusion damage in rats. The authors fabricated emulsions fusing sevoflurane, perfluorooctyl bromide as a settling specialist, and mixes of arginine polymer. Cell suitability and gene expression of tubulin and NeuN were assessed. The stability, morphology and functional group were evaluated utilizing dynamic light scattering (DLS), Transmission Electron Microscope (TEM), atomic force microscopy (AFM), and Fourier-transform infrared spectroscopy (FTIR). Cerebral aneurysms were prompted through hypertension and a solitary stereotactic infusion of elastase into the basal storage in rat. The capacity of the emulsions to decreased cerebral aneurysm was tried in vivo by regulating them IV delivery of Se/Arg samples to rats. Se/Arg pre-conditioning expanded cell feasibility in neuroblast (SK-N-DZ) cells. Se/Arg pre-conditioning diminished infarct volume and enhanced neurological result in rats subjected to cerebral hypoxia–ischemia. Se/Arg preconditioning expanded levels of tubulin and NeuN. The prepared sevoflurane/arginine material pre-conditioning-incited neuroprotective impacts in vitro as well as in vivo analyses. Sevoflurane/arginine post-molding decreased cerebral tissue misfortune detected 7 days after cerebrum hypoxia–ischemia. This impact was prompted by clinically significant focuses and canceled by Sevoflurane/arginine. These outcomes recommend that Sevoflurane/arginine post-conditioning ensures neonatal cerebrum against cerebrum hypoxia–ischemia.

Graphical Abstract

Combination of medicinal honey and 904 nm superpulsed laser-mediated photobiomodulation promotes healing and impedes inflammation, pain in full-thickness burn

Publication date: Available online 18 July 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Anju Yadav, Saurabh Verma, Gaurav K. Keshri, Asheesh Gupta

Abstract

Burn wound is a complex multi-factorial pathophysiology producing excruciating pain and psychological discomfort among patients, which imposes a major burden on the healthcare system. Multi-target therapy focuses on augmented healing by regulating different phases of tissue repair. Recently, photobiomodulation (PBM)-induced wound healing has achieved profound impetus as a non-invasive, drug-free biophysical therapeutic approach. On the other hand, medicinal honey known to possess antibacterial and immunomodulatory properties and is being used as an effective treatment option for infected wounds. The present study aimed to determine whether the combination of medicinal honey and PBM using superpulsed 904 nm laser treatment could additively accelerate full-thickness burn wound repair in rats. Animals were randomly allocated into 4 experimental groups: control (C), PBM superpulsed 904 nm laser treated (PBMT), honey treated (HT) and combined treatment (CT). The dual treatment exhibited an enhanced wound area contraction and hexosamine content as compared to the other groups. Histopathological analysis revealed increased cellular proliferation, extracellular matrix accumulation and decreased inflammation in the CT group. Further, the CT group demonstrated synergistically attenuated inflammation, pain and enhanced cell adhesion, migration as evidenced by significantly reduced protein expression of TNF-α, NF-κB, IL-1β, COX-2, substance-P receptor and up-regulation of fibronectin, respectively as compared with the other groups. Thus, the findings of present study signify that the combination of medicinal honey and PBMT accelerates the repair process of burn wounds. The study showed that therapeutic efficacy of 904 nm superpulsed laser-mediated PBM augments in the presence of medicinal honey by enhancing cellular proliferation and attenuation of inflammation and pain in burn wound healing.

Advancement of Near-infrared (NIR) laser interceded surface enactment of proline functionalized graphene oxide with silver nanoparticles for proficient antibacterial, antifungal and wound recuperating therapy in nursing care in hospitals

Publication date: Available online 18 July 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Xin Wu, Hui Li, Ning Xiao

Abstract

Medication obstruction of microscopic organisms has turned into a worldwide medical issue, as it makes the ordinary anti-toxins less effective. It is desperately expected to investigate novel antibacterial materials and create viable treatment techniques to defeat the medication obstruction of anti-infection agents. Herein, we effectively fabricated silver nanoparticles improved proline/graphene oxide nano-flakes (GO-Pro/n-Ag) as novel anti-pathogenic substance through simplistic technique. The property of the silver nanoparticles activated discharge gave amazing antibacterial and antifungal movement against the pathogenic microorganism. Upon supply of NIR, the graphene oxide based biomaterials privately increased the temperature, bringing about the high mortality of pathogenic microorganism. The GO-Pro biocomposite activated n-Ag particles discharging approach for antibacterial, antifungal enables n-Ag to be ensured by proline layout without influencing normal cells. The biocomposites provided antibacterial and antifungal movement against S. aureus, P.aeruginosa, C. albicans and S. cerevisia. Also, the L929 mouse fibroblast cells were utilized for cytocompatibility assessment, and the GO-Pro/n-Ag demonstrated low lethality. Likewise, the GO-Pro/n-Ag and GO-Pro/n-Ag + NIR are set up for in vivo tests and demonstrate incredible antibacterial property in wound model. As the fabricated GO-Pro/n-Ag biocomposite nano-flakes have the benefits of minimal effort and high anti-pathogenic activity, they may be of promising and helpful antibacterial and antifungal specialists for various biomedical applications.

Graphical Abstract

Journal of the American Academy of Dermatology: Original article Comorbidities in alopecia areata: A systematic review and meta-analysis

Publication date: Available online 18 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Solam Lee, Hanil Lee, Chung Hyeok Lee, Won-Soo Lee

Abstract

Background

Alopecia areata (AA) may be associated with various systemic diseases according to several studies.

Objective

To identify prevalent and incident diseases in AA patients and quantify their prevalence and odds and hazard ratio compared with those in non-AA controls.

Methods

A systematic review of the studies published before February 28, 2018 was performed using MEDLINE, Embase, Web of Science and Cochrane Library databases. Observational studies on prevalent or incident diseases in AA patients were included, whereas studies limited to pediatrics or providing only laboratory results or continuous data were excluded. Inverse variance method with random-effects model was used for meta-analyses.

Results

Eighty-seven studies were analyzed. Atopic diseases, metabolic syndrome, Helicobacter pylori infection, lupus erythematosus, iron deficiency anemia, thyroid diseases, psychiatric diseases, vitamin D deficiency, and audiologic and ophthalmic abnormalities were more prevalent in AA patients. AA patients had a higher risk of developing autoimmune diseases.

Limitations

Some diseases were investigated by an insufficient number of studies to be meta-analyzed. Meta-analysis on incident diseases was not performed owing to the limited availability on cohort studies.

Conclusion

AA is associated with various systemic and psychiatric diseases. Physicians are encouraged to evaluate and manage potential comorbid conditions to achieve better outcomes.

Long-term sheltering mustaches reduce incidence of lower lip actinic keratosis

Publication date: Available online 18 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Deede Y. Liu, Muhammad I. Gul, Jo Wick, Anand N. Rajpara, Prescilia Isedeh, Ting Wang, Daniel J. Aires

Site-specific investigation and spatial modeling of canopy drip effect on element concentrations in moss

Abstract

In this study, the canopy drip effect on the exposure of forests to atmospheric deposition of potentially toxic metals and nitrogen (N) and element accumulation was investigated. Thereby, the respective element concentrations of metals and N in moss specimens were investigated by example of North-Western Germany. To this end, on the one hand, the concentrations of Al, As, Cd, Cr, Cu, Fe, Hg, Pb, Ni, Sb, V, Zn, and N in mosses sampled under, outside, and at the edge of forest canopies were examined for statistical significant differences. On the other hand, vegetation structures parameterizing the canopy drip effect were quantified by use of information collected, in addition to the element data, at each moss sampling site. The statistical relations between ratios of vegetation parameters and ratios of element concentrations were modeled by regression analysis, and the respective element concentration in moss was geostatistically estimated and mapped for unsampled locations throughout Germany. This article tackles regression models with R² > 0.5 (Cu, Hg, Pb, Sb, and N) to adapt the element concentrations measured at the 400 sites of the European Moss Survey (EMS) to three different features of hypothetical vegetation structures. To this end, the continuum of vegetation structures were represented as follows: open land (meadows) described by a leaf area index (LAI) value of 2.96 and under canopy sites in coniferous forests represented by a LAI value of 11. The arithmetic mean of LAI values at 400 EMS sites throughout Germany amounts to 5.1. The element concentrations for these target LAIs representing three site categories were calculated and mapped. Then, these LAI-dependent element concentration maps were compared with the maps depicting the spatial patterns of "pure" element concentrations. Spatial differences were evaluated and supposed to be of great value for the validation of atmospheric deposition modeling.

¿Es la teledermatología una herramienta útil para médicos, pacientes y administración?

Publication date: Available online 18 July 2018

Source: Actas Dermo-Sifiliográficas

Author(s): E. Gimeno Carpio

Can a Call Make a Difference? Measured Change in Women’s Breastfeeding Self-efficacy Across Call Interactions on a Telephone Helpline

Abstract

Background Telephone helplines providing 24-h specialist-nurse contact present a source of immediate support for women encountering challenges with breastfeeding and may serve to prolong breastfeeding duration by building self-efficacy. To date there is little evidence on interaction effectiveness and still less on the relative effectiveness for women from different socio-economic backgrounds. Research Aim To establish the effect on maternal breastfeeding self-efficacy of calls made to a nurse-led parenting helpline. Methods From a corpus of calls made to the Australian Child Health Line (N = 723), those made by women presenting a breastfeeding concern as a prime issue (n = 60) were scored for breastfeeding self-efficacy at commencement and completion of recorded interactions. Analyses examined the significance and direction of change from beginning to end of calls and compared difference in change across calls originating from high and low social advantage locations. Results A significant increase in self-efficacy was found, but with low effect size. There was considerable variation among calls; 53% showed improvement, 25% showed no change and 22% showed reduction in breastfeeding self-efficacy. While most calls were made by women from socially advantaged locations, change was more positive for the small number of callers from disadvantaged locations. Conclusion The potential of nurse-led reactive telephone support is evident, but dependent on qualities of the interaction. For women living in disadvantaged locations telephone support may be of particular significance given the greater social barriers to breastfeeding they are likely to encounter.

Maternal Decision-Making and Uptake of Health Services for the Prevention of Mother-to-Child HIV Transmission: A Secondary Analysis

Abstract

Objectives We investigated whether a woman's role in household decision-making was associated with receipt of services to prevent mother-to-child HIV transmission (PMTCT). Methods We conducted a secondary analysis of the PEARL study, an evaluation of PMTCT effectiveness in Cameroon, Cote d'Ivoire, South Africa, and Zambia. Our exposure of interest was the women's role (active vs. not active) in decision-making about her healthcare, large household purchases, children's schooling, and children's healthcare (i.e., four domains). Our primary outcomes were self-reported engagement at three steps in PMTCT: maternal antiretroviral use, infant antiretroviral prophylaxis, and infant HIV testing. Associations found to be significant in univariable logistic regression were included in separate multivariable models. Results From 2008 to 2009, 613 HIV-infected women were surveyed and provided information about their decision-making roles. Of these, 272 (44.4%) women reported antiretroviral use; 281 (45.9%) reported infant antiretroviral prophylaxis; and 194 (31.7%) reported infant HIV testing. Women who reported an active role were more likely to utilize infant HIV testing services, across all four measured domains of decision-making (adjusted odds ratios [AORs] 2.00–2.89 all p < .05). However, associations between decision-making and antiretroviral use—for both mother and infant—were generally not significant. An exception was active decision-making in a woman's own healthcare and reported maternal antiretroviral use (AOR 1.69, p < 0.05). Conclusions for Practice Associations between decision-making and PMTCT engagement were inconsistent and may be related to specific characteristics of individual health-seeking behaviors. Interventions seeking to improve PMTCT uptake should consider the type of health-seeking behavior to better optimize health services.

State Requirements for Prenatal Syphilis Screening in the United States, 2016

Abstract

Objectives This study assesses U.S. state laws related to prenatal syphilis screening, including whether these laws align with CDC screening recommendations and include legal penalties for failing to screen. Methods Statutes and regulations regarding syphilis screening during pregnancy and at delivery effective in 2016 were examined for all 50 U.S. states and the District of Columbia (DC). Targeted search terms were used to identify laws in legal research databases. The timing of the screening mandates for each state law was coded for: (1) first visit, (2) third trimester, and (3) delivery. Descriptive statistics were calculated to examine the number of states with each type of requirement and whether requirements adhered to the CDC STD treatment guidelines. Results Only six states (11.8%) do not require prenatal syphilis screening. Of states with screening requirements (n = 45), the majority (84.3%) require testing at first prenatal visit or soon after. 17 states (33.3%) require screening during the third trimester with five requiring screening only if the patient is considered at high risk. 8 (15.7%) states require screening at delivery with five requiring testing only if the woman is at high risk. 14 (27.5%) states include punishments for failing to screen (civil penalties, criminal penalties and license revocation). Conclusions for Practice Most states had prenatal syphilis screening requirements; a minority corresponded to or extended CDC recommendations. States vary in when they require testing, who must be tested, and whether a failure to screen could result in a punishment for the provider.

Maternal Depression Scale: Do “Drop-In” Laborist Patients Have Increased Postpartum Screening Risks Compared to Patients with Adequate Prenatal Care?

Abstract

Objectives The Edinburgh Postnatal Depression Scale (EPDS) identifies women with depressive symptoms in pregnancy. Our primary objective was to determine the prevalence of EPDS screen-positive women delivering on our no prenatal care (laborist) service and to compare these patients to private patients delivering with prenatal care. Methods Retrospective cohort analysis of EPDS scores during January 1, 2015 to June 18, 2015 was conducted. Scores ≥ 10 were considered at-risk. Results were analyzed as an aggregate and then as no prenatal care versus prenatal care. Characteristics for patients with at-risk scores (EPDS ≥ 10) versus low-risk scores (EPDS < 10) were quantified. Results Analysis occurred on 970 women. EPDS ≥ 10 occurred in 12.4% (n = 120/970). Positive EPDS score was 21.1% without prenatal care versus 10.9% with adequate prenatal care (P = 0.003). Maternal demographics and delivery characteristics were clinically similar in patients with prenatal care compared to no prenatal care. Private insurance was more common in patients with prenatal care compared to no prenatal care (23.5 versus 8.1%, P = 0.0001). However, analysis of patients with EPDS > 10 showed non-significant distributions of ethnicity, private insurance, Medicaid, or no insurance compared to patients with EPDS < 10. Conclusion for Practice Patients without prenatal care who arrive solely for urgent "drop-in" delivery have a measurable increased risk factor for postpartum depressive symptoms. Ethnicity and payor status were related to adequacy of prenatal care but were not significant variables when analyzing patients with EPDS > 10. Laborist services providing care to "drop-in" patients should recognize this increased risk and develop policies for screening, referral and follow-up of at-risk patients.

Examining Temporal Trends in Documentation of Pregnancy Intentions in Family Planning Health Centers Using Electronic Health Records

Abstract

Objectives Few studies have examined the extent to which providers assess pregnancy intentions during clinical encounters. Our objective was to assess temporal trends in documentation of patient pregnancy intentions in electronic health records (EHR). Methods In this retrospective observational study using EHR data from 627,399 female patients visiting 214 family planning centers in 2012–2014, we assessed changes in the prevalence of pregnancy intention documentation with piecewise log-binomial regression models. We examined bivariate associations between patient/visit characteristics and pregnancy intention documentation in each year, and associations between patients' pregnancy intentions and contraceptive methods. Results The proportion of patients with a documented pregnancy intention increased sharply from the end of 2012 (42%) to the midpoint of 2013 (85%; adjusted quarterly prevalence ratio [APR] = 1.40, 95% CI 1.36–1.45). Thereafter, the rate of change slowed as documentation approached the maximum possible frequency (93%; APR = 1.01, 95% CI 1.00–1.02). Documentation varied by all patient/visit characteristics in 2012 and 2013; in 2014, there were no clinically significant differences. Among patients with a documented intention, 97% were not planning a pregnancy in the next year. Women not planning a pregnancy were more likely to use a most/moderately effective contraceptive method than those planning a pregnancy (73 vs. 35%, p < 0.0001). Conclusions for Practice Improvements in pregnancy intention documentation co-occurred with changes to EHR templates (e.g., placement of structured data fields) and with provider-focused initiatives promoting reproductive life planning. Patients' pregnancy intentions aligned with contraceptive use; however, these findings cannot address whether assessment of intentions affects contraceptive use.

Sexual Orientation Disparities in Pregnancy and Infant Outcomes

Abstract

Objectives Little is known about maternal and infant health among sexual minority women (SMW), despite the large body of research documenting their multiple preconception risk factors. This study used data from the 2006–2015 National Survey of Family Growth (NSFG) to investigate sexual orientation inequities in pregnancy and birth outcomes, including miscarriage, stillbirth, preterm birth, and birth weight. Methods Women reported 19,955 study eligible pregnancies and 15,996 singleton live births. Sexual orientation was measured using self-reported identity and histories of same-sex sexual experiences (heterosexual-WSM [women who only report sex with men]; heterosexual-WSW [women who report sex with women]; bisexual, and lesbian). Logistic regression models were used that adjusted for several maternal characteristics. Results Compared to heterosexual-WSM, heterosexual-WSW (OR 1.25, 95% CI 1.00–1.58) and bisexual and lesbian women (OR 1.77, 95% CI 1.34–2.35) were more likely to report miscarriage, and bisexual and lesbian women were more likely to report a pregnancy ending in stillbirth (OR 2.85, 95% CI 1.40–5.83). Lesbian women were more likely to report low birth weight infants (OR 2.64, 95% CI 1.38–5.07) and bisexual and lesbian women were more likely to report very preterm births (OR 1.84, 95% CI 1.11–3.04) compared to heterosexual-WSM. Conclusions for Practice This study documents significant sexual orientation inequities in pregnancy and birth outcomes. More research is needed to understand the mechanisms that underlie disparate outcomes and to develop interventions to improve sexual minority women's maternal and infant health.

Orf dermatovirosis in a farm in a developing country: guiding the diagnosis with clinical, histopathology, and electron microscopy

Publication date: Available online 18 July 2018

Source: Piel

Author(s): Alicia Minerva López López, Julio César Salas Alanis, Samuel Amezcua Gudiño, Manuel Soria Orozco, Marisol Ramírez Padilla, Bertha Lissette Sotelo García

The value of remembered pre-operative quick disabilities of the arm, shoulder and hand (QuickDASH) scores

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Candida auris: An emerging drug resistant yeast – A mini-review

Publication date: Available online 17 July 2018

Source: Journal de Mycologie Médicale

Author(s): A.L. Bidaud, A. Chowdhary, E. Dannaoui

Abstract

Candida auris is an emerging fungal pathogen responsible for nosocomial invasive infection outbreaks on five continents. Large healthcare-related outbreaks of C. auris infection and colonization have been reported from different countries. Whole genome sequence analysis identified strong phylogeographic C. auris clades specific to particular geographical areas suggesting transmission of particular clades within countries. However, the mode of transmission within the healthcare environment is not clear and is likely to be multifactorial. The emergence of C. auris is alarming because this organism can harbor or develop multidrug resistance. This explains why C. auris infections are difficult to treat. In addition, difficulties in its identification in the routine diagnostic laboratory have a significant impact on outbreak detection and management. This mini-review highlights the available literature on C. auris, with particular insight into its epidemiology and the problems caused by its antifungal resistance.

Reverse Distal Transverse Palmar Arch in Distal Digital Replantation.

Related Articles

Reverse Distal Transverse Palmar Arch in Distal Digital Replantation.

Ann Plast Surg. 2017 Nov;79(5):473-476

Authors: Wei CY, Orozco O, Vinagre G, Shafarenko M

Abstract
BACKGROUND: Refinements in microsurgery have made distal finger replantation an established technique with high success rates and good functional and aesthetic outcomes. However, it still represents a technically demanding procedure due to the small vessel caliber and frequent lack of vessel length, requiring the use of interpositional venous grafts in some instances. We describe a new technique for anastomosis in fingertip replantation, whereby the need for venous grafts is eliminated.
METHODS: Applying the reverse distal transverse palmar arch technique, 11 cases of distal digital replantation were performed between January 2011 and July 2016. The described procedure was used for arterial anastomosis in 10 cases and arteriovenous shunting for venous drainage in 1 case. A retrospective case review was conducted. The technical description and clinical outcome evaluations are presented.
RESULTS: Ten of the 11 replanted digits survived, corresponding to an overall success rate of 91%. One replant failed due to venous insufficiency. Blood transfusions were not required for any of the patients. Follow-up (range, 1.5-5 months) revealed near-normal range of motion and good aesthetic results. All of the replanted digits developed protective sensation. The average length of hospital admission was 5 days. All patients were satisfied with the results and were able to return to their previous work.
CONCLUSIONS: The use of the reverse distal transverse palmar arch is a novel and reliable technique in distal digital replantation when an increase in vessel length is required, allowing for a tension-free arterial repair without the need for vein grafts.

PMID: 28737563 [PubMed - indexed for MEDLINE]

Mitteilungen der ÖWAW

Monitoring Autophagy in Neurons

By Christina Towers, PhD.

Autophagy is a critical cellular process used by most cells in the body to recycle nutrients and prevent harmful buildup of damaged proteins. It is particularly important in the brain, where a handful of pathologies have been linked to autophagy dysregulation. Conditional neuronal knock out of the core autophagy gene, ATG7, results in viable mice that eventually succumb to neurodegeneration accompanied by an accumulation of ubiquitin protein aggregates^{1, 2}. Likewise, decreased levels of functional autophagy have been linked to the three most common neurodegenerative diseases including Parkinson's, Huntington's and Alzheimer's disease³. Despite these findings, it has been a hurtle to find the most accurate and practical ways to measure autophagy in the brain, particularly in neurons.

Learn more about autophagy in neurodegeneration

The most common methods to measure autophagy in all cell types include monitoring autophagic flux by looking at LC3-II lipidation via western blot or analyzing LC3 lysosomal turn over via pH-sensitive tandem tagged-LC3, as well as autophagy specific cargo proteins like p62 and NBR1. Electron Microscopy is also commonly used to detect autophagy structures. While all of these methods can be used, there are some critical considerations to take into account when studying autophagy in the brain.

First, there are a variety of different types of cells in the central nervous system in addition to neurons, including supportive microglia cells and astrocytes as well as oligodendrocytes and endothelial cells. To study autophagy in neurons specially, neuronal cell lines (e.g., SH-SY5Y, Neuro2A, SK-N-SH, etc.) or primary cultured neurons are often used, which are not optimal as neither can fully polarize and primary cultures can only be maintained for 3-5 days. Nonetheless, autophagic flux can be measured in these systems by treatment of the cultured neurons with lysosomal inhibitors (e.g., Bafilomycin) followed by western blotting for LC3-II conversion. Interestingly, it has been reported that neurons maintain a high level of basal autophagy and lysosomal inhibitors cause only a slight increase in LC3-II but a more dramatic decrease in LC3-I. This is in contrast with what is often seen in autophagic flux experiments carried out in cancer cells.

Western Blot: LC3B Antibody (1251D) [NBP2-59800] - Total protein from HeLa and Neuro2A cells treated with or without 50 uM chloroquine for 24 hours was separated on a 4-15% gel by SDS-PAGE, transferred to 0.2 um PVDF membrane and blocked in 5% non-fat milk in TBST. The membrane was probed with 2.0 ug/ml anti-LC3 (1251d) in blocking buffer and detected with an anti-rabbit HRP secondary antibody using chemiluminescence. Note the detection of LC3I and LC3II.

Second, cultured neurons are extremely sensitive and the dose and time course of lysosomal inhibition must be optimized to block LC3 turn over with minimal toxicity. The levels of cargo receptors like p62 and NBR1 may also be assessed via western blot to monitor flux. However, autophagic flux assays using flow cytometry to monitor pH-sensitive tandem constructs like mCherry-GFP-LC3 are not practical in these systems because these cells can be difficult to transfect and neuronal protrusions make these cells impossible to analyze in most flow cytometer machines.

Finally, one of the best methods to monitor autophagy in neurons is with transmission electron microscopy (TEM) using neurons cultured on glass cover slips. These images have enough resolution to identify double membrane autophagosomes and fused autolysosomes ⁴.

There is still much work to be done in the field of neuroscience to improve the methods to monitor autophagy: assays are desperately needed to understand the role of this relevant cellular process in the context of neurodegeneration.

Learn more about autophagy in neurodegeneration

Christina Towers, PhD
University of Colorado (AMC)
Dr. Towers studies the roles of autophagy, apoptosis and cell death in cancer.

References

1. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441(7095):880-4.
2. Karsli-Uzunbas G, Guo JY, Price S, Teng X, Laddha SV, Khor S, et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 2014;4(8):914-27.
3. Towers CG, Thorburn A. Therapeutic Targeting of Autophagy. EBioMedicine. 2016;14:15-23.
4. Benito-Cuesta I, Diez H, Ordonez L, Wandosell F. Assessment of Autophagy in Neurons and Brain Tissue. Cells. 2017;6(3).

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Continuous Neural Spikes and Information Theory

Abstract

Can information theory be used to understand neural signaling? Yes, but assumptions have to be made about the nature of that signaling. The traditional view is that the individual neural spike is an all-or-none phenomenon, which allows neural spikes to be viewed as discrete, binary pulses, similar in kind to the signals in digital computers. Under this assumption, the tools of information theory can be used to derive results about the properties of neural signals. However, new results from neuroscience demonstrate that the precise shape of the individual spike can be functionally significant, thus violating the assumption that spikes can always be treated as a binary pulse. Instead, spikes must sometimes be viewed as a continuous signal. Fortunately, information-theoretic tools exist for the study of continuous signals; unfortunately, their use in the continuous domain is very different from their use in the discrete domain, and not always well understood. Researchers interested in making precise claims about the nature of the information used, stored, and processed in neural systems must pay careful attention to these differences.

Comparison of Energy-Based Tissue Dissection Techniques in Abdominoplasty: A Randomized, Open-Label Study Including Economic Aspects

Abstract

Background

Abdominoplasty is one of the most common procedures in plastic surgery, and energy-based tissue dissection techniques have become the gold standard. Despite its frequency, abdominoplasty is still associated with high complication rates.

Objectives

We compare clinical and economic data of four methods of energy-based tissue dissection in a randomized, open-label study.

Methods

A total of 57 patients were preoperatively randomized into four groups: Electrocautery, Ultracision Harmonic Scalpel, Argon Plasma Coagulation, and PEAK-Plasmablade. Demographic and operational data, as well as information on the postoperative course and complications were collected. For economic analysis, quotes were obtained from the device companies or official suppliers.

Results

We found no significant difference in the duration of surgery, the drainage quantity, or wound healing complications between treatment groups. The Ultracision method caused significantly greater blood loss compared to all other techniques (p<0.01). When comparing surgical costs, we found PEAK and Ultracision devices more expensive compared to APC and Electrocautery.

Conclusions

All methods evaluated can be applied safely and effectively in abdominoplasty procedures. However, our data demonstrate a significantly higher blood loss for the Ultracision Harmonic Scalpel. Considering our clinical data, we are unable to find justification for the higher costs of PEAK and Ultracision methods.

Comparison of botulinum neurotoxin type A formulations in Asia.

Related Articles

Comparison of botulinum neurotoxin type A formulations in Asia.

Clin Cosmet Investig Dermatol. 2018;11:327-331

Authors: Frevert J, Ahn KY, Park MY, Sunga O

Abstract
Results: All protein-based therapeutics, such as botulinum neurotoxin type A (BoNT/A), are potentially immunogenic and can lead to anaphylaxis, autoimmunity, or diminished or complete absence of therapeutic efficacy, especially if administered repeatedly. Therefore, the protein quantity in BoNT/A products is an important consideration when selecting products for treatment. However, essential formulation data are not always publicly accessible.
Materials and methods: The neurotoxin protein content of products newly introduced in Asia, such as (listed alphabetically) Botulax®, Meditoxin®, Nabota®, and Relatox®, was measured by sandwich enzyme-linked immunosorbent assay with antisera directed against BoNT/A compared to Xeomin®.
Results: Compared to Xeomin with no inactive neurotoxin, although Botulax and Nabota contained 844 and 754 pg of neurotoxin protein, respectively, the percentage of inactive neurotoxin was calculated to be 103 and 81, respectively, while the potency per pg of neurotoxin was 0.118 and 0.133 U, respectively. Meditoxin and Relatox had 575 and 578 pg of neurotoxins, respectively, marginally higher than that of Xeomin, while the percentage of inactive neurotoxins was 38 and 33, respectively, and the potency per pg of neurotoxin was 0.174 and 0.173 U, respectively. However, Xeomin, which has 416 pg/vial of purified neurotoxin and 0.240 U of efficacy per pg of neurotoxin, has the lowest neurotoxin protein content and consequently the highest specific potency compared to the four Asian BoNT/A preparations in this study.
Conclusion: Although Botulax and Nabota had more neurotoxin than Xeomin in an equivalent volume, they contained greater amounts of inactive neurotoxin. In addition, although Meditoxin and Relatox had slightly more neurotoxin than Xeomin, both contained greater amounts of inactive neurotoxin.

PMID: 30013379 [PubMed]

Assessing the response of morphea and limited scleroderma to tranilast: a small prospective study comparing topical corticosteroids to a combination of topical corticosteroids and tranilast.

Related Articles

Assessing the response of morphea and limited scleroderma to tranilast: a small prospective study comparing topical corticosteroids to a combination of topical corticosteroids and tranilast.

Clin Cosmet Investig Dermatol. 2018;11:321-326

Authors: Noakes R

Abstract
Background: Scleroderma is traditionally managed with immunomodulatory agents such as methotrexate, mycophenolate mofetil and corticosteroids. There are anecdotal reports for, and theoretical reasons why, the anti-fibrotic agent tranilast may provide an additional treatment modality.
Objective: The objective of the current study was to demonstrate if the addition of topical tranilast to an established regime resulted in an improvement in the Localized Scleroderma Assessment Tool (LoSCAT) and modified Rodnan score.
Patients and methods: A small double-blinded randomized prospective study of 11 pairs of treatment sites in four patients; three with morphea and one with limited scleroderma was performed. All patients continued with their prescribed treatment and applied 0.1% betamethasone valerate in PCCA PracaSil™ (B) to the control site with 0.1% betamethasone valerate and 1% tranilast (B/T) to the comparator site over a period of 3 months. Photographs and monthly LoSCAT scores were performed on the morphea patients and a modified Rodnan score on the limited scleroderma patient. Statistical analysis was via sign test.
Results: The mean baseline LoScat score at the B treated sites was 6.6 which improved to 4.3 (p= 0.16). The mean baseline LoScat score at the B/T treated sites was 5.75 which improved to 2.8 following treatment. (p=0.04).
Limitations: This was a small single center study. The ideal concentration of tranilast is unknown. As all patients continued with standard management the expected response may be less than would have been anticipated in a single agent trial.
Conclusion: The role of tranilast in the management in scleroderma warrants further investigation in larger trials.

PMID: 30013378 [PubMed]

Prevention and treatment of tuberculosis infection in candidates for biologic therapy: A multidisciplinary consensus statement adapted to the dermatology patient

Publication date: Available online 18 July 2018

Source: Actas Dermo-Sifiliográficas (English Edition)

Author(s): P. Rodríguez-Jiménez, I. Mir-Viladrich, P. Chicharro, G. Solano-López, F.J. López-Longo, C. Taxonera, P. Sánchez-Martínez, X. Martínez-Lacasa, M. García-Gasalla, J. Dorca, M. Arias-Guillén, J.M. García-García, E. Dauden

Abstract

Patients with chronic inflammatory diseases being treated with immunosuppressive drugs, and with tumor necrosis factor inhibitors in particular, have an increased risk of infection by Mycobacterium tuberculosis. Screening for latent tuberculosis infection and preventive therapy to reduce the risk of progression to active tuberculosis are mandatory in this group of patients. This updated multidisciplinary consensus document presents the latest expert opinions on the treatment and prevention of tuberculosis in candidates for biologic therapy and establishes recommendations based on current knowledge relating to the use of biologic agents.

Resumen

El riesgo de infección por Mycobacterium tuberculosis se halla aumentado en los pacientes con enfermedades inflamatorias crónicas y en tratamiento inmunosupresor, en particular con terapia antifactor de necrosis tumoral α. La detección de la infección tuberculosa latente y el tratamiento preventivo dirigido a reducir el riesgo de progresión a tuberculosis activa es obligatoria en este grupo de pacientes. Este documento de consenso multidisciplinar actualiza la opinión de expertos y establece recomendaciones para el diagnóstico y tratamiento de la infección tuberculosa latente en estos pacientes, según los conocimientos actuales en terapias biológicas.

Allergic Contact Dermatitis Due to Paraphenylenediamine: An Update

Publication date: Available online 14 July 2018

Source: Actas Dermo-Sifiliográficas (English Edition)

Author(s): B. Encabo Durán, D. Romero-Pérez, J.F. Silvestre Salvador

Abstract

Paraphenylenediamine (PPD) is an amine that is mainly used as an ingredient in hair dyes and henna tattoos. The incidence of allergic contact dermatitis to PPD is increasing, particularly in younger patients. In this article, we review the main sources of PPD and the substances with which it can interact and present a practical algorithm for diagnosing and treating suspected cases of PPD allergy.

Resumen

La parafenilendiamina (PPD) es una amina empleada en la actualidad principalmente como componente de tintes capilares y en tatuajes de henna. Se ha observado un incremento en la incidencia de la dermatitis alérgica de contacto por PPD, y en edades cada vez más tempranas. En el presente trabajo se realiza una revisión de las principales fuentes que contienen PPD, así como de las sustancias con las que puede interaccionar, y se propone un algoritmo de manejo diagnóstico y terapéutico desde un enfoque práctico, para los pacientes que presenten una clínica compatible con sospecha de alergia a PPD.

Spatial and temporal variations in the geochemistry of shallow groundwater contaminated with nitrate at a residential site

Abstract

The concentrations of nitrate (NO₃⁻), major ions, and dissolved inorganic carbon (DIC) and the stable carbon isotopes of DIC (δ¹³C_DIC) in shallow groundwater below a 45 × 60 m residential property was investigated over a period of 38 months. Our aim was to identify the processes which control the spatial and temporal distribution of NO₃⁻ in the shallow groundwater and assess water-rock interactions linked to denitrification. Groundwater sampled quarterly from eight locations showed an average NO₃⁻ concentration of 36.8 mg/L and a range between 0.1 and 214.9 mg/L compared to the US EPA maximum contaminant level of 10 mg/L. Heterogeneity in nitrate distribution was from residential application of N-based fertilizers offsite and from onsite application on flower beds and for lawn care. The temporal behavior of nitrate at all eight groundwater locations was markedly different and independent of seasonal hydrologic variations. Nitrate attenuation was spatially controlled by heterogeneous denitrification and rain dilution near roof drains. Groundwater locations with active denitrification were characterized by higher DIC concentrations and lower δ¹³C_DIC from organic carbon mineralization and by higher ionic concentrations from weathering of aquifer minerals. The variation in the relative standard deviations (RSD) of the measured parameters over space (RSD-s) and time (RSD-t) was highest for NO₃⁻ associated with variable spatiotemporal input and lowest for pH, pCO₂, and δ¹³C_DIC indirectly controlled by denitrification. Denitrification induced mineral weathering products such as DIC, Ca²⁺, Mg²⁺, and HCO₃⁻ showed medium to high RSD-s and RSD-t. The RSD-s and RSD-t were positively correlated (R² = 0.85) with the RSD-s showing approximately twofold higher magnitude than RSD-t due to greater variability between monitoring wells locations than variability at each groundwater location over time. Nitrate contamination and denitrification represent important long-term driver of aquifer weathering and changes in groundwater geochemistry below residential communities.

Pathology of Benign and Malignant Neoplasms of Salivary Glands

Tumors of the salivary gland represent relatively rare neoplasms. Still, in spite of their scarcity, they demonstrate a wide spectrum of disease across both benign and malignant lesions. The purpose of this review is to provide a practical overview of the pathology of the more common salivary gland neoplasms, covering the morphologic, immunophenotypic, and molecular profiles with an emphasis on unique diagnostic challenges and prognostic indicators.

Microscale dispersion behaviors of dust particles during coal cutting at large-height mining face

Abstract

In order to ensure safe production and occupational health at a large-mining-height fully mechanized mining face in a coal mine, the present study firstly establishes an airflow-dust coupled model based on gas/solid two-phase flow equations and combines numerical simulation and field measurement for analyzing the dispersion pattern of dust particles with various sizes for different coal cutter locations. Results show that, due to the existence of drums, airflow deviates from the original direction and enters the footway. Driven by the airflow, dust particles enter the footway at different locations depending on coal cutter locations. The coal-cutting location (denoted as P_rl) and the location where dust particles enter the footway (denoted as P_dt) are correlated as follows: P_dt(P_rl) = − 0.0007P_rl² + 1.0343P_rl − 3.3536. When P_rl < 55 m, dust particles produced by the rear drum during coal cutting enter the footway earlier than those produced by the front drum, leading to the first and second dust concentration peaks in respiratory zones of footway. Dust suppression effects are assessed in these regions based on the first and second dust concentration peaks. Due to the superposition of the concentration fields associated with dust particles 2.5, 7, and 20 μm in diameter, dust concentration 25 m down the leeward side of the coal cutter can reach 1440 mg/m³. The concentration of dust particles with a diameter of 40 μm drops steadily and approaches 0 at the return corner. The dust particles 80 μm in diameter are fully settled within 22 m down the leeward side of the coal cutter. A comparison with the field measurement indicates that the present simulation results are highly accurate.

Graphical abstract

Long-term sheltering mustaches reduce incidence of lower lip actinic keratosis

Journal of the American Academy of Dermatology: Original article Comorbidities in alopecia areata: A systematic review and meta-analysis

Alopecia areata (AA) may be associated with various systemic diseases according to several studies.

Hair mercury concentrations in the spotted seal ( Phoca largha ) pups from the Sea of Japan

Abstract

This publication presents the results of a study of the total mercury (THg) concentration in the fetal hair (lanugo) of the young spotted seals inhabiting the Peter the Great Bay, Sea of Japan. We analyzed samples from pups that were collected in 2014–2017 at the seal breeding grounds. The concentration of total mercury was determined by atomic absorption spectrometry. The concentration of THg ranged from 1.52 to 6.68 μg/g dry weight. Mercury concentration in the lanugo exceeds that found in the environment (bottom sediments, sea water) and in other animals inhabiting the Bay. At the same time, the level was generally lower than that found in young seals of most other pinniped species (Steller sea lion Eumetopias jubatus, Northern fur seal Callorhinus ursinus, Harbor seal Phoca vitulina richardsi, Northern elephant seal Mirounga angustirostris, California sea lion Zalophus californianus) from the North Pacific.

Axonal Ensheathment in the Nervous System of Lamprey: Implications for the Evolution of Myelinating Glia

In the nervous system, myelination of axons enables rapid impulse conduction and is a specialized function of glial cells. Myelinating glia are the last cell type to emerge in the evolution of vertebrate nervous systems, presumably in ancient jawed vertebrates (gnathostomata) because jawless vertebrates (agnathans) lack myelin. We have hypothesized that, in these unmyelinated species, evolutionary progenitors of myelinating cells must have existed that should still be present in contemporary agnathan species. Here, we used advanced electron microscopic techniques to reveal axon–glia interactions in the sea lamprey Petromyzon marinus. By quantitative assessment of the spinal cord and the peripheral lateral line nerve, we observed a marked maturation-dependent growth of axonal calibers. In peripheral nerves, all axons are ensheathed by glial cells either in bundles or, when larger than the threshold caliber of 3 μm, individually. The ensheathing glia are covered by a basal lamina and express SoxE-transcription factors, features of mammalian Remak-type Schwann cells. In larval lamprey, the ensheathment of peripheral axons leaves gaps that are closed in adults. CNS axons are also covered to a considerable extent by glial processes, which contain a high density of intermediate filaments, glycogen particles, large lipid droplets, and desmosomes, similar to mammalian astrocytes. Indeed, by in situ hybridization, these glial cells express the astrocyte marker Aldh1l1. Specimens were of unknown sex. Our observations imply that radial sorting, ensheathment, and presumably also metabolic support of axons are ancient functions of glial cells that predate the evolutionary emergence of myelin in jawed vertebrates.

SIGNIFICANCE STATEMENT We used current electron microscopy techniques to examine axon–glia units in a nonmyelinated vertebrate species, the sea lamprey. In the PNS, lamprey axons are fully ensheathed either individually or in bundles by cells ortholog to Schwann cells. In the CNS, axons associate with astrocyte orthologs, which contain glycogen and lipid droplets. We suggest that ensheathment, radial sorting, and metabolic support of axons by glial cells predate the evolutionary emergence of myelin in ancient jawed vertebrates.

lncRNA TNXA-PS1 Modulates Schwann Cells by Functioning As a Competing Endogenous RNA Following Nerve Injury

As the major glia in PNS, Schwann cells play a critical role in peripheral nerve injury repair. Finding an efficient approach to promote Schwann cell activation might facilitate peripheral nerve repair. Long noncoding RNAs (lncRNAs) have been shown to regulate gene expression and take part in many biological processes. However, the role of lncRNAs in peripheral nerve regeneration is not fully understood. In this study, we obtained a global lncRNA portrayal following sciatic nerve injury in male rats using microarray and further investigated one of these dys-regulated lncRNAs, TNXA-PS1, confirming its vital role in regulating Schwann cells. Silencing TNAX-PS1 could promote Schwann cell migration and mechanism analyses showed that TNXA-PS1 might exert its regulatory role by sponging miR-24–3p/miR-152–3p and affecting dual specificity phosphatase 1 (Dusp1) expression. Systematic lncRNA expression profiling of sciatic nerve segments following nerve injury in rats suggested lncRNA TNXA-PS1 as a key regulator of Schwann cell migration, providing a potential therapeutic target for nerve injury repair.

SIGNIFICANCE STATEMENT The PNS has an intrinsic regeneration capacity after injury in which Schwann cells play a crucial role. Therefore, further exploration of functional molecules in the Schwann cell phenotype modulation is of great importance. We have identified a set of dys-regulated long noncoding RNAs (lncRNAs) in rats following sciatic nerve injury and found that the expression of TNXA-PS1 was significantly downregulated. Mechanically analyses showed that TNXA-PS1 might act as a competing endogenous RNA to affect dual specificity phosphatase 1 (Dusp1) expression, regulating migration of Schwann cells. This study provides for the first time a global landscape of lncRNAs following sciatic nerve injury in rats and broadens the known functions of lncRNA during nerve injury. The investigation of TNXA-PS1 might facilitate the development of novel targets for nerve injury therapy.

Complex Control of Striatal Neurotransmission by Nicotinic Acetylcholine Receptors via Excitatory Inputs onto Medium Spiny Neurons

The prevalence of nicotine dependence is higher than that for any other substance abuse disorder; still, the underlying mechanisms are not fully established. To this end, we studied acute effects by nicotine on neurotransmission in the dorsolateral striatum, a key brain region with respect to the formation of habits. Electrophysiological recordings in acutely isolated brain slices from rodent showed that nicotine (10 nm to 10 μm) produced an LTD of evoked field potentials. Current-clamp recordings revealed no significant effect by nicotine on membrane voltage or action potential frequency, indicating that the effect by nicotine is primarily synaptic. Nicotine did not modulate sIPSCs, or the connectivity between fast-spiking interneurons and medium spiny neurons, as assessed by whole-cell recordings combined with optogenetics. However, the frequency of sEPSCs was significantly depressed by nicotine. The effect by nicotine was mimicked by agonists targeting α7- or α4-containing nAChRs and blocked in slices pretreated with a mixture of antagonists targeting these receptor subtypes. Nicotine-induced LTD was furthermore inhibited by dopamine D2 receptor antagonist and occluded by D2 receptor agonist. In addition, modulation of cholinergic neurotransmission suppressed the responding to nicotine, which might reflect upon the postulated role for nAChRs as a presynaptic filter to differentially govern dopamine release depending on neuronal activity. Nicotine-induced suppression of excitatory inputs onto medium spiny neurons may promote nicotine-induced locomotor stimulation and putatively initiate neuroadaptations that could contribute to the transition toward compulsive drug taking.

SIGNIFICANCE STATEMENT To decrease smoking, prevalence factors that may contribute to the development of nicotine addiction need to be identified. The data presented here show that nicotine suppresses striatal neurotransmission by selectively reducing the frequency of excitatory inputs to medium spiny neurons (MSNs) while rendering excitability, inhibitory neurotransmission, and fast-spiking interneuron-MSN connectivity unaltered. In addition, we show that the effect displayed by nicotine outlasts the presence of the drug, which could be fundamental for the addictive properties of nicotine. Considering the inhibitory tone displayed by MSNs on dopaminergic cell bodies and local terminals, nicotine-induced long-lasting depression of striatal output could play a role in behavioral transformations associated with nicotine use, and putatively elicit neuroadaptations underlying compulsive drug-seeking habits.

Dysregulation of NAD+ Metabolism Induces a Schwann Cell Dedifferentiation Program

The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NAD⁺) is a crucial molecule in the regulation of cellular metabolism and redox homeostasis. Here, we investigated the roles of NAD⁺ metabolism in SC functions in vivo by mutating NAMPT, the rate-limiting enzyme of NAD⁺ biosynthesis, specifically in SCs. NAMPT SC knock-out male and female mice (NAMPT SCKO mice) had delayed SC maturation in development and developed hypomyelinating peripheral neuropathy without axon degeneration or decreased SC survival. JUN, a master regulator of SC dedifferentiation, is elevated in NAMPT SCKO SCs, suggesting that decreased NAD⁺ levels cause them to arrest at an immature stage. Nicotinic acid administration rescues the NAD⁺ decline and reverses the SC maturation defect and the development of peripheral neuropathy, indicating the central role of NAD⁺ in PNS development. Upon nicotinic acid withdrawal in adulthood, NAMPT SCKO mice showed rapid and severe peripheral neuropathy and activation of ERK/MEK/JUN signaling, which in turn promotes SC dedifferentiation. These data demonstrate the importance of NAD⁺ metabolism in SC maturation and nerve development and maintenance and suggest that altered SC NAD⁺ metabolism could underlie neuropathies associated with diabetes and aging.

SIGNIFICANCE STATEMENT In this study, we showed that Schwann cell differentiation status is critically dependent on NAD⁺ homeostasis. Aberrant regulation of NAD⁺ biosynthesis via NAMPT deletion results in a blockade of Schwann cell maturation during development and severe peripheral neuropathy without significant axon loss. The phenotype can be rescued by supplementation with nicotinic acid; however, withdrawal of nicotinic acid leads to Schwann cell dedifferentiation, myelination defects, and death. These results provide new therapeutic possibilities for peripheral neuropathies associated with NAD⁺ decline during aging or diabetes.

Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection

Because complement activation in the subacute or chronic phase after stroke was recently shown to stimulate neural plasticity, we investigated how complement activation and complement inhibition in the acute phase after murine stroke interacts with subsequent rehabilitation therapy to modulate neuroinflammation and neural remodeling. We additionally investigated how complement and complement inhibition interacts with tissue plasminogen activator (tPA), the other standard of care therapy for stroke, and a U.S. Food and Drug Administration preclinical requirement for translation of an experimental stroke therapy. CR2fH, an injury site-targeted inhibitor of the alternative complement pathway, significantly reduced infarct volume, hemorrhagic transformation, and mortality and significantly improved long-term motor and cognitive performance when administered 1.5 or 24 h after middle cerebral artery occlusion. CR2fH interrupted a poststroke inflammatory process and significantly reduced inflammatory cytokine release, microglial activation, and astrocytosis. Rehabilitation alone showed mild anti-inflammatory effects, including reduced complement activation, but only improved cognitive recovery. CR2fH combined with rehabilitation significantly potentiated cognitive and motor recovery compared with either intervention alone and was associated with higher growth factor release and enhanced rehabilitation-induced neuroblast migration and axonal remodeling. Similar outcomes were seen in adult, aged, and female mice. Using a microembolic model, CR2fH administered in combination with acute tPA therapy improved overall survival and enhanced the neuroprotective effects of tPA, extending the treatment window for tPA therapy. A human counterpart of CR2fH has been shown to be safe and nonimmunogenic in humans and we have demonstrated robust deposition of C3d, the CR2fH targeting epitope, in ischemic human brains after stroke.

SIGNIFICANCE STATEMENT Complement inhibition is a potential therapeutic approach for stroke, but it is not known how complement inhibition would interact with current standards of care. We show that, after murine ischemic stroke, rehabilitation alone induced mild anti-inflammatory effects and improved cognitive, but not motor recovery. However, brain-targeted and specific inhibition of the alternative complement pathway, when combined with rehabilitation, significantly potentiated cognitive and motor recovery compared with either intervention alone via mechanisms involving neuroregeneration and enhanced brain remodeling. Further, inhibiting the alternative pathway of complement significantly enhanced the neuroprotective effects of thrombolytic therapy and markedly expanded the therapeutic window for thrombolytic therapy.

Distinct Populations of Motor Thalamic Neurons Encode Action Initiation, Action Selection, and Movement Vigor

Motor thalamus (Mthal) comprises the ventral anterior, ventral lateral, and ventral medial thalamic nuclei in rodents. This subcortical hub receives input from the basal ganglia (BG), cerebellum, and reticular thalamus in addition to connecting reciprocally with motor cortical regions. Despite the central location of Mthal, the mechanisms by which it influences movement remain unclear. To determine its role in generating ballistic, goal-directed movement, we recorded single-unit Mthal activity as male rats performed a two-alternative forced-choice task. A large population of Mthal neurons increased their firing briefly near movement initiation and could be segregated into functional groups based on their behavioral correlates. The activity of "initiation" units was more tightly locked to instructional cues than movement onset, did not predict which direction the rat would move, and was anticorrelated with reaction time (RT). Conversely, the activity of "execution" units was more tightly locked to movement onset than instructional cues, predicted which direction the rat would move, and was anticorrelated with both RT and movement time. These results suggest that Mthal influences choice RT performance in two stages: short latency, nonspecific action initiation followed by action selection/invigoration. We discuss the implications of these results for models of motor control incorporating BG and cerebellar circuits.

SIGNIFICANCE STATEMENT Motor thalamus (Mthal) is a central node linking subcortical and cortical motor circuits, though its precise role in motor control is unclear. Here, we define distinct populations of Mthal neurons that either encode movement initiation, or both action selection and movement vigor. These results have important implications for understanding how basal ganglia, cerebellar, and motor cortical signals are integrated. Such an understanding is critical to defining the pathophysiology of a range of BG- and cerebellum-linked movement disorders, as well as refining pharmacologic and neuromodulatory approaches to their treatment.

Stimulation of the Prefrontal Cortex Reduces Intentions to Commit Aggression: A Randomized, Double-Blind, Placebo-Controlled, Stratified, Parallel-Group Trial

Although prefrontal brain impairments are one of the best-replicated brain imaging findings in relation to aggression, little is known about the causal role of this brain region. This study tests whether stimulating the dorsolateral prefrontal cortex using transcranial direct current stimulation (tDCS) reduces the likelihood of engaging in aggressive acts, and the mechanism underlying this relationship. In a double-blind, stratified, placebo-controlled, parallel-group, randomized trial, 81 human adults (36 males, 45 females) were randomly assigned to an active (N = 39) or placebo (N = 42) condition, and then followed up 1 d after the experiment session. Intentions to commit aggressive acts and behavioral aggression were assessed using hypothetical vignettes and a behavioral task, respectively. The secondary outcome was the perception of the moral wrongfulness of the aggressive acts. Compared with the sham controls, participants who received anodal stimulation reported being less likely to commit physical and sexual assault (p < 0.01). They also judged aggressive acts as more morally wrong (p < 0.05). Perceptions of greater moral wrongfulness regarding the aggressive acts accounted for 31% of the total effect of tDCS on intentions to commit aggression. Results provide experimental evidence that increasing activity in the prefrontal cortex can reduce intentions to commit aggression and enhance perceptions of the moral wrongfulness of the aggressive acts. Findings shed light on the biological underpinnings of aggression and theoretically have the potential to inform future interventions for aggression and violence.

SIGNIFICANCE STATEMENT Aggressive behaviors pose significant public health risks. Understanding the etiology of aggression is paramount to violence reduction. Investigations of the neural basis of aggression have largely supported correlational, rather than causal, interpretations, and the mediating processes underlying the prefrontal–aggression relationship remain to be well elucidated. Through a double-blind, stratified, placebo-controlled, parallel-group, randomized trial, this study tested whether upregulation of the prefrontal cortex reduces the likelihood of engaging in aggression. Results provide experimental evidence that increasing prefrontal cortical activity can reduce intent to commit aggressive acts. They also shed light on moral judgment as one mechanism that may link prefrontal deficits to aggression and, in theory, have the potential to inform future approaches toward reducing aggression.

Constitutive and Synaptic Activation of GIRK Channels Differentiates Mature and Newborn Dentate Granule Cells

Sparse neural activity in the dentate gyrus is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of the principal neurons, the dentate granule cells (GCs). Although the cellular and circuit properties that dictate synaptic inhibition are well studied, less is known about mechanisms that confer low GC intrinsic excitability. Here we demonstrate that intact G protein-mediated signaling contributes to the characteristic low resting membrane potential that differentiates mature dentate GCs from CA1 pyramidal cells and developing adult-born GCs. In mature GCs from male and female mice, intact G protein signaling robustly reduces intrinsic excitability, whereas deletion of G protein-activated inwardly rectifying potassium channel 2 (GIRK2) increases excitability and blocks the effects of G protein signaling on intrinsic properties. Similarly, pharmacological manipulation of GABA_B receptors (GABA_BRs) or GIRK channels alters intrinsic excitability and GC spiking behavior. However, adult-born new GCs lack functional GIRK activity, with phasic and constitutive GABA_BR-mediated GIRK signaling appearing after several weeks of maturation. Phasic activation is interneuron specific, arising primarily from nNOS-expressing interneurons rather than parvalbumin- or somatostatin-expressing interneurons. Together, these results demonstrate that G protein signaling contributes to the intrinsic excitability that differentiates mature and developing dentate GCs and further suggest that late maturation of GIRK channel activity is poised to convert early developmental functions of GABA_B receptor signaling into GABA_BR-mediated inhibition.

SIGNIFICANCE STATEMENT The dentate gyrus exhibits sparse neural activity that is essential for the computational function of pattern separation. Sparse activity is ascribed to strong local inhibitory circuits in combination with low intrinsic excitability of the principal neurons, the granule cells. Here we show that constitutive activity of G protein-coupled inwardly rectifying potassium channels (GIRKs) underlies to the hallmark low resting membrane potential and input resistance of mature dentate neurons. Adult-born neurons initially lack functional GIRK channels, with constitutive and phasic GABA_B receptor-mediated GIRK inhibition developing in tandem after several weeks of maturation. Our results reveal that GABA_B/GIRK activity is an important determinant of low excitability of mature dentate granule cells that may contribute to sparse DG activity in vivo.

Postsynaptic FMRP Regulates Synaptogenesis In Vivo in the Developing Cochlear Nucleus

A global loss of the fragile X mental retardation protein (FMRP; encoded by the Fmr1 gene) leads to sensory dysfunction and intellectual disabilities. One underlying mechanism of these phenotypes is structural and functional deficits in synapses. Here, we determined the autonomous function of postsynaptic FMRP in circuit formation, synaptogenesis, and synaptic maturation. In normal cochlea nucleus, presynaptic auditory axons form large axosomatic endbulb synapses on cell bodies of postsynaptic bushy neurons. In ovo electroporation of drug-inducible Fmr1-shRNA constructs produced a mosaicism of FMRP expression in chicken (either sex) bushy neurons, leading to reduced FMRP levels in transfected, but not neighboring nontransfected, neurons. Structural analyses revealed that postsynaptic FMRP reduction led to smaller size and abnormal morphology of individual presynaptic endbulbs at both early and later developmental stages. We further examined whether FMRP reduction affects dendritic development, as a potential mechanism underlying defective endbulb formation. Normally, chicken bushy neurons grow extensive dendrites at early stages and retract these dendrites when endbulbs begin to form. Neurons transfected with Fmr1 shRNA exhibited a remarkable delay in branch retraction, failing to provide necessary somatic surface for timely formation and growth of large endbulbs. Patch-clamp recording verified functional consequences of dendritic and synaptic deficits on neurotransmission, showing smaller amplitudes and slower kinetics of spontaneous and evoked EPSCs. Together, these data demonstrate that proper levels of postsynaptic FMRP are required for timely maturation of somatodendritic morphology, a delay of which may affect synaptogenesis and thus contribute to long-lasting deficits of excitatory synapses.

SIGNIFICANCE STATEMENT Fragile X mental retardation protein (FMRP) regulates a large variety of neuronal activities. A global loss of FMRP affects neural circuit development and synaptic function, leading to fragile X syndrome (FXS). Using temporally and spatially controlled genetic manipulations, this study provides the first in vivo report that autonomous FMRP regulates multiple stages of dendritic development, and that selective reduction of postsynaptic FMRP leads to abnormal development of excitatory presynaptic terminals and compromised neurotransmission. These observations demonstrate secondary influence of developmentally transient deficits in neuronal morphology and connectivity to the development of long-lasting synaptic pathology in FXS.

Pain-Related Expectation and Prediction Error Signals in the Anterior Insula Are Not Related to Aversiveness

The anterior insula has repeatedly been linked to the experience of aversive stimuli, such as pain. Previously, we showed that the anterior insula is involved in the integration of pain intensity and its prior expectation. However, it is unclear whether this integration occurs by a pain-specific expectation or a more general expectation of an aversive event. To dissociate these possibilities, we conducted an experiment using painful stimuli and aversive pictures with three levels of aversiveness on human male volunteers. Stimuli were preceded by a probabilistic, combined modality and intensity cue in a full factorial design. Subjective ratings of pain intensity and skin conductance responses were best explained by a combination of actual pain intensity and expected pain intensity. In addition, using fMRI, we investigated the neuronal implementation of the integration of prior expectation and pain intensity. Similar to subjective ratings and autonomic responses, the dorsal anterior insula represented pain intensity and expectations. The ventral anterior insula additionally represented the absolute difference of the two terms (i.e., the prediction error). The posterior insula only represented pain intensity. Importantly, the pattern observed in the anterior insula was only present if the cued modality was correct (i.e., expect pain); in case of an incorrect modality cue (i.e., expect aversive picture), the ventral anterior insula simply represented pain intensity. The stimulus expectation and prediction error specificity in the ventral anterior insula indicates the integration of expectation with painful stimuli in this area. Importantly, this pattern cannot be explained by aversiveness.

SIGNIFICANCE STATEMENT The anterior insula has been shown to integrate pain intensity and their expectation. However, it is unclear whether this integration is pain-specific or related more generally to an aversive event. To address this, we combined painful stimuli and aversive pictures with three levels of aversiveness. The ventral anterior insula represented pain intensity, expectation, and their absolute difference (i.e., the prediction error). Importantly, this pattern was only observed if the cued modality was correct. In case of an incorrect modality cue, this area simply represented as pain intensity. The stimulus expectation and prediction error specificity in the ventral anterior insula indicates the integration of expectation with painful stimuli in this area. Importantly, this pattern cannot be explained by aversiveness.

The State of the NIH BRAIN Initiative

The BRAIN Initiative arose from a grand challenge to "accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought." The BRAIN Initiative is a public-private effort focused on the development and use of powerful tools for acquiring fundamental insights about how information processing occurs in the central nervous system (CNS). As the Initiative enters its fifth year, NIH has supported >500 principal investigators, who have answered the Initiative's challenge via hundreds of publications describing novel tools, methods, and discoveries that address the Initiative's seven scientific priorities. We describe scientific advances produced by individual laboratories, multi-investigator teams, and entire consortia that, over the coming decades, will produce more comprehensive and dynamic maps of the brain, deepen our understanding of how circuit activity can produce a rich tapestry of behaviors, and lay the foundation for understanding how its circuitry is disrupted in brain disorders. Much more work remains to bring this vision to fruition, and the National Institutes of Health continues to look to the diverse scientific community, from mathematics, to physics, chemistry, engineering, neuroethics, and neuroscience, to ensure that the greatest scientific benefit arises from this unique research Initiative.

Delving Deep into Crossmodal Integration

The Critical Role of the Hippocampus in Mind Wandering

Cellular Effects of Repetition Priming in the Aplysia Feeding Network Are Suppressed during a Task-Switch But Persist and Facilitate a Return to the Primed State

Many neural networks are multitasking and receive modulatory input, which configures activity. As a result, these networks can enter a relatively persistent state in which they are biased to generate one type of output as opposed to another. A question we address is as follows: what happens to this type of state when the network is forced to task-switch? We address this question in the feeding system of the mollusc Aplysia. This network generates ingestive and egestive motor programs. We focus on an identified neuron that is selectively active when programs are ingestive. Previous work has established that the increase in firing frequency observed during ingestive programs is at least partially mediated by an excitability increase. Here we identify the underlying cellular mechanism as the induction of a cAMP-dependent inward current. We ask how this current is impacted by the subsequent induction of egestive activity. Interestingly, we demonstrate that this task-switch does not eliminate the inward current but instead activates an outward current. The induction of the outward current obviously reduces the net inward current in the cell. This produces the decrease in excitability and firing frequency required for the task-switch. Importantly, however, the persistence of the inward current is not impacted. It remains present and coexists with the outward current. Consequently, when effects of egestive priming and the outward current dissipate, firing frequency and excitability remain above baseline levels. This presumably has important functional implications in that it will facilitate a return to ingestive activity.

SIGNIFICANCE STATEMENT Under physiological conditions, an animal generating a particular type of motor activity can be forced to at least briefly task-switch. In some circumstances, this involves the temporary induction of an "antagonistic" or incompatible motor program. For example, ingestion can be interrupted by a brief period of egestive activity. In this type of situation, it is often desirable for behavioral switching to occur rapidly and efficiently. In this report, we focus on a particular aspect of this type of task-switch. We determine how the priming that occurs when a multitasking network repeatedly generates one type of motor activity can be retained during the execution of an incompatible motor program.

This Week in The Journal

Oligodendroglia Are Particularly Vulnerable to Oxidative Damage after Neurotrauma In Vivo

Loss of function following injury to the CNS is worsened by secondary degeneration of neurons and glia surrounding the injury and is initiated by oxidative damage. However, it is not yet known which cellular populations and structures are most vulnerable to oxidative damage in vivo. Using Nanoscale secondary ion mass spectrometry (NanoSIMS), oxidative damage was semiquantified within cellular subpopulations and structures of optic nerve vulnerable to secondary degeneration, following a partial transection of the optic nerve in adult female PVG rats. Simultaneous assessment of cellular subpopulations and structures revealed oligodendroglia as the most vulnerable to DNA oxidation following injury. 5-Ethynyl-2'-deoxyuridine (EdU) was used to label cells that proliferated in the first 3 d after injury. Injury led to increases in DNA, protein, and lipid damage in oligodendrocyte progenitor cells and mature oligodendrocytes at 3 d, regardless of proliferative state, associated with a decline in the numbers of oligodendrocyte progenitor cells at 7 d. O4⁺ preoligodendrocytes also exhibited increased lipid peroxidation. Interestingly, EdU⁺ mature oligodendrocytes derived after injury demonstrated increased early susceptibility to DNA damage and lipid peroxidation. However, EdU^– mature oligodendrocytes with high 8-hydroxyguanosine immunoreactivity were more likely to be caspase3⁺. By day 28, newly derived mature oligodendrocytes had significantly reduced myelin regulatory factor gene mRNA, indicating that the myelination potential of these cells may be reduced. The proportion of caspase3⁺ oligodendrocytes remained higher in EdU^– cells. Innovative use of NanoSIMS together with traditional immunohistochemistry and in situ hybridization have enabled the first demonstration of subpopulation specific oligodendroglial vulnerability to oxidative damage, due to secondary degeneration in vivo.

SIGNIFICANCE STATEMENT Injury to the CNS is characterized by oxidative damage in areas adjacent to the injury. However, the cellular subpopulations and structures most vulnerable to this damage remain to be elucidated. Here we use powerful NanoSIMS techniques to show increased oxidative damage in oligodendroglia and axons and to demonstrate that cells early in the oligodendroglial lineage are the most vulnerable to DNA oxidation. Further immunohistochemical and in situ hybridization investigation reveals that mature oligodendrocytes derived after injury are more vulnerable to oxidative damage than their counterparts existing at the time of injury and have reduced myelin regulatory factor gene mRNA, yet preexisting oligodendrocytes are more likely to die.

Papuloerythroderma of Ofuji successfully treated with methotrexate

Dermatologic Therapy, EarlyView.

Hyaluronic acid filler for skin rejuvenation: The role of diet on outcomes. A pilot study

Dermatologic Therapy, EarlyView.

Nitrogen and sulfur co-doped highly luminescent carbon dots for sensitive detection of Cd (II) ions and living cell imaging applications

Publication date: Available online 18 July 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Dan Gu, Liu Hong, Lei Zhang, Hao Liu, Shaoming Shang

Abstract

In this work, we have developed a green, simple and fast one-pot microwave-assisted strategy for synthesis of nitrogen and sulfur co-doped fluorescent carbon dots (CDs) using scallion (SL) as the carbon source. Optical properties of the SL-CDs have been measured by UV-visible and fluorescent spectroscopy. The morphology of the prepared SL-CDs has been performed by transmission electron microscopy (TEM). Surface functionality and elemental composition of SL-CDs was analyzed by Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) spectra. The photoluminescent (PL) quantum yield of the obtained scallion carbon dots (SL-CDs) can reach as high as 18.6%. We further demonstrated that the SL-CDs can be used as fluorescent probes for detection of Cd²⁺ ions with a high sensitivity and an excellent selectivity. Linear relationships between the variation of the luminescent intensity of the SL-CDs before and after exposing the Cd²⁺ ions versus the concentration of Cd²⁺ ions in the range of 0.1–3.0 μM and 5.0–30.0 μM. The detection limit of Cd²⁺ ions can reach 15.0 nM. Moreover, the as-prepared SL-CDs exhibit negligible or extremely low cytotoxicity, which makes them be able to be used as fluorescent probes for living cell imaging. Overall, the prepared SL-CDs have promising applications in sensing of Cd²⁺ ions and in vivo or in vitro bioimaging.

Graphical Abstract

Sunscreen Use and Melanoma Risk Among Young Australian Adults

This population-based, case-control family study of data collected for the Australian Melanoma Family Study assesses the association of sunscreen use in childhood and early adulthood with the risk of cutaneous melanoma before age 40 years.

Spiky Skin in a Renal Transplant Recipient

A woman in her 70s with a cadaveric renal transplant presented with a 1-year history of a facial cutaneous eruption and mildly pruritic lesions, initially affecting malar cheeks and eyebrows and subsequently spreading to involve the nose, chin, upper trunk, and extremities. What is your diagnosis?

Timing of Onset of Adverse Cutaneous Reactions Associated With PD-1 Inhibitor Therapy

This observational study assesses the timing of onset of cutaneous reactions after initiation of programmed cell death protein 1 therapy in patients with metastatic melanoma or carcinoma.

A Comparison of Tanning Habits Among Gym Tanners and Other Tanners

This survey study evaluates the incidence of tanning in adults who use indoor gyms.

Effect of Stress Ball Use or Hand-holding on Anxiety During Skin Cancer Excision

This randomized clinical trial examines the effects of hand-holding vs stress ball use compared with usual care on anxiety in patients undergoing excisional removal of nonmelanoma skin cancer of the head or neck with local anesthesia.

Scabies—An Ancient Disease With Unanswered Questions in Modern Times

This Viewpoint discusses the global disease burden of scabies, as well as its diagnosis and treatment.

Predicting Fluoropyrimidine-Related Toxicity: Turning Wish to Will, The Pamm-Eortc Position

Inconsistent HIV reservoir dynamics and immune responses following anti-PD-1 therapy in cancer patients with HIV infection

Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan Cooperative Oncology Group (TCOG) 1303 Study

Abstract

Background

Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation.

Patients and methods

This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received 3 cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m² cisplatin weekly during radiotherapy, which was delivered as 1.8–2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66–70 Gy to the involved neck. The primary endpoint was disease-free survival (DFS).

Results

In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm (5-year rate 61% vs 50%; hazard ratio = 0·739, 95% confidence interval (CI)= 0·565-0·965; P = 0·0264), after stratified for N3b and LDH, and adjusted for T stage.

Conclusion

Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved.

Clinical trial information

NCT00201396

Therapeutic advantage of genetically engineered Salmonella typhimurium carrying short hairpin RNA against inhibin alpha subunit in cancer treatment

Abstract

Background

In contrast to its well-known endocrine function, the role of inhibin in cancer development and therapeutic response is unclear. Salmonella, particularly less toxic attenuated Salmonella strains, are used to treat cancer in two ways. First, Salmonella accumulate around tumors, penetrate the cell barrier, and replicate inside the tumors. Second, Salmonella can act as a vehicle for delivering anti-cancer agents or pro-apoptotic genes to attack tumors. In this study, we aimed to develop a suitable cancer therapeutic strategy by genetically modifying attenuated Salmonella typhimurium to harbor short hairpin RNA (shRNA) expression plasmids targeting alpha subunit of inhibin (sh-INHA).

Methods

We analyzed the expression of human INHA in normal and cancer cells and tissues. We developed genetically engineered attenuated Salmonella typhimurium harboring sh-INHA (S. typhimurium/sh-INHA) and assessed its cancer therapeutic effects by using cell culture models and syngeneic mouse tumor models.

Results

INHA expression levels were markedly higher in colon cancer and melanoma cells and tissues than in their normal counterparts. Suppression of INHA expression mildly reduced cancer cell survival and induced caspase activation and downregulation of anti-apoptotic Bcl-2 and Bcl-xL expression. Although the genetically engineered S. typhimurium mildly interfered with the invasion of S. typhimurium into host colon cancer and melanoma cells, S. typhimurium/sh-INHA caused remarkable cytotoxicity in cancer compared with unmodified S. typhimurium or S. typhimurium expressing a control scrambled shRNA (S. typhimurium/sh-Cont). S. typhimurium/sh-INHA-treated mice also showed a significantly inhibited growth of colon cancers and melanomas, with a survival advantage.

Conclusion

Our results suggest that tumor-targeted therapy using S. typhimurium/sh-INHA may provide a novel cancer treatment option.

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high grade serous ovarian and squamous non-small cell lung cancer

Abstract

Background

We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients.

Patients and Methods

In dose escalation, weekly paclitaxel (80 mg/m²) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively.

Results

The dose escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. Based on toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m² paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28 - 18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%) and the mPFS was 5.8 months (95% CI: 2.76 - 21.25).

Discussion

In this phase I trial we report a highly active and well tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.

Clinical trial registration

ClinicialTrials.gov identifier: CNCT02193633

AJCC 8th Edition for Soft Tissue Sarcoma of the Extremities and Trunk

Novel therapies in urothelial carcinoma: a biomarker-driven approach

Abstract

Urothelial malignancies, including carcinomas of the bladder, ureters, and renal pelvis comprised approximately 8% of new cancer cases in the United States in 2016. In the metastatic setting, 15% of patients exhibit long-term survival following cisplatin-based chemotherapy and in patients with recurrent disease, response rates to second-line chemotherapy are generally 15-20% with a 3-month progression-free survival. However, recent advances in immunotherapy represent an opportunity to significantly improve patient outcomes. Moreover, the advent of next-generation sequencing (NGS) has resulted in both an improved understanding of the fundamental genetic changes that characterize urothelial carcinoma (UC) and identification of several candidate biomarkers of response to various therapies. Incorporation of prospective genotyping into clinical trials will allow for the identification and enrichment of patients most likely to respond to specific targeted therapies and chemotherapy. Combining different therapeutic classes to enhance outcomes is also an area of active research in UC.

Migraine and greater pain symptoms at 10-year follow-up among patients with major depressive disorder

No study has investigated the associations of migraine with pain symptoms over a ten-year period among outpatients with major depressive disorder (MDD). This study aimed to investigate this issue.

Vitamin D deficiency in patients with cluster headache: a preliminary study

Cluster headache is famous for attacks with seasonal and diurnal periodicity. This diurnal and seasonal variation might be related to sunlight and vitamin D metabolism. We investigated the serum vitamin D leve...

Increased thalamic glutamate/glutamine levels in migraineurs

Increased cortical excitability has been hypothesized to play a critical role in various neurological disorders, such as restless legs syndrome, epilepsy and migraine. Particularly for migraine, local hyperexc...

Illuminating Endocrine Evolution: The Power and Potential of Large-Scale Comparative Analyses

Abstract

Hormones are central mediators of genotype-phenotype and organism-environment interactions. Despite these important functions, the role of selection in shaping hormonal mediators of phenotype remains poorly understood. Thanks to decades of work by endocrinologists, circulating hormone levels have been measured in a diversity of organisms. Variation in other endocrine traits and mediators (e.g., receptor expression, binding globulins), and the hormonal response to standardized challenges (e.g., restraint, pharmacological challenges) are also increasingly measured in both captive and free-living populations. Large-scale comparative analyses of the multitude of available endocrine data represent a particularly promising approach to addressing the function and evolution of these key phenotypic mediators, and their potential to serve as indicators of disturbance. Several recent phylogenetic comparative analyses and meta-analyses have begun to reveal the power and potential of these approaches to address key questions in integrative biology. Here we highlight two recent developments that are facilitating such analyses: increasingly powerful and flexible phylogenetic comparative methods, and the release of two endocrine trait databases – HormoneBase (currently 474 species) and the Wildlife Endocrinology Information Network (currently 25 species) – that contain compiled measures of endocrine traits across vertebrates. Increasingly comprehensive comparative analyses of endocrine data could provide insight into many interesting questions, including how rapidly changing environments are impacting phenotypes, why endocrine traits differ so remarkably within and across populations, and the evolution of plasticity.

Non-branching personal persistence

Abstract

Given reductionism about people, personal persistence must fundamentally consist in some kind of impersonal continuity relation. Typically, these continuity relations can hold from one to many. And, if they can, the analysis of personal persistence must include a non-branching clause to avoid non-transitive identities or multiple occupancy. It is far from obvious, however, what form this clause should take. This paper argues that previous accounts are inadequate and develops a new proposal.

2-hydroxyglutarate MR Spectroscopy for Prediction of Isocitrate Dehydrogenase Mutant Glioma: A Systemic Review and Meta-analysis using Individual Patient Data

Abstract

Background

Noninvasive and accurate modality to predict Isocitrate dehydrogenase (IDH) mutant glioma may have great potential in routine clinical practice. We aimed to investigate the diagnostic performance of 2-hydroxyglutarate (2HG) magnetic resonance spectroscopy (MRS) for prediction of IDH mutant glioma and provide an optimal cut-off value for 2HG.

Methods

A systematic literature search of Ovid-MEDLINE and EMBASE was performed to identify original articles investigating the diagnostic performance of 2HG MRS up to March 20, 2018. Pooled sensitivity and specificity were calculated using a bivariate random-effects model. Subgroup analysis and meta-regression was performed to explain heterogeneity effects. An optimal cut-off value for 2HG was calculated from studies providing individual patient data.

Results

Fourteen original articles with 460 patients were included. The pooled sensitivity and specificity for the diagnostic performance of 2HG MRS for prediction of IDH mutant glioma were 95% (95% CI, 85–98%) and 91% (95% CI, 83–96%), respectively. The Higgins I² statistic demonstrated that heterogeneity was present in the sensitivity (I² = 50.69%), but not in the specificity (I² = 30.37%). In the meta-regression, echo time (TE) was associated with study heterogeneity. Among the studies using point-resolved spectroscopy (PRESS), a long TE (97 ms) resulted in higher sensitivity (92%) and specificity (97%) than a short TE (30–35 ms; sensitivity of 90%, specificity of 88%; p < 0.01). The optimal 2HG cut-off value of 2HG using individual patient data was 1.76 mM.

Conclusion

2HG MRS demonstrated excellent specificity for prediction of IDH mutant glioma, with TE being associated with heterogeneity in the sensitivity.