Impaired peripheral nerve regeneration in type-2 diabetic mouse model

Abstract

Peripheral neuropathy is one of the most common and serious complications of type-2 diabetes. Diabetic neuropathy is characterized by a distal symmetrical sensorimotor polyneuropathy, and its incidence increases in patients 40 years of age or older. In spite of extensive research over decades, there are few effective treatments for diabetic neuropathy besides glucose control and improved lifestyle. The earliest changes in diabetic neuropathy occur in sensory nerve fibers, with initial degeneration and regeneration resulting in pain. To seek its effective treatment, here we prepared a type-2 diabetic mouse model by giving mice 2 injections of streptozotocin and nicotinamide and examining the ability for nerve regeneration by using a sciatic nerve transection-regeneration model previously established by us. Seventeen weeks after the last injection, the mice exhibited symptoms of type-2 diabetes, i.e., impaired glucose tolerance, decreased insulin level, mechanical hyperalgesia, and impaired sensory nerve fibers in the plantar skin. These mice showed delayed functional recovery and nerve regeneration by 2 weeks compared with young healthy mice and by 1 week compared with age-matched non-diabetic mice after axotomy. Furthermore, type-2 diabetic mice displayed increased expression of PTEN in their DRG neurons. Administration of a PTEN inhibitor at the cutting site of the nerve for 4 weeks promoted the axonal transport and functional recovery remarkably. The present study demonstrates that peripheral nerve regeneration was impaired in type-2 diabetic model and that its combination with sciatic nerve transection is suitable for the study of the pathogenesis and treatment of early diabetic neuropathy.

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The neural representation of social status in the extended face-processing network

Abstract

Social status is a salient cue that shapes our judgment and memory for other people and ultimately guides our social interactions. Despite the pervasive influence of status on social behavior, how information about the status of others is represented in the brain remains unclear. Here, we tested the hypothesis that social-status information is embedded in our neural representations of other individuals. Participants learned to associate faces with names, job titles that that varied in associated status, and explicit markers of reputational status (star ratings). Trained stimuli were presented in an fMRI experiment where participants performed a target detection task orthogonal to the variable of interest. A network of face-selective brain regions extending from the occipital lobe to the orbitofrontal cortex was localized and served as regions of interest. Using multivoxel pattern analysis, we found that face-selective voxels in the lateral orbitofrontal cortex – a region involved in social and nonsocial valuation, could decode faces based on their status. Similar effects were observed with two different status manipulations – one based on stored semantic knowledge (e.g. different careers) and one based on learned reputation (e.g. star ranking). These data suggest that a face-selective region of the lateral orbitofrontal cortex may contribute to the perception of social status, potentially underlying the preferential attention and favorable biases humans display toward high status individuals.

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Proximity labeling: spatially resolved proteomic mapping for neurobiology

Publication date: June 2018
Source:Current Opinion in Neurobiology, Volume 50
Author(s): Shuo Han, Jiefu Li, Alice Y Ting
Understanding signaling pathways in neuroscience requires high-resolution maps of the underlying protein networks. Proximity-dependent biotinylation with engineered enzymes, in combination with mass spectrometry-based quantitative proteomics, has emerged as a powerful method to dissect molecular interactions and the localizations of endogenous proteins. Recent applications to neuroscience have provided insights into the composition of sub-synaptic structures, including the synaptic cleft and inhibitory post-synaptic density. Here we compare the different enzymes and small-molecule probes for proximity labeling in the context of cultured neurons and tissue, review existing studies, and provide technical suggestions for the in vivo application of proximity labeling.



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Gating of visual processing by physiological need

Publication date: April 2018
Source:Current Opinion in Neurobiology, Volume 49
Author(s): Christian R Burgess, Yoav Livneh, Rohan N Ramesh, Mark L Andermann
Physiological need states and associated motivational drives can bias visual processing of cues that help meet these needs. Human neuroimaging studies consistently show a hunger-dependent, selective enhancement of responses to images of food in association cortex and amygdala. More recently, cellular-resolution imaging combined with circuit mapping experiments in behaving mice have revealed underlying neuronal population dynamics and enabled tracing of pathways by which hunger circuits influence the assignment of value to visual objects in visual association cortex, insular cortex, and amygdala. These experiments begin to provide a mechanistic understanding of motivation-specific neural processing of need-relevant cues in healthy humans and in disease states such as obesity and other eating disorders.



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Molecular insights into cortico-striatal miscommunications in Huntington's disease

Publication date: February 2018
Source:Current Opinion in Neurobiology, Volume 48
Author(s): Matthew B Veldman, X William Yang
Huntington's disease (HD), a dominantly inherited neurodegenerative disease, is defined by its genetic cause, a CAG-repeat expansion in the HTT gene, its motor and psychiatric symptomology and primary loss of striatal medium spiny neurons (MSNs). However, the molecular mechanisms from genetic lesion to disease phenotype remain largely unclear. Mouse models of HD have been created that exhibit phenotypes partially recapitulating those in the patient, and specifically, cortico-striatal disconnectivity appears to be a shared pathogenic event shared by HD mouse models and patients. Molecular studies have begun to unveil converging molecular and cellular pathogenic mechanisms that may account for cortico-striatal miscommunication in various HD mouse models. Systems biological approaches help to illuminate synaptic molecular networks as a nexus for HD cortio-striatal pathogenesis, and may offer new candidate targets to modify the disease.



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Single-cell transcriptomic analysis of oligodendrocyte lineage cells

Publication date: December 2017
Source:Current Opinion in Neurobiology, Volume 47
Author(s): David van Bruggen, Eneritz Agirre, Gonçalo Castelo-Branco
Oligodendrocytes (OLs) are glial cells in the central nervous system (CNS), which produce myelin, a lipid-rich membrane that insulates neuronal axons. The main function ascribed to OLs is to regulate the speed of electric pulse transmission, and as such OLs have been widely considered as a single and discrete population. Nevertheless, OLs and their precursor cells (OPCs) throughout the CNS have different morphologies and regional functional differences have been observed. Moreover, OLs have recently been involved in other functional processes such as metabolic coupling with axons. In this review, we focus on recent advances in single-cell transcriptomics suggesting that OLs are more heterogeneous than previously thought, with defined subpopulations and cell states that are associated with different stages of lineage progression and might also represent distinct functional states.



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Insights on efficacious doses of PAMORAs for patients on chronic opioid therapy or opioid-naïve patients

Abstract

Background

Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.

Methods

A PubMed search of μ-opioid antagonists to counter μ-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.

Key Results

The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naïve subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naïve subjects compared to chronic opioid users. Opioid-naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.

Conclusions & Inferences

Opioid-naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ-opioid antagonist effect.

Constipation is a major side effect of opioid use (OIC). Opioid-naïve subjects require a higher dose of PAMORA compared to chronic opioid users to achieve beneficial µ-opioid antagonist effect on clinical or transit endpoints.

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Gastric accommodation in healthy subjects studied by ultrasound, manometry, and impedancemetry

Abstract

Background

Gastric accommodation to a meal may be important in the pathogenesis of upper gastrointestinal disorders, but has been difficult to investigate in a minimally invasive fashion.

Methods

We studied gastric and lower esophageal physiology during food intake, combining transabdominal ultrasound, multichannel high-resolution impedance-manometry (HRIM) and a symptom questionnaire. A HRIM catheter was distally positioned at incisura angularis and 300 mL saline with 75 g glucose was ingested. Target variables were recorded for 30 min after fluid intake.

Key Results

Fifteen healthy subjects' participated (11W/4M, median age 23.8 y) and all accepted the meal with few symptoms. At incisura angularis maximum change in pressure from pre-intake values was −7.4 mmHg after 60 s (P < .0001), rising to pre-intake values within 20 min. The corresponding area increased significantly from pre-intake values of 8.0 cm² to 14.1 cm² shortly after intake (P = .0012), peaked at 5 min and slowly decreased towards 30 min. The corresponding maximum change in stress from pre-intake pressure values was −59.2 mmHg shortly after (P < .0001), reaching pre-intake values within 20 min. Strain rose from 0 shortly before to 0.36 shortly after (P < .0001), peaking at 5 min. At incisura angularis, fullness was positively correlated with area and to strain, while fullness, area, and stress were negatively correlated with pressure.

Conclusions & Inferences

The multimodal method enabled assessment of the gastric accommodation reflex, stress and strain in the stomach. It triggered few symptoms in healthy volunteers. We propose it to be a more physiological replacement of the barostat technique.

By combining transabdominal ultrasound, multichannel high-resolution impedance-manometry and a symptom questionnaire, we studied gastric and lower esophageal physiology during intake of a 300 mL liquid meal. In the stomach, we found a positive correlation of fullness to area and strain, and a negative correlation of pressure to fullness, area and stress. We see this as expressions of the gastric accommodation reflex.

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Healthcare Utilization and Costs During the Initial Phase of Care Among Elderly Women With Breast Cancer

Background: Understanding the patterns of healthcare utilization and costs during the initial phase of care (12 months after breast cancer [BC] diagnosis) in older women (aged ≥65 years) is crucial in the allocation of Medicare resources. The objective of this study was to determine healthcare utilization and costs during the initial phase of care in older, female, Medicare fee-for-service beneficiaries diagnosed with BC, and to determine the factors associated with higher costs. Methods: A retrospective observational study using the SEER-Medicare linked database was conducted in 69,307 women aged ≥66 years diagnosed with primary incident BC in 2003–2009 to determine healthcare utilization, average costs, and costs for specific services during the initial phase of care. Generalized linear model regression was conducted to identify the factors associated with higher costs in a multivariate framework. Results: A total of 96% of women were treated with surgery during the initial phase of BC care, whereas 21% and 54% underwent chemotherapy and radiotherapy, respectively. Costs during the initial phase of care totalled $28,075 in 2012 USD, comprising $13,344 for physician services and $7,456 for outpatient services. Factors associated with higher costs during the initial phase of care were younger age (66–69 years), African American race, higher household income, advanced stages of BC, initial BC treatment, higher number of primary care physician visits, and presence of comorbidities and/or a mental condition. Conclusions: The economic burden of BC is substantial during the initial phase of care. Physician and outpatient services accounted for the highest proportion of costs. Predisposing factors, need-related factors, healthcare use, and external environmental healthcare factors significantly predicted costs during the initial phase of care.

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Do Published Data in Trials Assessing Cancer Drugs Reflect the Real Picture of Efficacy and Safety?

Background: The reporting quality of publications is of vital importance to ensure accurate evidence dissemination. This study aimed to compare the consistency of results reporting between the ClinicalTrials.gov results database and the respective matching publications. Methods: We identified 323 phase III/IV cancer drug trials with a randomized controlled design and searched PubMed for publications in a 50% random sample (n=160). Data were extracted independently from ClinicalTrials.gov and publications. A scoring system was applied to determine characteristics associated with reporting quality. Results: Of 117 reviewed trials with publications, result reporting was significantly more complete in ClinicalTrials.gov for efficacy measurement (92.3% vs 90.6%), serious adverse events (SAEs; 100% vs 43.6%), and other adverse events (OAEs; 100% vs 62.4%). For trials with both posted and published results for design information (n=117), efficacy measurements (n=98), SAEs (n=51), and OAEs (n=73), discrepancies were found in 16 (13.7%), 38 (38.8%), 26 (51.0%), and 54 (74.0%) trials, respectively. Overreporting of treatment effects (7 trials) and alteration of primary end points favoring statistically significant outcomes (11 trials) were the major discrepancies in efficacy reporting; incomplete (66 trials) and underreporting (20 trials) of SAEs were the predominant issues in benefit/risk reporting. Median quality score was 21 (range, 14–28). Trials that had parallel assignment, were phase IV, had primary funding by industry, were completed after 2009, and had earlier results posted possessed better reporting quality. Conclusions: Although most trials showed reasonable completeness and consistency, some discrepancies are prevalent and persistent, jeopardizing evidence-based decision-making. Our findings highlight the need to consult results systematically from both ClinicalTrials.gov and publications.

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NCCN News

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Oncology Research Program

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Who's Watching the Kids?

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Addition of Definitive Radiotherapy to Chemotherapy in Patients With Newly Diagnosed Metastatic Nasopharyngeal Cancer

Background: Management of metastatic (M1) nasopharyngeal cancer (NPC) is controversial; data suggest high overall survival (OS) rates with definitive chemoradiotherapy (CRT). Herein, we evaluated OS in patients with M1 NPC undergoing chemotherapy alone versus CRT. Methods: The National Cancer Data Base was queried for M1 NPC cases. Patients undergoing no/unknown chemotherapy and/or with unknown/nondefinitive radiotherapy (RT) doses (<60 Gy) were excluded. Logistic regression analysis ascertained clinical factors associated with RT administration. Kaplan-Meier analysis evaluated OS between both cohorts; Cox proportional hazards modeling assessed factors associated with OS. Survival was then evaluated between matched populations using inverse-probability–weighted regression adjustment. OS between groups was also measured in patients surviving ≥1 and ≥3 years to address bias from poor-prognostic subsets (eg, widely disseminated disease), and those receiving CRT ≤30 and ≤60 days of each other (surrogates for concurrent CRT) versus >30 and >60 days (sequential) of each other. Results: Of 555 patients, 296 (53%) received chemotherapy alone and 259 (47%) underwent CRT. Patients undergoing CRT more often had private insurance (P=.001) and lived in areas with higher education levels (P=.028). Median OS in the chemotherapy-only and CRT cohorts were 13.7 and 25.8 months, respectively (P<.001); differences persisted between matched populations (P<.001). On multivariate analysis, receipt of additional RT independently predicted for improved OS (P<.001). OS differences between cohorts remained apparent when evaluating patients surviving for ≥1 (P<.001) and ≥3 (P=.002) years. Patients who received concurrent or sequential CRT displayed improved OS over those receiving chemotherapy alone, for both the 30-day (P<.001) and 60-day cutoffs (P<.001). Conclusions: Patients with M1 NPC undergoing definitive RT and chemotherapy experienced higher survival than those receiving chemotherapy alone. Risk stratification and patient selection for such combined modality interventions is critical.

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Letter to the Editor: Defining "Standard of Care"

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Emerging Role of CAR T Cells in Non-Hodgkin's Lymphoma

Adoptive T-cell therapy with chimeric antigen receptor T cells (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies, and several groups have published positive results using anti-CD19 CAR-Ts for the treatment of B-cell acute lymphoblastic leukemia. Recently, new data from clinical trials have demonstrated the benefits of CAR-T therapy in the non-Hodgkin's lymphoma (NHL) setting. This review describes some of the most recent and promising advances in engineered T-cell therapy, with particular emphasis on the clinical benefits of NHL treatment.

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Sexual Health Is Paramount in the Counseling of Women at Risk for Breast or Ovarian Cancer Undergoing Risk-Reducing Surgery

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Nonadherence to Statins and Antihypertensives and Hospitalizations Among Elderly Medicare Beneficiaries With Incident Cancer

Background: Incident cancer diagnosis may increase the risk of coronary artery disease (CAD)–related hospitalizations, especially in older individuals. Adherence to statins and/or angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs)/β-blockers reduces CAD-related hospitalizations. This study examined the relationship between medication adherence and CAD-related hospitalizations immediately following cancer diagnosis. Patients and Methods: A retrospective observational longitudinal study was conducted using SEER-Medicare data. Elderly Medicare fee-for-service beneficiaries with preexisting CAD and incident breast, colorectal, or prostate cancer (N=12,096) were observed for 12 months before and after cancer diagnosis. Hospitalizations measured every 120 days were categorized into CAD-related hospitalization, other hospitalization, and no hospitalization. Medication adherence was categorized into 5 mutually exclusive groups: adherent to both statins and ACEIs/ARBs/β-blockers (reference group), not adherent to both statins and ACEIs/ARBs/β-blockers, adherent to either statins or ACEIs/ARBs/β-blockers, use of one medication class and adherent to that class, and use of one medication class and not adherent to that class. The relationship between medication adherence and hospitalization was analyzed using repeated measures multinomial logistic regressions. Inverse probability treatment weights were used to control for observed group differences among medication adherence categories. Results: Adherence to both statins and ACEIs/ARBs/β-blockers was estimated at 31.2% during the 120-day period immediately following cancer diagnosis; 13.7% were not adherent to both medication classes during the same period, and 27.4% had CAD-related hospitalizations immediately after cancer diagnosis, which declined to 10.6% during the last 4 months of the postdiagnosis period. In the adjusted analyses, those not adherent to both statins and ACEIs/ARBs/β-blockers were more likely to have CAD-related hospitalization compared with those adherent to both medication classes (adjusted odds ratio, 1.82; 95% CI, 1.72–1.92; P<.0001). Conclusions: Given the complexity of interaction between CAD and cancer, it is important to routinely monitor medication adherence in general clinical practice and to provide linkages to support services that can increase medication adherence.

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Time to Change: Supporting Sexual and Gender Minority People--An Underserved, Understudied Cancer Risk Population

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Sexual and Gender Minority Issues Across NCCN Guidelines: Results From a National Survey

Background: The lesbian, gay, bisexual, transgender, queer/questioning (LGBTQ) population is at higher risk for multiple types of cancers compared with the heterosexual population. Expert NCCN panels lead the nation in establishing clinical practice guidelines addressing cancer prevention, early detection, and treatment of cancer sites and populations. Given the emergence of new data identifying cancer disparities in the LGBTQ population, this study examined the inclusion of medical and/or psychosocial criteria unique to LGBTQ within NCCN Guidelines. Methods: Data were collected for 32 of the 50 NCCN Guidelines. Results: NCCN panel members reported that neither sexual orientation (84%) nor gender identity (94%) were relevant to the focus of their guidelines; 77% responded that their panels currently do not address LGBTQ issues, with no plans to address them in the future. Conclusions: Greater consideration should be given to the needs of LGBTQ patients across the cancer care continuum. Given that research concerning LGBTQ and cancer is in its infancy, additional empirical and evidence-based data are needed to bolster further integration of LGBTQ-specific criteria into clinical care guidelines.

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Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel MTOR-Activating Mutation

mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole-exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in VHL (p.W88L), a loss-of-function mutation in BAP1 (p.E454Rfs*15), and a novel missense mutation in MTOR (p.Y1974H). The MTOR mutation was present in all tumor regions, with similar allele frequency as the VHL mutation, and in vitro functional assessment of the MTOR variant demonstrated that it increased mTORC1 activity. Consistently, immunohistochemistry in the tumor samples demonstrated increased levels of phospho-S6. In conclusion, multiregion WES identified a novel MTOR mutation acquired early during tumor development as the event leading to a high sensitivity to temsirolimus treatment. This study supports tumor multiregion sequencing to detect truncal mutations in the mTOR pathway to identify patients sensitive to mTOR inhibitors.

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Apoyo con Carino: Strategies to Promote Recruiting, Enrolling, and Retaining Latinos in a Cancer Clinical Trial

Background: We present and describe tailored strategies to address known barriers to minority participation in clinical trial research. The strategies used allowed our team to engage communities and successfully recruit, enroll, and retain a diverse underserved population of Latinos with advanced cancer for this clinical trial. Methods: Participants were recruited from 3 urban and 7 rural sites. We identified 4 critical barriers to recruitment for this underserved population: (1) mistrust; (2) language and communication barriers; (3) lack of access to academic cancer center; and (4) inability to participate due to transportation, childcare, or work responsibilities. We developed tailored strategies to engage referring sites and patients to participate in the clinical trial. Results: We identified 318 potentially eligible participants; 34 were found to be ineligible, and 223 consented to participate in the study, representing a 79.0% enrollment rate. All patients (100%) self-identified as Latino, and 47.5% spoke Spanish as their primary language. Patients were socioeconomically disadvantaged: 53.6% had an annual income <$15,000 USD, and 50.2% had less than a high school education. A total of 177 participants completed the 3-month follow-up; 26 died before the 3-month follow interview, and 20 did not complete the follow-up evaluation (9% withdrawal rate). Conclusions: Our community-informed strategies were highly effective for recruiting, enrolling, and retaining an underserved diverse population of Latinos. The barriers we identified and the strategies we used have the potential to inform research to increase minority participation in cancer clinical trials. ClinicalTrials.gov identifier: NCT01695382

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Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer

Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.

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Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.

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NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

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Truth in Advertising: Do Clinical Trial Publications Tell It All?

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Open access: Is there a predator at the door?

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Effects of Proton Center Closure on Pediatric Case Volume and Resident Education at an Academic Cancer Center

Publication date: Available online 8 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James Galle, David Long, Tim Lautenschlaeger, Richard Zellars, Gordon Watson, Susannah Ellsworth
PurposeChanges in radiation oncology infrastructure influence referral/practice patterns, which may affect resident educational experiences. This study aimed to analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education.MethodsThis was a review of 412 consecutive pediatric (≤18 years) cases treated at a single institution from 2012-2016. Residents' Accreditation Council for Graduate Medical Education case logs for the same years were also analyzed. Characteristics of the patient population and resident case volumes before and after closure of the PTC are reported.ResultsOverall pediatric new starts declined by about 50%, from 35-70 per 6 months in 2012-2014 to 22-30 per 6 months in 2015-2016. CNS case volume declined sharply, from 121 patients treated in 2012-2015 to 18 patients in 2015-2016. In 2012-2014, our institution treated 36, 24, and 17 patients for medulloblastoma/intracranial PNET, ependymoma, and low grade glioma (LGG), respectively, compared to 0, 1, and 1 patients in 2015-2016. 49 patients were treated with craniospinal radiation (CSI) from 2012-2014, while only 2 patients underwent CSI between 2015-2016. Hematologic malignancy patient volume and use of total body irradiation remained relatively stable. Patients treated when the PTC was open were significantly younger (9.1 vs 10.7 years, p=0.010) and their radiation courses were longer (35.4 vs 20.9 days, p<0.0001) than those treated after its closure. Resident case logs showed only a small decline in total pediatric cases, as the percentage of pediatric cases covered by residents increased after PTC closure; however, residents logged fewer CNS cases after PTC closure vs. before.ConclusionsOverall pediatric case volume decreased following PTC closure, as did the number of patients treated for potentially curable CNS tumors. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become increasingly concentrated at specialized centers.

Teaser

Changes in radiation oncology infrastructure influence referral/practice patterns and resident educational experiences. This study aimed to analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education. We demonstrate a sharp decrease in overall pediatric cases and potentially curable CNS tumors treated at our center following PTC closure. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become concentrated at specialized centers.


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Delineation of neck clinical target volume specific to nasopharyngeal carcinoma based on lymph node distribution and the international consensus guidelines

Publication date: Available online 8 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Li Lin, Yao Lu, Xiao-Ju Wang, Hui Chen, Sha Yu, Jiao Tian, Guan-Qun Zhou, Lu-Lu Zhang, Zhen-Yu Qi, Jiang Hu, Jun Ma, Ying Sun
PurposeTo establish regional lymph node (LN) distribution probability map and draw neck clinical target volume (CTV) specific to nasopharyngeal carcinoma (NPC).Methods and MaterialsOne thousand patients with pathologically-proven NPC between January 2010 and December 2011 were enrolled. Center points of LNs with a minimal axial diameter (MID) ≥ 4 mm were marked on one single treatment planning computed tomography scan. Neck node levels I – X based on the 2013 updated international consensus guidelines were also contoured. LN distribution probability maps and distribution curves were established. Relationships between LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to NPC.ResultsA total of 10651 LNs from 959 patients were marked. Based on the distribution of LNs and consensus guidelines, the majority of node levels defined in the 2013 updated consensus guidelines were confirmed to be comprehensive and applicable for NPC. However, for level Vb, 13.3% (11/83) cases had LNs beyond the posteromedial border; for level VIIa (retropharyngeal LN), 1.5% (12/819) cases had LNs above the cranial boundary and 5 cases had LNs emerged in the medial group. Moreover, we confirmed that no LN had been detected in certain areas of level Ib, II, IVa and Vc. Accordingly, a new level VIIc was proposed to include medial group of retropharyngeal LNs, and moderate extended boundaries for levels Vb and VIIa were recommended, while reduced boundaries were possibly adaptable for levels Ib, II, IV and Vc.ConclusionThe majority of node levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. While, we propose a new level VIIc to include medial group of retropharyngeal LNs, recommend moderate extended boundaries for levels Vb and VIIa, and suggested that boundaries for levels Ib, II, IV and Vc might be reduced.

Teaser

Neck node distribution probability maps and curves for NPC were established based on 10651 nodes from 956 patients. Relationships between node distribution and international consensus guidelines for delineation of neck node levels were analyzed. Our findings demonstrate that the majority of node levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. We propose a new level VIIc to include medial group of retropharyngeal LNs, recommend moderate extended boundaries for levels Vb and VIIa, and suggest that boundaries for levels Ib, II, IV and Vc might be reduced.


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The influence of dexamethasone on postoperative swelling and neurosensory disturbances after orthognathic surgery: a randomized controlled clinical trial

Orthognathic surgery is associated with considerable swelling and neurosensory disturbances. Serious swelling can lead to great physical and psychological strain. A randomized, prospective, controlled clinical...

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The involvement of N-methyl-D-aspartate receptors in plasticity induced by paired corticospinal-motoneuronal stimulation in humans

Plasticity can be induced at human corticospinal-motoneuronal synapses by delivering repeated, paired stimuli to corticospinal axons and motoneurones in a technique called paired corticospinal-motoneuronal stimulation (PCMS). To date, the mechanisms of the induced plasticity are unknown. To determine whether PCMS-induced plasticity is dependent on N-methyl-D-aspartate receptors (NMDARs), the effect of the non-competitive NMDAR antagonist, dextromethorphan, on PCMS-induced facilitation was assessed in a two-day, double-blind, placebo-controlled experiment. PCMS consisted of 100 pairs of stimuli, delivered at an interstimulus interval that produces facilitation at corticospinal-motoneuronal synapses that excite biceps brachii motoneurones. Transcranial magnetic stimulation (TMS) elicited corticospinal volleys, which were timed to arrive at corticospinal-motoneuronal synapses just prior to antidromic potentials elicited in motoneurones using electrical brachial plexus stimulation. To measure changes in the corticospinal pathway at a spinal level, biceps responses to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were measured before and for 30 min after PCMS. Individuals who displayed a ≥10% increase in CMEP size after PCMS on screening were eligible to take part in the two-day experiment. Following PCMS, there was a significant difference in CMEP area between placebo and dextromethorphan days (p=0.014). On the placebo day, PCMS increased average CMEP areas to 127±46% of baseline, whereas on the dextromethorphan day, CMEP area was decreased to 86±33% of baseline (mean±SD; placebo: n=11; dextromethorphan: n=10). Therefore, dextromethorphan suppressed the facilitation of CMEPs after PCMS. This indicates that plasticity induced at synapses in the human spinal cord by PCMS may be dependent on NMDARs.

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Inflow of oxygen and glucose into brain tissue induced by intravenous norepinephrine: relationships with central metabolic and peripheral vascular responses

As an essential part of sympathetic activation that prepares the organism for "fight or flight," peripheral norepinephrine (NE) plays an important role in regulating cardiac activity and the tone of blood vessels, increasing blood flow to the heart and the brain and decreasing blood flow to the organs not as necessary for immediate survival. To assess whether this effect is applicable to the brain, we used high-speed amperometry to measure the changes in nucleus accumbens (NAc) levels of oxygen and glucose induced by intravenous (iv) injections of NE in awake, freely-moving rats. We found that NE at low doses (2-18 –g/kg) induces correlative increases in NAc oxygen and glucose, suggesting local vasodilation and enhanced entry of these substances into brain tissue from the arterial blood. By using temperature recordings from the NAc, temporal muscle, and skin, we show that this central effect is associated with strong skin vasoconstriction and phasic increases in intra-brain heat production, indicative of metabolic neural activation. A tight, direct correlation between NE-induced changes in metabolic activity and NAc levels of oxygen and glucose levels suggests that local cerebral vasodilation is triggered via a neuro-vascular coupling mechanism. Our data suggest that NE, by changing vascular tone and cardiac activity, triggers a visceral sensory signal that rapidly reaches the CNS via sensory nerves and induces neural activation. This neural activation leads to a chain of neuro-vascular events that promote entry of oxygen and glucose into brain tissue, thus preventing any possible metabolic deficit during functional activation.

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Endocannabinoid-Mediated Potentiation of Non-Nociceptive Synapses Contributes to Behavioral Sensitization

Endocannabinoids, such as 2-arachidonoyl glycerol (2-AG) and anandamide, can elicit long-term depression of both excitatory and inhibitory synapses. This latter effect will result in disinhibition and would therefore be expected to produce an increase in neural circuit output. However, there have been no examples directly linking endocannabinoid-mediated disinhibition to a change in a functional neurobehavioral circuit. The present study uses the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana, to examine the functional/behavioral relevance of endocannabinoid modulation of an identified afferent synapse. Bath-application of 2-AG potentiates synaptic transmission by pressure-sensitive sensory neurons (P cell) as well as the magnitude of the defensive shortening reflex elicited by P cell stimulation. This potentiation requires activation of TRPV-like channels. Endocannabinoid/TRPV signaling was found to produce sensitization of the shortening reflex elicited by either direct stimulation of nearby nociceptive afferents (N cells) or noxious stimulation applied to skin several segments away. In both cases heterosynaptic potentiation of P cell synapses were observed in parallel with an increase in the magnitude of the elicited shortening and both synaptic and behavioral effects were blocked by pharmacological inhibition of 2-AG synthesis or TRPV-like channel activation. Serotonin (5-HT) is known to play a critical role in sensitization in Hirudo and other animals and the 5-HT2 receptor antagonist, ritanserin, also blocked behavioral sensitization and the accompanying synaptic potentiation. These findings suggest a novel, endocannabinoid-mediated contribution to behavioral sensitization that may interact with known 5-HT-dependent modulatory processes.

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Vestibular short latency evoked potential (VsEP) is abolished by low frequency noise exposure in rats

The vestibular system plays a critical role in detection of head movements and is essential for normal postural control. Because of their anatomical proximity to the cochlea, the otolith organs are selectively exposed to sound pressure and are at risk for noise overstimulation. Clinical reports suggest a link between noise exposure and balance problems, but the structural and physiological basis for this linkage is not well understood. The goal of this study is to determine the effects of low frequency noise (LFN), on the otolith organs by correlating changes in vestibular short latency evoked potentials, (VsEPs), with changes in saccular afferent endings following noise exposure. LFN exposure transiently abolished the VsEP and reduced the number of stained calyces within the sacculus. Although some recovery of the VsEP waveform could be observed within three days post-noise, at three weeks, recovery was only partial in most animals, consistent with a reduced number of afferents with calyceal endings. These data show that a single intense noise exposure is capable of causing a vestibular deficit that appears to mirror the synaptic deficit associated with hidden hearing loss after noise-induced cochlear injury.

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Optimal use of limb mechanics distributes control during bimanual tasks

Bimanual tasks involve the coordination of both arms, which often offers redundancy in the ways a task can be completed. The distribution of control across limbs is often considered from the perspective of handedness. In this context, although there are differences across dominant and non-dominant arms during reaching control (Sainburg 2002), previous studies have shown that the brain tends to favor the dominant arm when performing bimanual tasks (Salimpour and Shadmehr 2014). However, biomechanical factors known to influence planning and control in unimanual tasks may also generate limb asymmetries in force generation, but their influence on bimanual control has remained unexplored. We investigated this issue in a series of experiments in which participants were instructed to generate a 20-N force with both arms, with or without perturbation of the target force during the trial. We modeled the task in the framework of optimal feedback control of a two-link model with six human-like muscles groups. The biomechanical model predicted a differential contribution of each arm dependent on the orientation of the target force and joint configuration that was quantitatively matched by the participants' behavior, regardless of handedness. Responses to visual perturbations were strongly influenced by the perturbation direction, such that online corrections also reflected an optimal use of limb biomechanics. These results show that the nervous system takes biomechanical constraints into account when optimizing the distribution of forces generated across limbs during both movement planning and feedback control of a bimanual task.

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Rapid feedback responses are flexibly coordinated across arm muscles to support goal-directed reaching

A transcortical pathway helps support goal-directed reaching by processing somatosensory information to produce rapid feedback responses across multiple joints and muscles. We tested whether such feedback responses can account for changes in arm configuration and for arbitrary visuomotor transformations - two manipulations that alter how muscles at the elbow and wrist need to be coordinated to achieve task success. Participants used a planar three degree-of-freedom exoskeleton robot to move a cursor to a target following a mechanical perturbation that flexed the elbow. In our first experiment, the cursor was mapped to the veridical position of the robot handle, but participants grasped the handle with two different hand orientations (thumb pointing upward or thumb point downward). We found that large rapid feedback responses were evoked in wrist extensor muscles when wrist extension helped move the cursor to the target and in wrist flexor muscles when wrist flexion helped move the cursor to the target. In our second experiment, participants grasped the robot handle with their thumb pointing upward, but the cursor's movement was either veridical, or was mirrored such that flexing the wrist moved the cursor as if the participant extended their wrist, and vice versa. After extensive practice, we found that rapid feedback responses were appropriately tuned to the wrist muscles that supported moving the cursor to the target when the cursor was mapped to the mirrored movement of the wrist, but were not tuned to the appropriate wrist muscles when the cursor was remapped to the wrist's veridical movement.

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A fast, invariant representation for human action in the visual system

Humans can effortlessly recognize others' actions in the presence of complex transformations, such as changes in viewpoint. Several studies have located the regions in the brain involved in invariant action recognition, however, the underlying neural computations remain poorly understood. We use magnetoencephalography (MEG) decoding and a dataset of well-controlled, naturalistic videos of five actions (run, walk, jump, eat, drink) performed by different actors at different viewpoints to study the computational steps used to recognize actions across complex transformations. In particular, we ask when the brain discriminates between different actions, and when it does so in a manner that is invariant to changes in 3D viewpoint. We measure the latency difference between invariant and non-invariant action decoding when subjects view full videos as well as form-depleted and motion-depleted stimuli. We were unable to detect a difference in decoding latency or temporal profile between invariant and non-invariant action recognition in full videos. However, when either form or motion information is removed from the stimulus set, we observe a decrease and delay in invariant action decoding. Our results suggest that the brain recognizes actions and builds invariance to complex transformations at the same time, and that both form and motion information are crucial for fast, invariant action recognition.

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Binocular deprivation induces both age-dependent and age-independent forms of plasticity in parvalbumin inhibitory neuron visual response properties

Activity of cortical inhibitory interneurons is rapidly reduced in response to monocular deprivation during the critical period for ocular dominance plasticity and in response to salient events encountered during learning. In the case of primary sensory cortex, a decrease in mean evoked firing rate of parvalbumin-positive (PV) inhibitory neurons is causally linked to a reorganization of excitatory networks following sensory perturbation. Converging evidence indicates that it is deprivation, and not an imbalance between open and closed eye inputs, that triggers rapid plasticity in PV neurons. However, this has not been directly tested in-vivo. Using two-photon guided cell-attached recording we examined the impact of closing both eyes for 24 hours on PV neuron response properties in mouse primary visual cortex. We found that binocular deprivation induces a 30% reduction in stimulus-evoked mean firing rate, and that this reduction is specific to critical period-aged mice. In contrast to evoked mean firing rate, measurements of trial-to-trial variability revealed that stimulus-driven decreases in variability are significantly dampened by deprivation during both the critical period and the post-critical period. These data establish that open-eye inputs are not required to drive the deprivation-induced weakening of PV neuron evoked activity that defines critical period plasticity, and that other aspects of in-vivo PV neuron activity are malleable throughout life.

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Control of saccadic latency in a dynamic environment: allocation of saccades in time follows the matching law

When exploring the visual environment, one uses saccades to shift gaze and fixation to gather spatially and temporally localized information. We propose that the temporal structure of our environment should constrain the temporal allocation of saccades. Here, we probe the possibility of learning to control saccadic latencies in a choice paradigm. Six participants made saccades within 80-300ms following a target horizontally stepping by 10 deg between two fixed locations. For each participant we constructed two classes of latencies, "short" and "long", using the first and last quartiles of the individual baseline distribution (e.g. [80;152]ms and [185;300]ms respectively). We then concurrently reinforced each class in three blocked conditions across about 60 experimental sessions per participant using different reinforcement probabilities such that the relative ratio of reinforcement rates for "short" versus "long" latencies was either 9/1, 1/9, or 1/1. Latency distributions followed the reinforcement conditions: distributions shifted toward the shorter or longer values or became strongly bimodal. Moreover, the relative rates of "short" over "long" latencies matched the relative rates of reinforcers earned for the corresponding latencies (slope up to 0.95), which reveal the ability to choose when to saccade. Our results reveal that learned contingencies considerably affect the allocation of saccades in time and are in line with recent studies on the temporal adjustment of behavior to dynamic environments. This study provides strong evidence for fine operant control of saccadic latency, supporting the hypothesis of a cost-benefit control of saccade latencies.

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Duration Analysis Using Matching Pursuit Algorithm Reveals Longer Bouts of Gamma Rhythm

The gamma rhythm (30 to 80 Hz), often associated with high-level cortical functions, is believed to provide a temporal reference frame for spiking activity, for which it should have a stable center frequency and linear phase for an extended duration. However, recent studies that have estimated the power and phase of gamma as a function of time suggest that gamma occurs in short bursts and lacks the temporal structure required to act as a reference frame. Here we show that the bursty appearance of gamma arises from the variability in the spectral estimator used in these studies. To overcome this problem, we use another duration estimator based on a matching pursuit algorithm that robustly estimates the duration of gamma in simulated data. Applying this algorithm to gamma oscillations recorded from implanted microelectrodes in the primary visual cortex of awake monkeys, we show that the median gamma duration is greater than 300 ms, which is three times longer than previously reported values.

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Effects of Muscle Action Type on Corticospinal Excitability and Triceps Surae Muscle-Tendon Mechanics

This study investigated if the specific motor control strategy reported for eccentric muscle actions is dependent of muscle mechanical behavior. Motor-evoked potentials (MEP), Hoffman reflex (H-reflex), fascicle length (FL), pennation angle (PA) and fascicle velocity (FV) of soleus (SOL) muscle were compared between isometric and two eccentric conditions. Ten volunteers performed maximal plantarflexion trials in isometric, slow eccentric (25º/s) and fast eccentric (100º/s) conditions, each on a different randomized testing session. Normalized H-reflex (H/M) was depressed in both eccentric conditions as compared to isometric (P < 0.001), while no differences in FL and PA were found among conditions. Furthermore, although the fast eccentric condition had greater fascicle velocity than slow eccentric (P = 0.001), there were no differences in H/M ratio. There were no differences in MEP size between conditions, and silent period was shorter for both eccentric conditions as compared to isometric (P = 0.009). Taken together, the present results corroborates with the hypothesis that the central nervous system has an unique activation strategy during eccentric muscle actions and suggests that sensory feedback does not play an important role in modulating these muscle actions.

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Bayesian optimal adaptation explains age-related human sensorimotor changes

The brain uses information from different sensory systems to guide motor behavior, and aging is associated with a simultaneous decline in the quality of sensory information provided to the brain and a deterioration in motor control. Correlations between age-dependent decline in sensory anatomical structures and behavior have been demonstrated, and it has recently been suggested that a Bayesian framework could explain these relationships. Here we show that age-dependent changes in a human sensorimotor reflex, the vestibulo-ocular reflex, are explained by a Bayesian optimal adaptation in the brain occurring in response to death of motion-sensing hair cells. Specifically, we found that the temporal dynamics of the reflex as a function of age are predicted (r=0.93, p<0.001) by a Kalman filter model which determines the optimal behavioral output when the sensory signal-to-noise characteristics are degraded by death of the transducers. These findings demonstrate that the aging brain is capable of generating the ideal and statistically optimal behavioral response when provided with deteriorating sensory information. While the Bayesian framework has been shown to be a general neural principle for multimodal sensory integration and dynamic sensory estimation, these findings provide evidence of longitudinal Bayesian processing over the human lifespan. These results illuminate how the aging brain strives to optimize motor behavior when faced with deterioration in the peripheral and central nervous system, and have implications in the field of vestibular and balance disorders, as they will likely provide guidance for physical therapy and for prosthetic aids that aim to reduce falls in the elderly.

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Speech Production Quality of Cochlear Implant Users with Respect to Duration and Onset of Hearing Loss

Purpose: To assess whether postlingual onset and shorter duration of deafness before cochlear implant (CI) provision predict higher speech intelligibility results of CI users. Methods: For an objective judgement of speech intelligibility, we used an automatic speech recognition system computing the word recognition rate (WR) of 50 adult CI users and 50 age-matched control individuals. All subjects were recorded reading a standardized text. Subjects were divided into three groups: pre- or perilingual deafness (A), both >2 years before implantation, postlingual deafness 2 years before implantation (C). Results: CI users with short duration of postlingual deafness (B) had a significantly higher WR (median 74%) than CI users with long duration of postlingual deafness (C; 68%, p p Conclusions: The speech production quality of adult CI users shows dependencies on the onset and duration of deafness. These features need to be considered while planning rehabilitation.
ORL 2017;79:282-294

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Venetoclax is effective in small cell lung cancers with high BCL-2 expression

Purpose: Small cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% five-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets. Experimental Design: We used a high-throughput drug screen to identify a venetoclax sensitive SCLC sub-population, and validated the findings with multiple patient-derived xenografts of SCLC. Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo. BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of SCLC patients could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs. Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2 expressing SCLCs.

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Venous collapse regulates intracranial pressure in upright body positions

Recent interest in intracranial pressure (ICP) in the upright posture has revealed that the mechanisms regulating postural changes in ICP are not fully understood. We have suggested an explanatory model where the postural changes in ICP depend on well-established hydrostatic effects in the venous system and where these effects are interrupted by collapse of the internal jugular veins (IJVs) in more upright positions. The aim of this study was to investigate this relationship by simultaneous invasive measurements of ICP, venous pressure and IJV collapse in healthy volunteers. ICP (monitored via the lumbar route), central venous pressure (PICC-line) and IJV cross-sectional area (ultrasound) were measured in 11 healthy volunteers (47±10 years) in seven positions, from supine to sitting (0°-69°). Venous pressure and anatomical distances were used to predict ICP in accordance with the explanatory model, and IJV area was used to assess IJV collapse. The hypothesis was tested by comparing measured ICP to predicted ICP. Our model accurately described the general behavior of the observed postural ICP changes (mean difference: -0.03±2.7 mmHg). No difference was found between predicted and measured ICP for any tilt-angle (p-values: 0.65 - 0.94). The results support the hypothesis that postural ICP changes are governed by hydrostatic effects in the venous system and IJV collapse. This improved understanding of the postural ICP regulation may have important implications for the development of better treatments for neurological and neurosurgical conditions affecting ICP.

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The orchestration of autonomous and behavioral thermoregulation

There seems to be an efficient order in the recruitment of thermo-effectors, which allows for body temperature regulation at minimal cost of nutrients and water. But how does thermal behaviour fit in this order? In this edition Schlader et al. hypothesized that thermal behavior fits in the orderly recruitment of thermo-effectors as follows: 1) vasomotor responses, 2) behavioral responses, and 3) sweating or metabolic responses. Their results support this hypothesis by showing consistently for heating and cooling that non-glabrous skin blood flow changes immediately with changes in skin temperature, followed by the initiation of a behavioral response. The editorial focus is on old and new questions that are raised by the findings of Schlader et al, and how they pave the way to better understand the underlying regulatory and integrative human physiology of thermoregulation.

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Role of Immune Factors in Angiotensin II-Induced Hypertension and Renal Damage in Dahl Salt-Sensitive Rats

The present study assessed the importance of immunity in AngII (5 ng/kg/min, iv)-mediated hypertension in Dahl Salt Sensitive (SS) rats and SS rats deficient in T- and B-lymphocytes (SS ^Rag1-/-) fed a 0.4% NaCl diet. Baseline mean arterial blood pressure (MAP) was not different between groups. AngII infusion significantly increased MAP in both groups; though MAP increased more rapidly in SS, and the maximal MAP achieved in SS (190±3 mmHg) was significantly greater than that in SS^Rag1-/- (177±3 mmHg) after 12 days. Renal damage, as assessed by albumin excretion rate, was significantly increased after 12 days of AnglI infusion in the SS (from 32±4 to 81±9 mg/day) and in the SS^Rag1-/- (from 12±2 to 51±8 mg/day); albumin excretion rate was significantly different between the SS and SS^Rag1-/- rats at all points measured. Following 9 days of recovery from AngII, MAP was decreased to a greater extent in SS^Rag1-/- (143±5 mmHg) than in SS (157±8 mmHg) when compared to the peak MAP during AngII infusion. At this same time point, the albumin excretion rate of SS^Rag1-/- was significantly lower (42±8 mg/day) than that observed in the SS (66±7 mg/day). Further studies demonstrated that the kidneys of AngII-treated SS had increased CD45+ total leukocytes, CD11b/c+ macrophages/monocytes, and CD3+ T Cells compared to vehicle-treated SS. The present data suggest that infiltrating T cells in the kidney exacerbate renal damage in AngII-induced hypertension in SS rats maintained on a 0.4% NaCl diet, similar to the results observed with a salt stimulus in SS rats.

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Tonic aortic depressor nerve stimulation does not impede baroreflex dynamic characteristics concomitantly mediated by the stimulated nerve

Although electrical activation of the carotid sinus baroreflex (baroreflex activation therapy) is being explored as a device therapy for resistant hypertension, possible effects on baroreflex dynamic characteristics of interaction between electrical stimulation and pressure inputs are not fully elucidated. To examine whether the electrical stimulation of the baroreceptor afferent nerve impedes normal short-term arterial pressure (AP) regulation mediated by the stimulated nerve, we electrically stimulated the right aortic depressor nerve (ADN) while estimating the baroreflex dynamic characteristics by imposing pressure inputs to the isolated baroreceptor region of the right ADN in nine anesthetized rats. A Gaussian white noise signal with a mean of 120 mmHg and standard deviation of 20 mmHg was used for the pressure perturbation. A tonic ADN stimulation (2 or 5 Hz, 10 V, 0.1-ms pulse width) decreased mean sympathetic nerve activity (367.0 ± 70.9 vs. 247.3 ± 47.2 arbitrary units, P < 0.01) and mean AP (98.4 ± 7.8 vs. 89.2 ± 4.5 mmHg, P < 0.01) during dynamic pressure perturbation. The ADN stimulation did not affect the slope of dynamic gain in the neural arc transfer function from pressure perturbation to sympathetic nerve activity (16.9 ± 1.0 vs. 14.7 ± 1.6 dB/decade, not significant). These results indicate that electrical stimulation of the baroreceptor afferent nerve does not significantly impede the dynamic characteristics of the arterial baroreflex concomitantly mediated by the stimulated nerve. Short-term AP regulation by the arterial baroreflex may be preserved during the baroreflex activation therapy.

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Arsenic Exposure Induces Glucose Intolerance and Alters Global Energy Metabolism

Environmental pollutants acting as endocrine disrupting chemicals (EDCs) are recognized as potential contributors to metabolic disease pathogenesis. One such pollutant, arsenic, contaminates the drinking water of approximately 100 million people globally and has been associated with insulin resistance and diabetes in epidemiological studies. Despite these observations, the precise metabolic derangements induced by arsenic remain incompletely characterized. In the present study, arsenic's impact on in vivo metabolic physiology was examined in 8 week old male C57BL/6J mice exposed to 50 mg/L inorganic arsenite in their drinking water for 8 weeks. Glucose metabolism was assessed via in vivo metabolic testing, and feeding behavior was analyzed using indirect calorimetry in metabolic cages. Pancreatic islet composition was assessed via immunofluorescence microscopy. Arsenic-exposed mice exhibited impaired glucose tolerance as compared to controls; however, no difference in peripheral insulin resistance was noted between groups. Instead, early insulin release during glucose challenge was attenuated relative to the rise in glycemia. Despite decreased insulin secretion, pancreatic β­cell mass was not altered, suggesting that arsenic primarily disrupts β­cell function. Finally, metabolic cage analyses revealed that arsenic exposure induced novel alterations in the diurnal rhythm of food intake and energy metabolism. Taken together, these data suggest that arsenic exposure impairs glucose tolerance through functional impairments in insulin secretion from β­cells rather than by augmenting peripheral insulin resistance. Further elucidation of the mechanisms underlying arsenic-induced behavioral and β­cell-specific metabolic disruptions will inform future intervention strategies to address this ubiquitous environmental contaminant and novel diabetes risk factor.

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Viscerosensory input drives angiotensin II type 1A receptor expressing neurons in the solitary tract nucleus.

Homeostatic regulation of visceral organ function requires integrated processing of neural and neurohormonal sensory signals. The nucleus of the solitary tract (NTS) is the primary sensory nucleus for cranial visceral sensory afferents. Angiotensin II (Ang II) is known to modulate peripheral visceral reflexes, in part, by activating Ang II type 1A receptors (AT_1AR) in the NTS. AT_1AR-expressing NTS neurons occur throughout the NTS with a defined sub-nuclear distribution and most of these neurons are depolarized by Ang II. In this study we determined whether AT_1AR-expressing NTS neurons receive direct visceral sensory input, and whether this input is modulated by Ang II. Using AT_1AR-GFP mice to make targeted whole cell recordings from AT_1AR-expressing NTS neurons, we demonstrate that two thirds (37 of 56) of AT_1AR-expressing neurons receive direct excitatory, visceral sensory input. In half of the neurons tested (4 of 8) the excitatory visceral sensory input was significantly reduced by application of the transient receptor potential vallinoid type 1 receptor agonist, capsaicin, indicating AT_1AR-expressing neurons can receive either C or A-fibre mediated input. Application of Ang II to a subset of second order AT_1AR-expressing neurons did not affect spontaneous, evoked or asynchronous glutamate release from visceral sensory afferents. Thus it is unlikely that AT_1AR-expressing viscerosensory neurons terminate on AT_1AR-expressing NTS neurons. Our data suggest that Ang II is likely to modulate multiple visceral sensory modalities by altering the excitability of second order AT_1AR-expressing NTS neurons.

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Acyloxyacyl hydrolase modulates pelvic pain severity

Chronic pelvic pain causes significant patient morbidity and is a bane to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice, relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2CxB progeny identified a polymorphism on chromosome 13, rs6314295, significantly associated with allodynia (LOD=3.11). The nearby gene encoding acyloxyacyl hydrolase, (Aoah), was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and post-bacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and TNF production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH-deficient mice had significantly higher levels of bladder VEGF, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC.

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Th17 cells contribute to pulmonary fibrosis and inflammation during chronic kidney disease progression following acute ischemia

Acute kidney injury (AKI) is associated with high mortality rates and predisposes development of chronic kidney disease (CKD). Distant organ damage, particularly in the lung, may contribute to mortality in AKI patients. Animal models of AKI demonstrate an increase in pulmonary infiltration of lymphocytes and reveal an acute compromise of lung function, but the chronic effects of AKI on pulmonary inflammation are unknown. We hypothesized that in response to renal I/R, there is a persistent systemic increase in Th17 cells with potential effects on pulmonary structure and function. Renal ischemia/reperfusion (I/R) injury was performed on rats and CKD progression was hastened by unilateral nephrectomy and exposure to 4.0% sodium diet between 35-63 days post-I/R. Th17 cells in peripheral blood showed a progressive increase up to 63 days following recovery from I/R injury. Infiltration of leukocytes including Th17 cells was also elevated in bronchiolar lavage (BAL) fluid 7 days following I/R and remained elevated for up to 63 days. Lung histology demonstrated an increase in alveolar cellularity and a significant increase in picrosirius red staining. Suppression of lymphocytes with mycophenolate mofetil (MMF) or an IL-17 antagonist significantly reduced Th17 cell infiltration and fibrosis in lung. In addition, tracheal smooth muscle contraction to acetylcholine was significantly enhanced 63-days following I/R relative to sham-operated controls. These data suggest that AKI is associated with a persistent increase in circulating and lung Th17 cells which may promote pulmonary fibrosis and the potential alteration in airway contractility.

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Complement activation via a C3a receptor pathway alters CD4+ T lymphocytes and mediates lung cancer progression

The complement cascade is a part of the innate immune system which acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/- mice), with tumors undetectable in many subjects. Growth inhibition was associated with increased numbers of IFNγ+/TNFα+/IL-10+ CD4+ and CD8+ T cells. Immunodepletion of CD4+ but not CD8+ T cells in tumor-bearing subjects reversed the inhibitory effects of C3 deletion. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth. Investigations using multiple tumor cell lines in the orthotopic model suggested the involvement of a C3/C3 receptor autocrine signaling loop in regulating tumor growth. Overall, our findings offer functional evidence that complement activation serves as a critical immunomodulator in lung cancer progression, acting to drive immune escape via a C3/C5-dependent pathway.

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Oncolytic virotherapy blockade by microglia and macrophages requires STAT1/3

The first oncolytic virotherapy employing HSV-1 (oHSV-1) was approved recently by the FDA to treat cancer, but further improvements in efficacy are needed to eradicate challenging refractory tumors such as glioblastomas (GBM). Microglia/macrophages comprising ~40% of a GBM tumor may limit virotherapeutic efficacy. Here we show these cells suppress oHSV-1 growth in gliomas by internalizing the virus through phagocytosis. Internalized virus remained capable of expressing reporter genes while viral replication was blocked. Macrophage/microglia formed a nonpermissive OV barrier, preventing dissemination of oHSV-1 in the glioma mass. The deficiency in viral replication in microglial cells was associated with silencing of particular viral genes. Phosphorylation of STAT1/3 was determined to be responsible for suppressing oHSV-1 replication in macrophages/microglia. Treatment with the oxindole/imidazole derivative C16 rescued oHSV-1 replication in microglia/macrophages by inhibiting STAT1/3 activity. In the U87 xenograft model of GBM, C16 treatment overcame the microglia/macrophage barrier, thereby facilitating tumor regression without causing a spread of the virus to normal organs. Collectively, our results suggest a strategy to relieve a STAT1/3 dependent therapeutic barrier and enhance oHSV-1 oncolytic activity in GBM.

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IDO Immune Status after Chemoradiation May Predict Survival in Lung Cancer Patients

Host immunity influences the impact of radiotherapy (RT) in cancer but mechanistic connections remain obscure. In this study, we investigated the relationship of indoleamine 2,3-dioxygenase (IDO) systemic activity on clinical outcomes in RT-treated non-small cell lung cancer (NSCLC). IDO-mediated production of kynurenine and the kynurenine:tryptophan ratio in patient blood serum were determined for stage III NSCLC patients at times before, during and after RT administration and then correlated to overall survival (OS), progression-free survival and disease progression rate in patients. We found the impact of RT on these serum IDO markers to be heterogeneous in patients. On average, kynurenine:tryptophan ratios were reduced during RT but restored after RT. Notably, both baseline levels of kynurenine:tryptophan and changes in the levels of kynurenine after RT were significantly associated with OS. When combined, favorable change and favorable baseline corresponded with very long-term OS (median OS was not reached after 57 months median follow-up). Favorable change combined with unfavorable baseline still corresponded with a lack of distant metastases. Our results suggest that RT alters IDO-mediated immune status in NSCLC patients and that changes in this serum biomarker may be useful to predict outcomes and perhaps personalize RT dosage to improve survival.

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Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases

Abstract

Aims

The present study analysed the usability of an immunohistochemical (IHC) analysis compared to a frequently used mutation detection analysis and examined the extent of intra- and inter-tumour heterogeneity of BRAF V600E in primary tumours and their corresponding metastases. In the development of inter-tumour heterogeneity between the primary tumour and the corresponding metastases, time as a factor was also investigated.

Methods

In total, 227 samples from 224 melanoma patients were analysed using both the Cobas^® 4800 BRAF V600 Mutation test and IHC anti-BRAF V600E staining. In 82 primary tumours and 224 corresponding metastases, the extent of inter- and intra-tumour heterogeneity was investigated using IHC staining.

Results

In 15 cases, disagreement between IHC analysis and the Cobas test was seen. In all but one of the examined patients, homogeneity between the primary tumour and the corresponding metastasis was found. Except for this one case, no heterogeneity developed over longer periods.

Conclusion

IHC analysis can be safely used as a BRAF pre-therapy screening tool, and no additional test is needed when staining is positive. However, if stains are negative, additional tests are essential for detection of other BRAF mutations. We suggest that using primary melanoma tissues is just as safe as using metastatic tissue for detection of BRAF V600E, since BRAF inter-tumour heterogeneity is extremely rare. In addition, the time between diagnosis of the primary tumour and diagnosis of the corresponding metastasis seems not to increase the risk of inter-tumour heterogeneity

This article is protected by copyright. All rights reserved.

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Correction to: Apocynin and dimethyl sulfoxide synergistically protect against ischemia-reperfusion injury in a rat hind limb ischemia-reperfusion model

Abstract

Dr. Ozer Sehirli's affiliation needs to be updated as he was transferred from Marmara University Faculty of Pharmacy to Near East University Faculty of Dentistry two years ago. The updated information is provided in the affiliation section below.

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Papillary Adenocarcinoma in a Gastric Duplication Cyst

Abstract

Gastric duplication cysts are rare and mostly present in the first year of life. In adulthood presentation is in the form of obstruction, ulceration, bleeding, fistulization etc. Malignancy is extremely rare with only 12 cases reported to date. We came across a gastric duplication cyst with papillary adenocarcinoma in a 63 year old man. He underwent cyst excision with radical subtotal gastrectomy. The awareness of such a condition made it possible for us to have a suspicion of malignancy preoperatively based on imaging and thus a radical surgery was performed. High index of suspicion is necessary to diagnose this condition preoperatively on CT scan. Literature review revealed that this is the first case to be reported from India.

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An atypical pituitary adenoma with a high degree of malignancy: a case report

Abstract

Background

Pituitary carcinoma is very rare and hard to diagnose. However, some atypical pituitary adenomas present with a high rate of proliferation and extensive invasion, suggesting a tumor with a high degree of malignancy.

Case presentation

Here, we present a case study of this type of tumor. A 46 years old women was admitted for headaches and impaired vision, and MRI and CT revealed a sellar lesion. She underwent a transsphenoidal surgery followed by radiotherapy, but the tumor recurred only one month later. She decided to undergo a second and third operation. The final pathology showed a non-functioning adenoma that was approximately 80% ki-67-positive and extensively p53-positive. No metastasis was found. The tumor progressed extremely quickly, and the patient died 7 months after the initial diagnosis.

Conclusions

A pituitary adenoma like this should be treated like a carcinoma, and early treatment may increase the likelihood of survival. A traditional diagnosis standard is unfit for this type of tumor.

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Global oral health status of athletes with intellectual disabilities

Abstract

Background

The aim of this study is to identify the oral health status and treatment needs of Special Olympics athletes with intellectual disabilities from 181 countries by the assessment of oral health parameters and differences between world regions.

Material and methods

Data were collected through interview and oral examinations within the Healthy Athletes Screening. These data were analysed with descriptive statistics of oral health parameters of athletes from Africa, Asia Pacific, East Asia, Europe/Eurasia, Latin America, Middle East North Africa (MENA) and North America. Mean differences of untreated visible dental caries, gingival signs and missing teeth were tested between regions by one-way ANOVA test and between age groups (8–11, 12–18, 19–39 and 40+) by chi-square tests for multiple comparisons with Hochberg-adjusted p value. The level of significance for all tests was set at a p value < 0.05.

Results

A total of 149,272 athletes with intellectual disabilities were screened. More than 80% of the athletes reported that they cleaned their mouths at least once a day. Athletes in Europe/Eurasia, Latin America, and MENA presented higher rates of signs of gingival disease than other regions. The prevalence of untreated dental caries was significantly higher in Latin America and the group of 8–11-year-olds from Latin America, Europe/Eurasia and Asia Pacific.

Conclusions

The data provided by this study demonstrate that continuous efforts for preventive and restorative oral health care are needed for the oral health of these athletes with ID especially in Latin America, MENA and Europe/Eurasia regions.

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Correction to: Apocynin and dimethyl sulfoxide synergistically protect against ischemia-reperfusion injury in a rat hind limb ischemia-reperfusion model

Abstract

Dr. Ozer Sehirli's affiliation needs to be updated as he was transferred from Marmara University Faculty of Pharmacy to Near East University Faculty of Dentistry two years ago. The updated information is provided in the affiliation section below.

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Global oral health status of athletes with intellectual disabilities

Abstract

Background

The aim of this study is to identify the oral health status and treatment needs of Special Olympics athletes with intellectual disabilities from 181 countries by the assessment of oral health parameters and differences between world regions.

Material and methods

Data were collected through interview and oral examinations within the Healthy Athletes Screening. These data were analysed with descriptive statistics of oral health parameters of athletes from Africa, Asia Pacific, East Asia, Europe/Eurasia, Latin America, Middle East North Africa (MENA) and North America. Mean differences of untreated visible dental caries, gingival signs and missing teeth were tested between regions by one-way ANOVA test and between age groups (8–11, 12–18, 19–39 and 40+) by chi-square tests for multiple comparisons with Hochberg-adjusted p value. The level of significance for all tests was set at a p value < 0.05.

Results

A total of 149,272 athletes with intellectual disabilities were screened. More than 80% of the athletes reported that they cleaned their mouths at least once a day. Athletes in Europe/Eurasia, Latin America, and MENA presented higher rates of signs of gingival disease than other regions. The prevalence of untreated dental caries was significantly higher in Latin America and the group of 8–11-year-olds from Latin America, Europe/Eurasia and Asia Pacific.

Conclusions

The data provided by this study demonstrate that continuous efforts for preventive and restorative oral health care are needed for the oral health of these athletes with ID especially in Latin America, MENA and Europe/Eurasia regions.

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Blood eosinophils: The forgotten man of inhaled steroid dose titration

Abstract

Blood eosinophil counts which were once regarded as normal, have become of increasing interest in the era of Interluekin-5 (IL-5) asthma treatment. Blood eosinophils as low as 150 cells/μL have been suggested as treatment cut-offs for eosinophil depleting therapies such as mepolizumab [1], whilst a value of 300 cells/μL has been deemed a more pragmatic cut off by the National Institute for Health and Care Excellence (United Kingdom). In this era of eosinophil post-truths, inhaled corticosteroids (ICS), the eosinophil's oldest adversary, are very much the forgotten man.

This article is protected by copyright. All rights reserved.

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CLDN6 promotes chemoresistance through GSTP1 in human breast cancer

Claudin-6 (CLDN6), a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer ch...

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STAT3-blocked whole-cell hepatoma vaccine induces cellular and humoral immune response against HCC

Whole-cell tumor vaccines have shown much promise; however, only limited success has been achieved for the goal of eliciting robust tumor-specific T-cell responses.

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Unilateral vertebral artery injury in a patient with displaced upper cervical spine fractures: the treatment for one case of vertebral artery embolism

Abstract

Purpose

To report a novel treatment method for vertebral artery injury. Vertebral artery injuries may be caused during trauma by fracture and excessive motion with subluxation from C2 to C6 in spite of vertebral artery deeply seated and normally well protected inside the transverse foramen. Optimal medical management of the occluded vertebral artery has yet to be determined.

Methods

We report on a severely displaced C2–C3 fracture that was found to have a vertebral artery injury. Medical records and imaging were reviewed.

Results

A 50-year-old lady was hit by steel tube without loss of consciousness, but complaining of severe cervical and bilateral periscapular pain. Physical examination identified a neurologically intact patient with frontotemporal ecchymosis and posterior cervical tenderness. MRA and DSA showed an occluded left vertebral artery. After 3 days of observation, the patient showed no symptoms of brain ischemia or abnormal sensation and motor at four limbs. To ensure safety, we took the left vertebral artery embolism at the C2 and C5 levels before operation.

Conclusions

To our knowledge, this is the first report of a displaced C2–C3 fracture in which transcatheter unilateral VAI embolization was used to prevent VAI bleeding during operation.

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Linear IgA bullous dermatosis: a rare manifestation of vancomycin hypersensitivity

Vancomycin is one of the most widely used antibiotics and, because of its prevalent use, several common side effects have been well described, such as "red man" syndrome, agranulocytosis, and ototoxicity. In addition, it has been associated with hypersensitivity reactions including immunoglobulin E–mediated anaphylaxis, linear immunoglobulin A (IgA) bullous dermatosis (LABD), drug reaction with eosinophilia and systemic symptoms syndrome, acute interstitial nephritis, and Stevens-Johnson syndrome and toxic epidermal necrolysis.

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Patients’ experience of the monitoring of free flaps after reconstruction for oral cancer

Regular monitoring of free flaps is essential after microvascular free tissue transfer, but the frequency and duration of the observations vary between units and there is no consensus nationally. Best practice can be informed by the feedback of patients, but as we know of no such studies, we did a cross-sectional survey of a consecutive group of patients after free tissue transfer to find out what they thought about monitoring. We designed a study-specific questionnaire after consultation with the patient and carer forum, and sent it to 150 patients who had had free tissue transfer in the maxillofacial department at Aintree University Hospital during 2015 and 2016.

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Clusterin protects neurons against intracellular proteotoxicity

It is now widely accepted in the field that the normally secreted chaperone clusterin is redirected to the cytosol during endoplasmic reticulum (ER) stress, although the physiological function(s) of this physi...

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A pilot study of endoscopically inserted biodegradable biliary stents in the treatment of benign biliary strictures and cystic duct leaks

Self-expanding biodegradable biliary stents (BDBSs) have recently become available for use in endoscopic retrograde cholangiography (ERC). The aim was to evaluate the effectiveness and safety of novel BDBS in iatrogenic cystic duct leaks and benign biliary strictures (BBSs).

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Three-dimensionally printed personalized guide plate for percutaneous radiofrequency thermal coagulation in idiopathic trigeminal neuralgia

Radiofrequency thermocoagulation (RFT) is used widely for the treatment of idiopathic trigeminal neuralgia (TN). Precise puncture and placement of the electrode needle tip are crucial for successful RFT. This technical note introduces a novel method for performing RFT using a customized, three-dimensionally (3D)-printed guide plate. Eleven patients with idiopathic TN were treated using this method between February and July 2016. Three had V2 branch TN and eight had V3 branch TN. Punctures in eight patients were successful at the first attempt; slight adjustments were required subsequently in the other three patients.

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Who has anaphylaxis in Brazil? Validation of a questionnaire for population studies

The incidence of anaphylaxis is increasing in several parts of the world; thus, determining the prevalence of the disease in a given region is important to understand the factors involved and to promote measur...

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Liquid Biopsy: Using DNA in Blood to Detect, Track, and Treat Cancer

Research studies show tests that analyze tumor DNA in blood, called liquid biopsies, may help detect cancer early, guide precision cancer treatment, and tracking treatment response.

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Neuroprotective effect of neuroserpin in non-tPA-induced intracerebral hemorrhage mouse models

The neuroprotective effects of neuroserpin (NSP) have been well documented in both patients and animal models with cerebral ischemia; however, have never been investigated in hemorrhagic stroke. The aim of thi...

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Non-protease native allergens partially purified from bodies of eight domestic mites using p-aminobenzamidine ligand

Publication date: Available online 8 November 2017
Source:Allergologia et Immunopathologia
Author(s): T. Erban, R. Klubal
BackgroundOptimised purification steps for concentrating trace target native antigens are needed. Combining the p-aminobenzamidine ligand with protease inactivation enables partial purification of mite non-protease allergens lacking proteases.ObjectiveWe sought to analyse in detail proteins obtained using this method from eight species of synanthropic acaridid mites and tested IgE reactivity using pooled human sera.Materials and methodsProteins affinity bound to p-aminobenzamidine as a ligand were identified by MALDI TOF/TOF. After electroblotting, the proteins were visualised using the fluorescent SYPRO-Ruby protein blot stain, and IgE reactivity was further analysed using pooled human sera collected from patients allergic to house dust mites.ResultsMS/MS identification confirmed previous results that no proteases were purified. Protein patterns corresponding to the allergens Der f 7, Der f 30 and actins indicated that these proteins are purified using p-aminobenzamidine and are present across a wide spectrum of acaridid mites. When using Dermatophagoides farinae, apolipophorins (Der f 14), chitinase-like Der f 15 and 18, 70-kDa heat shock protein, and a Der f Alt a10 allergen homolog (gi|37958173) were also detected. The target antigens tropomyosins and paramyosins showed similar IgE binding among the mite species tested. IgE reactivity with miscellaneous D. farinae antigen was also observed.ConclusionsPartial purification of mite non-protease antigens using a strategy combining p-aminobenzamidine with protease inactivation was verified by 1D-E and 2D-E analyses. IgE binding to p-aminobenzamidine-purified native non-protease mite antigens was tested using pooled sera. This preliminary study allows for further work on individual serum samples, allowing confirmation of immunoreactivity.



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The Korean Version of the Voice Symptom Scale for Patients with Thyroid Operation, and Its Use in a Validation and Reliability Study

The Voice Symptom Scale (VoiSS) questionnaire is a self-reported measure of voice function. Compared with previous voice-rating tools, the VoiSS focuses more on communication difficulties, pharyngeal symptoms, and psychosocial distress. This study aimed to translate the VoiSS into the Korean language, validate it, and assess its reliability.

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Liquid Biopsy: Using DNA in Blood to Detect, Track, and Treat Cancer

Research studies show tests that analyze tumor DNA in blood, called liquid biopsies, may help detect cancer early, guide precision cancer treatment, and tracking treatment response.

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Opioid Crisis Inflaming Hep C, HIV in Hard-Hit Communities

The opioid epidemic is having an effect on hepatitis C and HIV transmissions, new state-by-state data show, but funding shortcomings are translating into treatment gaps that have some experts worried.
Medscape Medical News

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Intestinal Permeabiliy in Relapsing-Remitting Multiple Sclerosis

Abstract

Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care.

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Endovascular Ischemic Stroke Models in Nonhuman Primates

Abstract

To bridge the gap between rodent and human studies, the Stroke Therapy Academic Industry Roundtable committee suggests that nonhuman primates (NHPs) be used for preclinical, translational stroke studies. Owing to the fact that vast majority of ischemic strokes are caused by transient or permanent occlusion of a cerebral blood vessel eventually leading to brain infarction, ischemia induced by endovascular methods closely mimics thromboembolic or thrombotic cerebrovascular occlusion in patients. This review will make a thorough summary of transient or permanent occlusions of a cerebral blood vessel in NHPs using endovascular methods. Then, advantages and disadvantages, and potential applications will be analyzed for each kind of models. Additionally, we also make a further analysis based on different kinds of emboli, various occlusion sites, infract size, abnormal hemodynamics, and potential dysfunctions. Experimental models of ischemic stroke in NHPs are valuable tools to analyze specific facets of stroke in patients, especially those induced by endovascular methods.

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