Anatomic consistencies across epilepsies: a stereotactic-EEG informed high-resolution structural connectivity study

Abstract

Drug-resistant localization-related epilepsies are now recognized as network diseases. However, the exact relationship between the organization of the epileptogenic network and brain anatomy overall remains incompletely understood. To better understand this relationship, we studied structural connectivity obtained from diffusion weighted imaging in patients with epilepsy using both stereo-electroencephalography (SEEG)-determined epileptic brain regions and whole-brain analysis. High resolution structural connectivity analysis was applied in 15 patients with drug-resistant localization-related epilepsies and 36 healthy control subjects to study structural connectivity changes in epilepsy. Two different methods of structural connectivity analysis were carried out using diffusion weighted imaging, one focusing on the relationship between epileptic regions determined by SEEG investigations and one blinded to epileptic regions looking at whole-brain connectivity. First, we performed zone-based analysis comparing structural connectivity findings in patients and controls within and between SEEG-defined zones of interest. Next, we performed whole-brain structural connectivity analysis in all subjects and compared findings to the same SEEG-defined zones of interest. Finally, structural connectivity findings were correlated against clinical features. Zone-based analysis revealed no significant decreased structural connectivity within nodes of the epilepsy network at the group level, but did demonstrate significant structural connectivity differences between nodes of the epileptogenic network (regions involved in seizures generation and propagation) and the remaining of the brain in patients compared to controls. Whole-brain analyses showed a total of 133 clusters of significantly decreased structural connectivity across all patients. One cluster of significantly increased structural connectivity was identified in a single patient. Clusters of decreased structural connectivity showed topographical preference for both the salience and default mode networks despite clinical heterogeneity within our patient sample. Correlation analysis did not reveal any significant findings regarding either the effect of age at disease onset, disease duration or post-surgical outcome on structural connectivity. Taken together, this work demonstrates that structural connectivity disintegration targets distributed functional networks while sparing the epilepsy network.

http://ift.tt/2u2f2cA

Using national hip fracture registries and audit databases to develop an international perspective

Publication date: Available online 2 August 2017
Source:Injury
Author(s): Antony Johansen, David Golding, Louise Brent, Jacqueline Close, Jan-Erik Gjertsen, Graeme Holt, Ami Hommel, Alma B. Pedersen, Niels Dieter Röck, Karl-Göran Thorngren
Hip fracture is the commonest reason for older people to need emergency anaesthesia and surgery, and leads to prolonged dependence for many of those who survive. People with this injury are usually identified very early in their hospital care, so hip fracture is an ideal marker condition with which to audit the care offered to older people by health services around the world.We have reviewed the reports of eight national audit programmes, to examine the approach used in each, and highlight differences in case mix, management and outcomes in different countries.The national audits provide a consistent picture of typical patients − an average age of 80 years, with less than a third being men, and a third of all patients having cognitive impairment − but there was surprising variation in the type of fracture, of operation and of anaesthesia and hospital length of stay in different countries.These national audits provide a unique opportunity to compare how health care systems of different countries are responding to the same clinical challenge. This review will encourage the development and reporting of a standardised dataset to support international collaboration in healthcare audit.



http://ift.tt/2uZ5j9F

Glucocorticoids: the mode of action in bullous pemphigoid

Abstract

Bullous pemphigoid (BP) is the most common of pemphigoid diseases caused by autoantibodies against the structures of dermoepidermal junction followed by complement activation, innate immune cell infiltration, neutrophil proteinase secretion and subepidermal blister formation. The first line treatment of BP is topical and systemic glucocorticoids (GC).

Regulation of the immune system and inflammatory cells is the main target of GC actions. GCs act through genomic and non-genomic mechanisms. The human glucocorticoid receptor (GR) mediates most of the biologic effects of glucocorticoids: cytosolic GR binds GCs and is capable to bind to glucocorticoid response elements in DNA and either transactivate or transrepress genes depending on the tissue and cell-type. In addition, GR exerts rapid, non-genomic effects possibly mediated by membrane-localized receptors or by translocation to mitochondria. GCs can also interact directly with several enzymes and cytokines.

As a target treatment for BP, the production of autoantibodies should be discontinued. GCs, in spite of their wide immunosuppressive actions, are weak to stop immunoglobulin G (IgG) autoantibody formation. However, both systemic and topical GCs are able to reduce the clinical symptoms of BP. GCs are used to inhibit the secondary inflammation and symptoms, such as blistering and pruritus, and it is shown that GC treatment will gradually decrease also the autoantibody formation. Our review article analyzes the mode of action of GC treatment in BP, as far it is possible due to paucity of modern immunological studies.

This article is protected by copyright. All rights reserved.

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Caring for transgender patients with epilepsy

Summary

Objective

Approximately 25 million individuals older than age 15 identify as transgender, representing about 0.3–0.9% of the world's population. The aim of this paper is to identify and describe important medical and social considerations facing transgender persons with epilepsy.

Methods

We performed literature searches on the following terms: transgender AND epilepsy, transgender AND neurology, gender dysphoria AND epilepsy, gender dysphoria AND neurology. We also performed literature searches for common feminizing or masculinizing treatment regimens, and searched for interactions of those treatment regimens with antiepileptic drugs (AEDs) and with seizures.

Results

There are multiple bidirectional interactions between AEDs and the commonly used treatments for aligning external sex characteristics with identified gender. The scope of the transgender population with epilepsy remains to be elucidated.

Significance

Transgender patients with epilepsy face significant social and medical challenges. Interactions between medical gender-affirming treatments and AEDs are common, and management must depend on knowledge of these interactions to provide appropriate treatment.

http://ift.tt/2w8TCLY

Molecular pathology of cerebral TNF-α, IL-1β, iNOS and Nrf2 in forensic autopsy cases with special regard to deaths due to environmental hazards and intoxication

Abstract

Deaths involved with environmental hazards and intoxication might present with minimal or nonspecific morphological features, which are insufficient to establish a diagnosis. The present study investigated the postmortem brain mRNA and immunohistochemical expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) and nuclear factor erythroid-2-related factor-2 (Nrf2) in forensic cases. Relative mRNA quantification using Taqman real-time PCR assay demonstrated higher expression of IL-1β, TNF-α and iNOS, and lower expression of Nrf2 in methamphetamine intoxication and hyperthermia cases, higher expression of iNOS in phenobarbital intoxication cases, and higher expression of Nrf2 in phenobarbital intoxication and hypothermia cases. Immunostaining results showed substantial inter-individual variations in each group, showing no evident differences in distribution or intensity. These findings suggest that different inflammatory and antioxidant responses were involved in deaths from different etiologies, and these markers may be useful for evaluating brain damage and responses.

http://ift.tt/2uYVwQX

Neck injury and conjunctival petechiae in a woman who underwent cardiopulmonary resuscitation and subsequently died from meningococcal sepsis

Abstract

Cardiopulmonary resuscitation (CPR) can create a range of unusual lesions and injuries, which may complicate forensic evaluation. Although potentially sinister findings, neck injury and conjunctival petechiae may also be seen in patients who have undergone CPR. We report a case of an individual with subcutaneous bruising and hemorrhage in the deep structures of the neck and florid conjunctival petechiae at autopsy that can be explained by cardiopulmonary resuscitation and meningococcal sepsis.

http://ift.tt/2w8JQtx

Ongoing issues with the diagnosis of excited delirium

http://ift.tt/2uYEkuY

A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK

A novel causative variant (c. 464T>C, p.Leu155Pro) in the heterogeneous nuclear ribonucleoprotein K (HNRNPK) gene.

http://ift.tt/2vrijFI

IgG subclass and vaccination stimulus determine changes in antigen specific antibody glycosylation in mice

Immunoglobulin G (IgG) glycosylation can modulate antibody effector functions. Depending on the precise composition of the sugar moiety attached to individual IgG glycovariants either pro- or anti-inflammatory effector pathways can be initiated via differential binding to type I or type II Fc-receptors. However, an in depth understanding of how individual IgG subclasses are glycosylated during the steady state and how their glycosylation pattern changes during vaccination is missing. To monitor IgG subclass glycosylation during the steady state and upon vaccination of mice with different T cell dependent and independent antigens, tryptic digests of serum and antigen specific IgG preparations were analysed by reversed phase-liquid chromatography-mass spectrometry. We show that there is a remarkable difference with respect to how individual IgG subclasses are glycosylated during the steady state. More importantly, upon T cell dependent and independent vaccinations, individual antigen specific IgG subclasses reacted differently with respect to changes in individual glycoforms, suggesting that the IgG subclass itself is a major determinant of restricting or allowing alterations in specific IgG glycovariants.

This article is protected by copyright. All rights reserved

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Trends in adjuvant therapies after breast-conserving surgery for hormone receptor-positive ductal carcinoma in situ: findings from the National Cancer Database, 2004–2013

Abstract

Purpose

Breast-conserving surgery (BCS) followed by radiotherapy (RT) with or without endocrine therapy (ET) is a standard treatment option for ductal carcinoma in situ (DCIS). We sought to investigate national patterns in the use of adjuvant therapy after BCS for hormone receptor (HR)-positive DCIS over time.

Patients and methods

Using data from the National Cancer Data Base, we identified patients diagnosed with DCIS and treated with BCS between 2004 and 2013. Multivariable logistic regression was used to estimate the odds of adjuvant therapy use controlling for clinicopathologic demographic and facility-level characteristics.

Results

We identified 66,079 patients who underwent BCS for DCIS. Overall, 21% received no adjuvant treatment, 71% received RT, 48% received ET, and 38% received the combination therapy. In adjusted analyses among the patients with HR-positive DCIS (n = 50,147), the administration of RT decreased (odds ratio [OR] 0.86, 95% CI 0.77–0.97), while the use of ET increased (OR 1.5, 95% CI 1.4–1.6) in 2013 compared to 2004. Young patients, elderly patients, positive margin status, and Medicare insurance were associated with lower use of both RT and ET. We observed both clinicopathologic and geographic variation in the use of adjuvant therapies. In the lowest risk subgroup, the use of RT decreased from 57% in 2004 to 48% in 2013 (OR 0.64, 95% CI 0.45–0.89).

Conclusion

Our study suggests a shift in patterns of care for DCIS that is impacted by both clinicopathologic and demographic factors, with the use of RT decreasing and the use of ET increasing in HR-positive DCIS patients. Current trials are designed to address the possible over-treatment of low-risk DCIS.

http://ift.tt/2v1vyuu

The impact of mediolateral episiotomy on the incidence of obstetrical anal sphincter injuries (OASIS) diagnosed by endoanal ultrasound

Publication date: Available online 2 August 2017
Source:Women and Birth
Author(s): Angeliki Antonakou, Dimitrios Papoutsis




http://ift.tt/2umqQ8D

Validation of a Simple Scoring System to Predict Sorafenib Effectiveness in Patients with Hepatocellular Carcinoma

Abstract

Background

Sorafenib is recommended for the treatment of advanced-stage hepatocellular carcinoma (HCC). Nonetheless, it is expensive, effective in few patients, and may cause significant adverse effects. Therefore, accurate selection of patients is needed. In a previous study, we constructed a simple scoring system to predict patients' outcomes based on the occurrence of sorafenib adverse effects.

Objective

The present study aimed to validate this scoring system in a real-life cohort of HCC patients.

Patients and Methods

Clinical records of 279 outpatients treated with sorafenib in eight Italian centers were retrospectively analyzed. Adverse effects considered to calculate the score were skin toxicity, diarrhea, and arterial hypertension, occurring during the first month of therapy. For each adverse effect, 1 point was assigned if present; and 0 points if absent (resulting in a total score between 0 and 3).

Results

Median overall survival (OS) was 10.8 months and median time to progression (TTP) was 5.1 months. At multivariate analysis, performance status, α-fetoprotein (AFP), and Child-Pugh score were independently associated with TTP and OS. A progressive increase of OS and TTP was observed in patients with scores from 0 to 3 (p < 0.001). Six-, 12-, and 24-month survival probabilities were 55.1, 24.5, and 7.9% in score 0 patients, and 100, 80.9, and 46.2% in score 3 patients, respectively. Complete response was observed in one patient (0.4%), partial responses in 41 (15.2%), and stable disease in 117 (43.5%). The disease control rate in patients with scores of 0, 1, 2, and 3 was 34.3, 51.6, 80.9, and 96.3%, respectively (p < 0.001). Complete or partial responses were not observed in score 0 patients.

Conclusions

We have validated a useful scoring system to predict outcomes in sorafenib-treated HCC patients. This score is easy to calculate and suitable for implementation in daily clinical practice.

http://ift.tt/2u5Nk2G

HOXA13 is associated with unfavorable survival and acts as a novel oncogene in prostate carcinoma

Future Oncology, Ahead of Print.


http://ift.tt/2vriOzy

Boosting anti-HER2 CD4 T-helper responses in HER2 expressing ductal carcinoma in situ

Future Oncology, Ahead of Print.


http://ift.tt/2u2fYxf

Meta-analysis of clinical significance of p53 protein expression in patients with osteosarcoma

Future Oncology, Ahead of Print.


http://ift.tt/2vrg8BR

Regorafenib as treatment for patients with advanced hepatocellular cancer

Future Oncology, Ahead of Print.


http://ift.tt/2u264fo

Co-administration of a tumor-penetrating peptide improves the therapeutic efficacy of paclitaxel in a novel air-grown lung cancer 3D spheroid model

Abstract

Three-dimensional (3D) cell culture platforms are increasingly being used in cancer research and drug development since they mimic avascular tumors in vitro. In the present study, we focused on the development of a novel air-grown multicellular spheroid (MCS) model to mimic in vivo tumors for understanding lung cancer biology and improvement in the evaluation of aerosol anticancer therapeutics. 3D MCS were formed using A549 lung adenocarcinoma cells, comprising cellular heterogeneity with respect to different proliferative and metabolic gradients. The growth kinetics, morphology, and 3D structure of air-grown MCS were characterized by brightfield, fluorescent, and scanning electron microscopy. MCS demonstrated a significant decrease in growth when the tumor-penetrating peptide iRGD and paclitaxel (PTX) were co-administered as compared to PTX alone. It was also found that when treated with both iRGD and PTX, A549 MCS exhibited an increase in apoptosis and decrease in clonogenic survival capacity in contrast to PTX treatment alone. This study demonstrated that co-administration of iRGD resulted in the improvement of the tumor penetration ability of PTX in an in vitro A549 3D MCS model. In addition, this is the first time a high-throughput air-grown lung cancer tumor spheroid model has been developed and evaluated. This article is protected by copyright. All rights reserved.

http://ift.tt/2vv74wH

Cancers, Vol. 9, Pages 100: Crosstalk between microRNA and DNA Methylation Offers Potential Biomarkers and Targeted Therapies in ALK-Positive Lymphomas

Cancers, Vol. 9, Pages 100: Crosstalk between microRNA and DNA Methylation Offers Potential Biomarkers and Targeted Therapies in ALK-Positive Lymphomas

Cancers doi: 10.3390/cancers9080100

Authors: Coralie Hoareau-Aveilla Fabienne Meggetto

The discovery of microRNA (miRNA) has provided new and powerful tools for studying the mechanism, diagnosis and treatment of human cancers. The down-regulation of tumor suppressive miRNA by hypermethylation of CpG island (CpG is shorthand for 5′-C-phosphate-G-3′, that is, cytosine and guanine separated by only one phosphate) is emerging as a common hallmark of cancer and appears to be involved in drug resistance. This review discusses the role of miRNA and DNA methylation in drug resistance mechanisms and highlights their potential as anti-cancer therapies in Anaplastic Lymphoma Kinase (ALK)-positive lymphomas. These are a sub-type of non-Hodgkin's lymphomas that predominantly affect children and young adults and are characterized by the expression of the nucleophosmin (NPM)/ALK chimeric oncoprotein. Dysregulation of miRNA expression and regulation has been shown to affect several signaling pathways in ALK carcinogenesis and control tumor growth, both in cell lines and mouse models. These data suggest that the modulation of DNA methylation and/or the expression of these miRNA could serve as new biomarkers and have potential therapeutic applications for ALK-positive malignancies.

http://ift.tt/2ulPYwc

Biomechanical behavior of titanium and zirconia frameworks for implant-supported full-arch fixed dental prosthesis

Abstract

Background

The biomechanical behavior of implant-supported titanium and zirconia full-arch fixed dental prosthesis (FAFDP) frameworks require further investigation.

Purpose

Strains transferred by implant-supported titanium (Ti) and zirconia (Zr) FAFDP frameworks were analyzed.

Materials and Methods

Maxillary 14-unit FAFDPs supported by 6 implants and 12-unit FAFDPs supported by 4 implants were tested. One-piece frameworks were fabricated by computer-aided design/computer-aided manufacturing. Four groups were divided (n = 3): G1, Ti-6 implants; G2, Zr-6 implants; G3, Ti-4 implants; G4, Zr-4 implants. A 250 N single-point load was applied on the second premolar. A three-dimensional digital image correlation system recorded framework and maxilla model surface deformation.

Results

The following strains (μS) averaged over the length of the second premolar were calculated: frameworks, G1 (321.82 ± 111.29), G2 (638.87 ± 108.64), G3 (377.77 ± 28.64), G4 (434.18 ± 132.21); model surface, G1 (473.99 ± 48.69), G2 (653.93 ± 45.26), G3 (1082.50 ± 71.14), G4 (1218.26 ± 230.37). Zirconia frameworks supported by 6 implants (G2) presented higher surface strains (P < .05). FAFDPs with titanium frameworks transferred significantly lower strains to the supporting maxilla when 6 implants were used (G1) (P < .05). Both framework materials transferred similar strains when supported by 4 implants (G3 and G4) (P > .05).

Conclusions

Zirconia frameworks supported by 6 implants showed higher strains. FAFDPs supported by 6 implants transferred less strains to the supporting maxilla, irrespective of framework material.

http://ift.tt/2faI2My

Gut microbiome composition is associated with cardiac disease in zoo-housed western lowland gorillas ( Gorilla gorilla gorilla )

Abstract

Cardiac disease is a leading cause of mortality in zoo-housed western lowland gorillas (Gorilla gorilla gorilla). The gut microbiome is associated with cardiac disease in humans and similarly the gut microbiome may be associated with cardiac diseases in close relatives of humans, such as gorillas. We assessed the relationship between cardiac disease and gut bacterial composition in eight zoo-housed male western lowland gorillas (N = 4 with and N = 4 without cardiac disease) utilizing 16S rRNA gene analysis on the Illumina MiSeq sequencing platform. We found bacterial composition differences between gorillas with and without cardiac disease. Bacterial operational taxonomic units from phyla Bacteroidetes, Spirochaetes, Proteobacteria and Firmicutes were significant indicators of cardiac disease. Our results suggest that further investigations between diet and cardiac disease could improve the management and health of zoo-housed populations of this endangered species.

http://ift.tt/2tnNM78

Diauxic growth of Fibrobacter succinogenes S85 on cellobiose and lactose

Abstract

Fibrobacter succinogenes rapidly colonizes the preruminant calf rumen and becomes a dominant cellulolytic bacterium in the rumen after weaning. Although F. succinogenes actively degrades cellulose in the rumen, it seems that there is no or little of its substrate, cellulose, in the rumen of preweaned calves. We thus evaluated the ability of F. succinogenes to utilize lactose, a main sugar of milk, with or without the presence of cellobiose. We grew F. succinogenes S85 on media containing 2.5% lactose combined with 0%–0.2% cellobiose or a medium with 0.2% cellobiose but without lactose. The generation times on the 0.2% cellobiose medium and the 2.5% lactose medium were 1.9 and 16.2 h, respectively. The bacterium showed rapid growth on cellobiose and diauxic growth on the lactose media containing 0.05%–0.2% cellobiose. Moreover, the production of β-galactosidase was low in the presence of 0.1%–0.2% cellobiose. Since the β-galactosidase contained a signal peptide and a Por secretion system C-terminal sorting domain, we speculate that the β-galactosidase would be secreted from the bacterial cells by the Por secretion system. Our data indicate the possibility that F. succinogenes could colonize preruminant calf rumen, consuming the lactose present in cow milk.

http://ift.tt/2tRTB0d

The role of multispecies social interactions in shaping Pseudomonas aeruginosa pathogenicity in the cystic fibrosis lung

Abstract

Pseudomonas aeruginosa is a major pathogen in the lungs of cystic fibrosis (CF) patients. However, it is now recognised that a diverse microbial community exists in the airways comprising aerobic and anaerobic bacteria as well as fungi and viruses. This rich soup of microorganisms provides ample opportunity for interspecies interactions, particularly when considering secreted compounds. Here, we discuss how P. aeruginosa-secreted products can have community-wide effects, with the potential to ultimately shape microbial community dynamics within the lung. We focus on three well-studied traits associated with worsening clinical outcome in CF: phenazines, siderophores and biofilm formation, and discuss how secretions can shape interactions between P. aeruginosa and other commonly encountered members of the lung microbiome: Staphylococcus aureus, the Burkholderia cepacia complex, Candida albicans and Aspergillus fumigatus. These interactions may shape the evolutionary trajectory of P. aeruginosa while providing new opportunities for therapeutic exploitation of the CF lung microbiome.

http://ift.tt/2sSYHX5

Salmonella enterica serovar Typhi siderophore production is elevated and Fur inactivation causes cell filamentation and attenuation in macrophages

Abstract

Salmonella enterica serovars Typhi and Typhimurium are two closely related bacteria causing different types of infection in humans. Iron acquisition is considered essential for virulence. Siderophores are important iron chelators and production of enterobactin and salmochelins by these serovars was quantified. Overall, Salmonella Typhi produced higher levels of siderophores than Salmonella Typhimurium. The role of the global regulator Fur, involved in iron homeostasis, present and conserved in both these serovars, was then investigated. Deletion of the fur gene led to distinct phenotypes in these serovars. Defective growth in iron-rich and iron-limiting conditions and formation of filamentous cells was only observed in the S. Typhi fur mutant. Furthermore, Fur was required for optimal motility in both serovars, but motility was more reduced for the fur mutant of S. Typhi compared to S. Typhimurium. During interaction with human-cultured macrophages, Fur was more important for S. Typhi, as the fur mutant had severe defects in uptake and survival. Globally, these results demonstrate that Fur differentially affects the physiology and the virulence phenotypes of the two strains and is more critical for S. Typhi growth, morphology, motility and interaction with host cells than it is for S. Typhimurium.

http://ift.tt/2sSVS8o

Autotrophic microbial arsenotrophy in arsenic-rich soda lakes

Abstract

A number of prokaryotes are capable of employing arsenic oxy-anions as either electron acceptors [arsenate; As(V)] or electron donors [arsenite; As(III)] to sustain arsenic-dependent growth ('arsenotrophy'). A subset of these microorganisms function as either chemoautotrophs or photoautotrophs, whereby they gain sufficient energy from their redox metabolism of arsenic to completely satisfy their carbon needs for growth by autotrophy, that is the fixation of inorganic carbon (e.g. HCO₃⁻) into their biomass. Here we review what has been learned of these processes by investigations we have undertaken in three soda lakes of the western USA and from the physiological characterizations of the relevant bacteria, which include the critical genes involved, such as respiratory arsenate reductase (arrA) and the discovery of its arsenite-oxidizing counterpart (arxA). When possible, we refer to instances of similar process occurring in other, less extreme ecosystems and by microbes other than haloalkaliphiles.

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Emerging Evidence for the Association Between Non-Alcoholic Fatty Liver Disease and Cardiac Arrhythmias.

http://ift.tt/2hpBuug

Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages

To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0-20 μg/kg/h) or intracerebroventricularly (0-1 μg/kg/h). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin. In this phase, leptin suppressed the rise in plasma TNF-α, and accelerated the recoveries from hypothermia and hypotension. Suppression of TNF-α was not accompanied by changes in other cytokines or prostaglandins. Leptin suppressed TNF-α when infused peripherally, but not when infused into the brain. Importantly, the leptin dose that suppressed TNF-α corresponded to the lowest dose that limited food consumption; this dose elevated plasma leptin within the physiological range (to 5.9 ng/ml). We then conducted in-vitro experiments to investigate whether an action of leptin on macrophages could parallel our in-vivo observations. The results revealed that, when sensitized by food deprivation, LPS-stimulated peritoneal macrophages can be inhibited by leptin at concentrations that are lower than those reported to promote cytokine release. It is concluded that physiological levels of leptin do not exert a pro-inflammatory effect, but rather an anti-inflammatory effect involving selective suppression of TNF-α via an action outside the brain. The mechanism of this effect might involve a previously unrecognized, suppressive action of leptin on macrophage subpopulations sensitized by food deprivation, but future studies are warranted.

http://ift.tt/2vkyLYD

Detection of Maltodextrin and Its Discrimination from Sucrose are Independent of the T1R2+T1R3 Heterodimer

Maltodextrins, such as Maltrin and Polycose, are glucose polymer mixtures of varying chain lengths that are palatable to rodents. Although glucose and other sugars activate the T1R2+T1R3 "sweet" taste receptor, recent evidence from T1R2 or T1R3 knockout (KO) mice suggests that maltodextrins, despite their glucose polymer composition, activate a separate receptor mechanism to generate a taste percept qualitatively distinguishable from that of sweeteners. However, explicit discrimination of maltodextrins from prototypical sweeteners has not yet been psychophysically tested in any murine model. Therefore, mice lacking T1R2+T1R3 and wild-type controls were tested in a two-response taste discrimination task to determine if maltodextrins are 1) detectable when both receptor subunits are absent, and 2) perceptually distinct from that of sucrose irrespective of viscosity, intensity, and hedonics. Most KO mice displayed similar Polycose sensitivity as controls. However, some KO mice were only sensitive to the higher Polycose concentrations, implicating potential allelic variation in the putative polysaccharide receptor or downstream pathways unmasked by the absence of T1R2+T1R3. Varied Maltrin and sucrose concentrations of approximately matched viscosities were then presented to render the oral somatosensory features, intensity, and hedonic value of the solutions irrelevant. While both genotypes competently discriminated Maltrin from sucrose, performance was apparently driven by the different orosensory percepts of the two stimuli in control mice and the presence of a Maltrin but not sucrose orosensory cue in KO mice. These data support the proposed presence of an orosensory receptor mechanism that gives rise to a qualitatively distinguishable sensation from that of sucrose.

http://ift.tt/2v1744q

Energy homeostasis in apolipoprotein AIV and cholecystokinin-deficient mice

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 weeks of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.

http://ift.tt/2vknQ12

Regulation of energy metabolism during social interactions in rainbow trout: A role for AMP-activated protein kinase

Rainbow trout (Oncorhynchus mykiss) confined in pairs form social hierarchies in which subordinate fish typically experience fasting and high circulating cortisol levels, resulting in low growth rates. The present study investigated the role of AMP-activated protein kinase (AMPK) in mediating metabolic adjustments associated with social status in rainbow trout. After 3 d of social interaction, liver AMPK activity in subordinate trout was significantly higher than that of dominant or sham (fish handled in the same fashion as paired fish but held individually) trout. Elevated liver AMPK activity in subordinate fish likely reflected a significantly higher ratio of phosphorylated AMPK (phospho-AMPK) to total AMPK protein, which was accompanied by significantly higher AMPKα1 relative mRNA abundance. Liver ATP and creatine phosphate (CrP) concentrations in subordinate fish also were elevated, perhaps as a result of AMPK activity. Sham fish that were fasted for 3 d exhibited effects parallel to those of subordinate fish, suggesting that low food intake was an important trigger of elevated AMPK activity in subordinate fish. Effects on white muscle appeared to be influenced by the physical activity associated with social interaction. Overall, muscle AMPK activity was significantly higher in dominant and subordinate trout than sham fish. Muscle phospho-AMPK:total AMPK protein abundance was highest in subordinate fish, while muscle AMPKα1 relative mRNA abundance was elevated by social dominance. Muscle ATP and CrP concentrations were high in dominant and subordinate fish at 6 h of interaction, decreasing significantly thereafter. Collectively, the findings of the present study support a role for AMPK in mediating the liver and white muscle metabolic adjustments associated with social hierarchy formation in rainbow trout.

http://ift.tt/2v175W2

Split-Hand Malformation in a 4-Year-Old Child

Split-hand deformity is one of the milder manifestations of a congenital disorder called split-hand/split-foot malformation. We present a case of a 4-year-old child with split-hand malformation in his left hand since birth. A median cleft was present in the affected hand with absence of the 3rd and 4th digits, giving rise to a characteristic lobster-claw appearance. Functionality of the affected hand was modestly impaired. As none of the close family members of the patient had similar limb malformations, the deformity was postulated to arise most likely from a de novo mutation. The patient was discharged after the parents were provided with genetic counseling.

http://ift.tt/2vr25wp

Pre-movement planning processes in people with congenital mirror movements

Congenital mirrormovements (CMM), a disorder characterised by unintentional mirroring of motor systems on the contralateral side of voluntary movements, usually of the hands and wrists, is regarded as a rare condition of human movement (Schott and Wyke, 1981); its prevalence is unknown. CMM can be difficult to detect due to its isolated occurrence in the distal portions of the upper limbs in most individuals affected, and in particular, because there are no other known comorbidities (Franz, 2003; Franz et al., 2015).

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ERCP (Ensuring Really Competent Practitioners). Action please

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Hereditary angioedema: an overlooked cause of recurrent abdominal pain and free peritoneal fluid

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The Distensibility Index as a biomarker for lower esophageal sphincter opening pressure

http://ift.tt/2ulxMTF

Portal Vein Thrombosis After Percutaneous Liver Biopsy

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“Migrated replacement PEG-tube leading to jejunoduodenal intussusception”

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An Unusual Porta Mass: EUS FNA solves the mystery

http://ift.tt/2ulQnyE

Photon and proton radiotherapy utilization in a population of over 100 million commercially insured patients

This is the largest and most geographically diverse description of RT utilization to date. Proton beam utilization remains low and has had little impact on overall utilization compared to IMRT. The utilization rate for pediatric patients remains low and the greatest change in RT use was the increase in IMRT for prostate cancer. Our findings indicate that overall utilization of proton therapy has been low and that its use has likely had little impact on national expenditures on cancer care in the current environment.

http://ift.tt/2vv0era

Gastric Medullary Carcinoma with Sporadic Mismatch Repair Deficiency and a TP53 R273C Mutation: An Unusual Case with Wild-Type BRAF

Medullary carcinoma has long been recognized as a subtype of colorectal cancer associated with microsatellite instability and Lynch syndrome. Gastric medullary carcinoma is a very rare neoplasm. We report a 67-year-old male who presented with a solitary gastric mass. Total gastrectomy revealed a well-demarcated, poorly differentiated carcinoma with an organoid growth pattern, pushing borders, and abundant peritumoral lymphocytic response. The prior cytology was cellular with immunohistochemical panel consistent with upper gastrointestinal/pancreaticobiliary origin. Overall, the histopathologic findings were consistent with gastric medullary carcinoma. A mismatch repair panel revealed a mismatch repair protein deficient tumor with loss of MLH1 and PMS2 expression. BRAF V600E immunostain (VE1) and BRAF molecular testing were negative, indicating a wild-type gene. Tumor sequencing of MLH1 demonstrated a wild-type gene, while our molecular panel identified TP53 c.817C>T (p.R273C) mutation. These findings were compatible with a sporadic tumor. Given that morphologically identical medullary tumors often occur in Lynch syndrome, it is possible that mismatch repair loss is an early event in sporadic tumors with p53 mutation being a late event. Despite having wild-type BRAF, this tumor is sporadic and unrelated to Lynch syndrome. This case report demonstrates that coordinate ancillary studies are needed to resolve sporadic versus hereditary rare tumors.

http://ift.tt/2vqIWum

Accelerating Wright-Fisher Forward Simulations on the Graphics Processing Unit

Forward Wright-Fisher simulations are powerful in their ability to model complex demography and selection scenarios, but suffer from slow execution on the CPU, thus limiting their usefulness. The single-locus Wright-Fisher forward algorithm is, however, exceedingly parallelizable, with many steps which are so-called embarrassingly parallel, consisting of a vast number of individual computations that are all independent of each other and thus capable of being performed concurrently. The rise of modern Graphics Processing Units (GPUs) and programming languages designed to leverage the inherent parallel nature of these processors have allowed researchers to dramatically speed up many programs that have such high arithmetic intensity and intrinsic concurrency. The presented GPU Optimized Wright-Fisher simulation, or GO Fish for short, can be used to simulate arbitrary selection and demographic scenarios while running over 250-fold faster than its serial counterpart on the CPU. Even modest GPU hardware can achieve an impressive speedup of over two orders of magnitude. With simulations so accelerated, one can not only do quick parametric bootstrapping of previously estimated parameters, but also use simulated results to calculate the likelihoods and summary statistics of demographic and selection models against real polymorphism data - all without restricting the demographic and selection scenarios that can be modeled or requiring approximations to the single-locus forward algorithm for efficiency. Further, as many of the parallel programming techniques used in this simulation can be applied to other computationally intensive algorithms important in population genetics, GO Fish serves as an exciting template for future research into accelerating computation in evolution. GO Fish is part of the Parallel PopGen Package available at: http://ift.tt/2vrgFUF

http://ift.tt/2u2agf9

Feasibility and safety of virtual-reality-based early neurocognitive stimulation in critically ill patients

Growing evidence suggests that critical illness often results in significant long-term neurocognitive impairments in one-third of survivors. Although these neurocognitive impairments are long-lasting and devas...

http://ift.tt/2v13veA

Assessment of sepsis-induced immunosuppression at ICU discharge and 6 months after ICU discharge

Increase in mortality and in recurrent infections in the year following ICU discharge continues in survivors of septic shock, even after total clinical recovery from the initial septic event and its complicati...

http://ift.tt/2vjuapS

A Cost Comparison for Telehealth Utilization in the Kidney Transplant Waitlist Evaluation Process.

Background: There have been limited publications on telehealth utilization in transplantation with no prior reports of telehealth-related costs for pretransplant evaluations. The aim of this study is to compare costs throughout the evaluation process for those patients assessed initially by telehealth to those seen in-person. Methods: All patients approved for kidney transplant waitlist evaluation at our center from March 2013 thru May 2016 with decisions were included in this study. Patients approved for evaluation were scheduled for either an initial telehealth or in-person visit, partly based on patient factors. Clinically-related and travel-related costs were calculated. Time estimates for patient time needed to complete visit, time from application approval to initial visit, and time from application approval to decision were obtained. Comparisons were made using t tests. Results: Thirty-nine months were included for 302 patients. All categories of clinically or travel-related costs were significantly less for the telehealth cohort (p

http://ift.tt/2u5Eou2

Refractory Vascular Rejection in a Hand Allograft in the Presence of Antibodies Against Angiotensin II (Type 1) Receptor.

No abstract available

http://ift.tt/2ulzWmh

Gender equity in Transplantation: A Report from the Women in Transplantation Workshop of the Transplantation Society of Australia and New Zealand.

The exponential growth of young talented females choosing science and medicine as their professional career over the past decade is substantial. Currently, more than half of the Australian medical doctoral graduates and early career researchers are comprised of women, but less than 20% of all academic professorial staff are female. The loss of female talent in the hierarchical ladder of Australian academia is a considerable waste of government investment, productivity and scientific innovation. Gender disparity in the professional workforce composition is even more striking within the field of transplantation. Women are grossly under-represented in leadership roles, with currently no female Heads of Unit in any of the Australian and New Zealand Transplanting centres. At the same time, there is also gender segregation with a greater concentration of women in lower-status academic position compared to their male counterparts. Given the extent and magnitude of the disparity, the Women In Transplantation Committee, a subcommittee of the Transplantation Society of Australia and New Zealand established a workshop comprising 8 female clinicians/scientists in transplantation. The key objectives were to i) identify potential gender equity issues within the transplantation workforce, ii) devise and implement potential strategies and interventions to address some of these challenges at a societal level, iii) set realistic and achievable goals to enhance and facility gender equality, equity and diversity in transplantation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2u5HVIN

Semi-Automatic Electronic Stent Register: a novel approach to preventing ureteric stents lost to follow up

Background

Ureteric stents are indispensable tools in modern urology; however, the risk of them not being followed-up once inserted poses medical and medico-legal risks. Stent registers are a common solution to mitigate this risk; however, manual registers are logistically challenging, especially for busy units.

Methods

Western Sydney Local Health District developed a novel Semi-Automatic Electronic Stent Register (SAESR) utilizing billing information to track stent insertions. To determine the utility of this system, an audit was conducted comparing the 6 months before the introduction of the register to the first 6 months of the register.

Results

In the first 6 months of the register, 457 stents were inserted. At the time of writing, two of these are severely delayed for removal, representing a rate of 0.4%. In the 6 months immediately preceding the introduction of the register, 497 stents were inserted, and six were either missed completely or severely delayed in their removal, representing a rate of 1.2%. A non-inferiority analysis found this to be no worse than the results achieved before the introduction of the register.

Conclusion

The SAESR allowed us to improve upon our better than expected rate of stents lost to follow up or severely delayed. We demonstrated non-inferiority in the rate of lost or severely delayed stents, and a number of other advantages including savings in personnel costs. The semi-automatic register represents an effective way of reducing the risk associated with a common urological procedure. We believe that this methodology could be implemented elsewhere.

http://ift.tt/2vk6WzA

Umbilical endometriosis: a potential encounter for general surgeons

http://ift.tt/2vjZowM

Plastic surgery ward round: can we do better?

http://ift.tt/2v0JvZK

Response to Re: The Australasian contribution to the development of neurosurgery in Singapore

http://ift.tt/2vkhdMp

Re-expansion pulmonary oedema: an unusual and unsettling complication

http://ift.tt/2vkhcIl

Issue information - TOC

http://ift.tt/2v0Yxi3

Medicine in small doses

http://ift.tt/2vktQal

General surgery's game changer and the unanswered question

http://ift.tt/2v0pWRq

Porocarcinoma: a rare cutaneous lesion

http://ift.tt/2vk8XMx

Renaming a section of the journal: Professional Skills for Surgeons

http://ift.tt/2vkozPN

Issue information - JEB

http://ift.tt/2v0SxpG

The Garnett Passe and Rodney Williams Memorial Foundation: 25 years on

http://ift.tt/2wncmqI

Re: Single-stage laparoscopic cholecystectomy and intraoperative endoscopic retrograde cholangiopancreatography: is this strategy feasible in Australia?

http://ift.tt/2vul0r3

Correction: The Effects of Vitamin D Supplementation on Glucose Metabolism and Lipid Profiles in Patients with Gestational Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Horm Metab Res
DOI: 10.1055/s-0037-1600933

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Correction: Maternal High-Fat Diet During Pregnancy and Lactation has Opposite Effects on Gonadal Expression of Leptin and Leptin Receptor in Rat Dams and Their Offspring

Horm Metab Res
DOI: 10.1055/s-0037-1600932

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2w83khT

Pancreatic gangliocytic paraganglioma harboring lymph node metastasis: a case report and literature review

Gangliocytic paraganglioma (GP) is a rare neuroendocrine neoplasm, which occurs mostly in the periampullary portion of the duodenum; the majority of the reported cases of duodenal GP has been of benign nature ...

http://ift.tt/2ulgoOE

Simultaneous primary invasive cutaneous aspergillosis in two preterm twins: case report and review of the literature

Primary invasive cutaneous aspergillosis is a rare fungal infection that occurs mostly in immunocompromised patients. Newborns of very low birth weight present a high risk for this type of infection due to an ...

http://ift.tt/2uldDgg

Lumbar puncture as possible cause of sudden paradoxical herniation in patient with previous decompressive craniectomy: report of two cases

Lumbar puncture is often used for the diagnosis and treatment of subarchnoid hemorrhage, infection of Cerebro-spinal Fluid (CSF), hydrocephalus in neurosurgery department patients. It is general that paradoxic...

http://ift.tt/2vquSRI

Improved anticancer drug response prediction in cell lines using matrix factorization with similarity regularization

Abstract

Background

Human cancer cell lines are used in research to study the biology of cancer and to test cancer treatments. Recently there are already some large panels of several hundred human cancer cell lines which are characterized with genomic and pharmacological data. The ability to predict drug responses using these pharmacogenomics data can facilitate the development of precision cancer medicines. Although several methods have been developed to address the drug response prediction, there are many challenges in obtaining accurate prediction.

Methods

Based on the fact that similar cell lines and similar drugs exhibit similar drug responses, we adopted a similarity-regularized matrix factorization (SRMF) method to predict anticancer drug responses of cell lines using chemical structures of drugs and baseline gene expression levels in cell lines. Specifically, chemical structural similarity of drugs and gene expression profile similarity of cell lines were considered as regularization terms, which were incorporated to the drug response matrix factorization model.

Results

We first demonstrated the effectiveness of SRMF using a set of simulation data and compared it with two typical similarity-based methods. Furthermore, we applied it to the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets, and performance of SRMF exceeds three state-of-the-art methods. We also applied SRMF to estimate the missing drug response values in the GDSC dataset. Even though SRMF does not specifically model mutation information, it could correctly predict drug-cancer gene associations that are consistent with existing data, and identify novel drug-cancer gene associations that are not found in existing data as well. SRMF can also aid in drug repositioning. The newly predicted drug responses of GDSC dataset suggest that mTOR inhibitor rapamycin was sensitive to non-small cell lung cancer (NSCLC), and expression of AK1RC3 and HINT1 may be adjunct markers of cell line sensitivity to rapamycin.

Conclusions

Our analysis showed that the proposed data integration method is able to improve the accuracy of prediction of anticancer drug responses in cell lines, and can identify consistent and novel drug-cancer gene associations compared to existing data as well as aid in drug repositioning.

http://ift.tt/2vqwACn

A comparative assessment of antiproliferative properties of resveratrol and ethanol leaf extract of Anogeissus leiocarpus (DC) Guill and Perr against HepG2 hepatocarcinoma cells

Epidemiological and experimental evidences have shown cancer as a leading cause of death worldwide. Although the folklore use of plants as a reliable source of health-restoring principles is well-documented, t...

http://ift.tt/2vqA4Vx

Estrogen-like and tissue-selective effects of 7-methoxycoumarin from Ficus umbellata (Moraceae): an in vitro and in vivo study

Ficus umbellata is a medicinal plant previously shown to endow estrogenic properties. Its major component was isolated and characterized as 7-methoxycoumarin (MC). Noteworthy, coumarin...

http://ift.tt/2u1L5cm

Erratum to: Severely deranged vital signs as triggers for acute treatment modifications on an intensive care unit in a low-income country

http://ift.tt/2v0BALU

In vivo and in vitro performance of a China-made hemodialysis machine: a multi-center prospective controlled study

To evaluate the in vivo and in vitro performance of a China-made dialysis machine (SWS-4000).

http://ift.tt/2vu86cB

Book Review: Further understanding of the human machine. The road to bioengineering

Max E. Valentinuzzi (editor)

http://ift.tt/2wnbJNT

Pros and cons: Free dental care in exchange for community service

The majority of low-income Michigan residents and dentists who participated in a program that provided free dental care in exchange for volunteer work said they liked it, and most patients felt their oral health had improved.

http://ift.tt/2ulnUt2

Why and how are we living longer?

New Findings

• What is the topic of this review?

  The reasons for the continuing increase in human life expectancy are examined in the light of progress in understanding the physiological basis of ageing. Prospects for further extending the health span – the period free of age-related disability and disease – are critically assessed.

• What advances does it highlight?

  No active programming directly causes ageing, which instead results as a side effect of how evolution optimises the physiological allocation of resources between growth, reproduction and maintenance. Under pressure of natural selection, there was insufficient priority in maintaining the body well enough that it could endure without progressive accumulation of multiple kinds of molecular and cellular damage.

Understanding human ageing is a major challenge for the physiological sciences. It is made all the more urgent by the survival of inreasing numbers of people to advanced old age and by a shift in the underlying causes of the continuing increase in life expectancy. The previous increase was caused almost entirely by the prevention of deaths in the early and middle years of life; a process that has seen such success that in developed countries there remains little scope for significant further increase from this cause. The more recent increase is driven by something new. We are reaching old age in generally better health, and it is the death rates at advanced ages that are now falling fast. At the same time, biology has established that there is almost certainly no fixed programme for ageing, which is caused instead by the lifelong accumulation of damage. It is becoming evident that the ageing process is much more malleable than we used to think. We need urgently to establish the factors that govern this malleability and to identify the interactions between, on the one hand, intrinsic biological processes that drive the many chronic diseases and disabilities for which age is by far the largest risk factor and, on the other hand, the social and lifestyle factors that influence our individual trajectories of health in old age. Ageing is no longer as mysterious and intractable a process as used to be thought, offering new opportunities for contributions from other branches of the physiological sciences.

http://ift.tt/2ul2Lit

An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection

Abstract

The clinical successes of immune checkpoint therapies for cancer make it important to identify mechanisms of resistance to anti-tumor immune responses. Numerous resistance mechanisms have been identified employing studies of single genes or pathways, thereby parsing the tumor microenvironment complexity into tractable pieces. However, this limits the potential for novel gene discovery to in vivo immune attack. To address this challenge, we developed an unbiased in vivo genome-wide RNAi screening platform that leverages host immune selection in strains of immune-competent and immunodeficient mice to select for tumor cell-based genes that regulate in vivo sensitivity to immune attack. Utilizing this approach in a syngeneic triple-negative breast cancer (TNBC) model, we identified 709 genes that selectively regulated adaptive anti-tumor immunity and focused on five genes (CD47, TGFβ1, Sgpl1, Tex9 and Pex14) with the greatest impact. We validated the mechanisms that underlie the immune-related effects of expression of these genes in different TNBC lines, as well as tandem synergistic interactions. Furthermore, we demonstrate the impact of different genes with previously unknown immune functions (Tex9 and Pex14) on anti-tumor immunity. Thus, this innovative approach has utility in identifying unknown tumor-specific regulators of immune recognition in multiple settings to reveal novel targets for future immunotherapies.

http://ift.tt/2uWUapJ

An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection

Abstract

The clinical successes of immune checkpoint therapies for cancer make it important to identify mechanisms of resistance to anti-tumor immune responses. Numerous resistance mechanisms have been identified employing studies of single genes or pathways, thereby parsing the tumor microenvironment complexity into tractable pieces. However, this limits the potential for novel gene discovery to in vivo immune attack. To address this challenge, we developed an unbiased in vivo genome-wide RNAi screening platform that leverages host immune selection in strains of immune-competent and immunodeficient mice to select for tumor cell-based genes that regulate in vivo sensitivity to immune attack. Utilizing this approach in a syngeneic triple-negative breast cancer (TNBC) model, we identified 709 genes that selectively regulated adaptive anti-tumor immunity and focused on five genes (CD47, TGFβ1, Sgpl1, Tex9 and Pex14) with the greatest impact. We validated the mechanisms that underlie the immune-related effects of expression of these genes in different TNBC lines, as well as tandem synergistic interactions. Furthermore, we demonstrate the impact of different genes with previously unknown immune functions (Tex9 and Pex14) on anti-tumor immunity. Thus, this innovative approach has utility in identifying unknown tumor-specific regulators of immune recognition in multiple settings to reveal novel targets for future immunotherapies.

http://ift.tt/2uWUapJ

Preoperative endoscopic titanium clip placement facilitates intraoperative localization of early-stage esophageal cancer or severe dysplasia

Abstract

Background

Accurate intraoperative localization of esophageal lesions is essential for successful surgical resection. We tested whether preoperative endoscopic placement of titanium clips could facilitate intraoperative localization of early-stage esophageal cancer or severe dysplasia.

Methods

A prospective randomized clinical trial was performed between May 2012 and July 2014. All enrolled patients received preoperative endoscopy and esophageal endoscopic ultrasound, as well as pathological study on the biopsy specimen, to confirm early stage esophageal cancer or severe dysplasia. One day before the surgical operation, patients in the experimental group received the preoperative endoscopic titanium labeling of esophageal lesions. Then, during the surgical operation, palpitation of titanium clips was used to localize the lesions in these patients. In patients in the control group, palpitation of nodules or esophageal wall mucosal thickening, together with the consideration of the results from preoperative endoscopic and ultrasound studies, was applied to estimate the location of the esophageal lesions. Study outcomes included the proportions of patients having successful intraoperative pre-resection lesion localization, post-esophagectomy lesion visualization, negative upper surgical margin, change of surgical approaches, and positive postoperative pathological diagnosis.

Results

A total of 27 patients were enrolled into the study, with 14 in the experimental group and 13 in the control group. Compared to the patients in the control group, a higher proportion of patients in the experimental group had statistically significant successful intraoperative esophageal lesion localization (100 versus 15.3% in the experimental versus control group).

Conclusions

Preoperative endoscopic titanium clip placement could facilitate intraoperative localization of early-stage esophageal cancer or severe dysplasia.

Trial registration

Current study was registered in Chinese Clinical Trial Registry and World Health Organization International Clinical Trials Registry Platform, ChiCTR-INR-17010949. Registered 22 March 2017, retrospectively registered.

http://ift.tt/2u5eVkw

Succinate dehydrogenase deficiency in a PDGFRA mutated GIST

Abstract

Background

Most gastrointestinal stromal tumors (GISTs) harbor mutually exclusive gain of function mutations in the receptor tyrosine kinase (RTK) KIT (70–80%) or in the related receptor PDGFRA (~10%). These GISTs generally respond well to therapy with the RTK inhibitor imatinib mesylate (IM), although initial response is genotype-dependent. An alternate mechanism leading to GIST oncogenesis is deficiency in the succinate dehydrogenase (SDH) enzyme complex resulting from genetic or epigenetic inactivation of one of the four SDH subunit genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHX). SDH loss of function is generally seen only in GIST lacking RTK mutations, and SDH-deficient GIST respond poorly to imatinib therapy.

Methods

Tumor and normal DNA from a GIST case carrying the IM-resistant PDGFRA D842V mutation was analyzed by whole exome sequencing (WES) to identify additional potential targets for therapy. The tumors analyzed were separate recurrences following progression on imatinib, sunitinib, and the experimental PDGFRA inhibitor crenolanib. Tumor sections from the GIST case and a panel of ~75 additional GISTs were subjected to immunohistochemistry (IHC) for the SDHB subunit.

Results

Surprisingly, a somatic, loss of function mutation in exon 4 of the SDHB subunit gene (c.291_292delCT, p.I97Mfs*21) was identified in both tumors. Sanger sequencing confirmed the presence of this inactivating mutation, and IHC for the SDHB subunit demonstrated that these tumors were SDH-deficient. IHC for the SDHB subunit across a panel of ~75 GIST cases failed to detect SDH deficiency in other GISTs with RTK mutations.

Conclusions

This is the first reported case of a PDGFRA mutant GIST exhibiting SDH-deficiency. A brief discussion of the relevant GIST literature is included.

http://ift.tt/2v0jZnz

Neural Circuitry That Mediates Behavior Governing the Tradeoffs Between Survival and Reproduction in Caenorhabditis elegans

Abstract

In all outcrossing sexual species there is a mechanism that brings two parents together. For animals, this reproductive requirement may at times conflict with other needs, such as foraging for food. This tension has been studied using the tiny (1 mm) nematode worm, Caenorhabditis elegans. In a trade off between certainty of survival and possibility of reproduction, the C. elegans male will abandon a food patch lacking mates and explore its environment to find one where mates are present. A quantitative behavioral assay has been used to study the behavioral mechanism of mate searching and nutritional, sexual, and neurohormonal pathways that influence the underlying drive state. Taking advantage of the known connectivity of the C. elegans nervous system, neural pathways have been identified that influence the male's behavior in the presence of food with and without mates.

http://ift.tt/2wmxqNV

Inferring Arthropod Phylogeny: Fossils and their Interaction with Other Data Sources

Abstract

The past five years have witnessed a renewed interest in discrete morphological characters as a source of phylogenetic data, after a decade or more of their dismissal in favor of molecules-only approaches. This has stemmed in large part from refinements in total evidence dating, which requires morphological character matrices for extinct and extant taxa as well as temporal data from fossils. The unique contribution of palaeontology is stem groups, revealing the sequence of character acquisition in long-branch terminals and otherwise unknown character combinations and/or character states in extinct phenotypes. The origin of mandibles exemplifies an integrative approach to analyzing the origin of a complex phenotypic feature using molecular, anatomical, and palaeontological data: (1) transcriptomics defends a single origin of mandibles in the clade Mandibulata; (2) Cambrian fossils inform on morphological changes in the gnathal appendages in the mandibulate stem group; (3) molecular dating, calibrated by fossils in novel modes of exceptional preservation, draws the mandibulate crown group into the early Cambrian and constrains the timing of character evolution; and (4) functional studies in extant taxa identify genes that specify mandibular identity from a maxilla and, ultimately, a trunk limb-like precursor, as predicted by the serial similarity of these appendages in Cambrian stem-group fossils.

http://ift.tt/2vug7OF

Physiological and Biomechanical Mechanisms of Distance Specific Human Running Performance

Abstract

Running events range from 60-m sprints to ultra-marathons covering 100 miles or more, which presents an interesting diversity in terms of the parameters for successful performance. Here, we review the physiological and biomechanical variations underlying elite human running performance in sprint to ultramarathon distances. Maximal running speeds observed in sprint disciplines are achieved by high vertical ground reaction forces applied over short contact times. To create this high force output, sprint events rely heavily on anaerobic metabolism, as well as a high number and large cross-sectional area of type II fibers in the leg muscles. Middle distance running performance is characterized by intermediates of biomechanical and physiological parameters, with the possibility of unique combinations of each leading to high-level performance. The relatively fast velocities in mid-distance events require a high mechanical power output, though ground reaction forces are less than in sprinting. Elite mid-distance runners exhibit local muscle adaptations that, along with a large anaerobic capacity, provide the ability to generate a high power output. Aerobic capacity starts to become an important aspect of performance in middle distance events, especially as distance increases. In distance running events, V˙O_2max is an important determinant of performance, but is relatively homogeneous in elite runners. V˙O₂ and velocity at lactate threshold have been shown to be superior predictors of elite distance running performance. Ultramarathons are relatively new running events, as such, less is known about physiological and biomechanical parameters that underlie ultra-marathon performance. However, it is clear that performance in these events is related to aerobic capacity, fuel utilization, and fatigue resistance.

http://ift.tt/2wmLuXH

Horizontal Whole Mount: A Novel Processing and Imaging Protocol for Thick, Three-dimensional Tissue Cross-sections of Skin

This work presents a novel processing and imaging protocol for thick, three-dimensional tissue cross-section analysis that enables the full exploitation of confocal imaging modalities. This protocol preserves antigenicity and represents a robust system to analyze skin histology and potentially other tissue types.

http://ift.tt/2uX2E0a

Colorectal cancer in a patient with intestinal schistosomiasis: a case report from Kilimanjaro Christian Medical Center Northern Zone Tanzania

Abstract

Background

Colorectal cancer associated with chronic intestinal schistosomiasis has been linked with the chronic inflammation as a result of schistosomal ova deposition in the submucosal layer of the intestine. Among all species Schistosoma japonicum has been more linked to development of colorectal cancer as compared to Schistosoma mansoni due to absence of population-based studies to support the association. Despite the weak evidence, some cases have been reported associating S. mansoni with development of colorectal cancer.

Case Presentation

We report a patient who presented to us as a case of intestinal obstruction and found to have a constrictive lesion at the sigmoid colon at laparotomy, then later found to have colorectal cancer with deposited S. mansoni ova at histology.

Conclusion

Given the known late complications of schistosomiasis, and as S. mansoni is endemic in some parts of Tanzania, epidemiological studies are recommended to shed more light on its association with colorectal cancer.

http://ift.tt/2hnKJLk

Examining the Feasibility and Utility of Estimating Partial Expected Value of Perfect Information (via a Nonparametric Approach) as Part of the Reimbursement Decision-Making Process in Ireland: Application to Drugs for Cancer

Abstract

Background

In Ireland, all new drugs for which reimbursement by the healthcare payer is sought undergo a health technology assessment by the National Centre for Pharmacoeconomics. The National Centre for Pharmacoeconomics estimate expected value of perfect information but not partial expected value of perfect information (owing to computational expense associated with typical methodologies).

Objective

The objective of this study was to examine the feasibility and utility of estimating partial expected value of perfect information via a computationally efficient, non-parametric regression approach.

Methods

This was a retrospective analysis of evaluations on drugs for cancer that had been submitted to the National Centre for Pharmacoeconomics (January 2010 to December 2014 inclusive). Drugs were excluded if cost effective at the submitted price. Drugs were excluded if concerns existed regarding the validity of the applicants' submission or if cost-effectiveness model functionality did not allow required modifications to be made. For each included drug (n = 14), value of information was estimated at the final reimbursement price, at a threshold equivalent to the incremental cost-effectiveness ratio at that price. The expected value of perfect information was estimated from probabilistic analysis. Partial expected value of perfect information was estimated via a non-parametric approach. Input parameters with a population value at least €1 million were identified as potential targets for research.

Results

All partial estimates were determined within minutes. Thirty parameters (across nine models) each had a value of at least €1 million. These were categorised. Collectively, survival analysis parameters were valued at €19.32 million, health state utility parameters at €15.81 million and parameters associated with the cost of treating adverse effects at €6.64 million. Those associated with drug acquisition costs and with the cost of care were valued at €6.51 million and €5.71 million, respectively.

Conclusion

This research demonstrates that the estimation of partial expected value of perfect information via this computationally inexpensive approach could be considered feasible as part of the health technology assessment process for reimbursement purposes within the Irish healthcare system. It might be a useful tool in prioritising future research to decrease decision uncertainty.

http://ift.tt/2u0OHv7

Quantifying Infra-slow Dynamics of Spectral Power and Heart Rate in Sleeping Mice

Here, we present experimental and analytical procedures to describe the temporal dynamics of the neural and cardiac variables of non-REM sleep in mice, which modulate sleep responsiveness to acoustic stimuli.

http://ift.tt/2uWkTms

Live-cell calcium imaging of adherent and non-adherent GL261 cells reveals phenotype-dependent differences in drug responses

Abstract

Background

The tumor-derived GL261 cell line is used as a model for studying glioblastoma and other high-grade gliomas, and can be cultured adherently or as free-floating aggregates known as neurospheres. These different culture conditions give rise to distinct phenotypes, with increased tumorigenicity displayed by neurosphere-cultured cells. An important technique for understanding GL261 pathobiology is live cell fluorescent imaging of intracellular calcium. However, live cell imaging of GL261 neurospheres presents a technical challenge, as experimental manipulations where drugs are added to the extracellular media cause the cells to move during analysis. Here we present a method to immobilize GL261 neurospheres with low melting point agarose for calcium imaging using the fluorescent calcium sensor fura-2.

Methods

GL261 cells were obtained from the NCI-Frederick Cancer Research Tumor Repository and cultured as adherent cells or induced to form neurospheres by placing freshly trypsinized cells into serum-free media containing fibroblast growth factor 2, epidermal growth factor, and B-27 supplement. Prior to experiments, adherent cells were loaded with fura-2 and cultured on 8-well chamber slides. Non-adherent neurospheres were first loaded with fura-2, placed in droplets onto an 8-well chamber slide, and finally covered with a thin layer of low melting point agarose to immobilize the cells. Ratiometric pseudocolored images were obtained during treatment with ATP, capsaicin, or vehicle control. Cells were marked as responsive if fluorescence levels increased more than 30% above baseline. Differences between treatment groups were tested using Student's t-tests and one-way ANOVA.

Results

We found that cellular responses to pharmacological treatments differ based on cellular phenotype. Adherent cells and neurospheres both responded to ATP with a rise in intracellular calcium. Notably, capsaicin treatment led to robust responses in GL261 neurospheres but not adherent cells.

Conclusions

We demonstrate the use of low melting point agarose for immobilizing GL261 cells, a method that is broadly applicable to any cell type cultured in suspension, including acutely trypsinized cells and primary tumor cells. Our results indicate that it is important to consider GL261 phenotype (adherent or neurosphere) when interpreting data regarding physiological responses to experimental compounds.

http://ift.tt/2uZW6fu

Lymphocyte count or percentage: which can better predict the prognosis of advanced cancer patients following palliative care?

Abstract

Background

The lymphocytes played an important role in the natural history of cancer. The aim of this study was to explore the prognostic value of lymphocyte count and percentage for survival in advanced cancer patients receiving palliative care.

Methods

A retrospective review of clinicopathological data from 378 consecutive advanced cancer patients and 106 extended follow-up patients treated with palliative care was conducted. Kaplan–Meier curves and multivariate cox regression analyses were used to evaluate the relationships of peripheral lymphocyte count (LC) and lymphocyte to white blood cell ratio (LWR) with overall survival (OS).

Results

The median values for pretreatment LC and LWR were 1.1 (IQR, 0.8 ~ 1.5 × 10⁹/L) and 0.138 (IQR, 0.086 ~ 0.208). The median survival times across LWR quartiles were 19, 47, 79, and 101 days (P < 0.001). Multivariate analysis indicated that patients in the highest quartiles of LC and LWR had an HR of 1.082 (95% CI 0.777 ~ 1.506, P = 0.642) and 0.466 (95% CI 0.328 ~ 0.661, P < 0.001), respectively, compared with patients in the lowest quartiles. Furthermore, only the dynamic changes of LWR were confirmed as an independent prognostic factor for overall survival during the follow-up (HR = 0.396, 95% CI 0.243 ~ 0.668; P = 0.001), as were primary tumor site and ECOG. No effect was observed for the dynamic changes of LC.

Conclusions

Our findings demonstrate that measurement of the dynamic changes of LWR prior to treatment and during follow-up may represent a simple and new powerful prognostic factor for patients with advanced cancer, unlike measurement of LC. As a bedside marker of immune status, the prognostic role of LWR should be further evaluated in prospective studies.

http://ift.tt/2vjspIX

Hybrid clone cells derived from human breast epithelial cells and human breast cancer cells exhibit properties of cancer stem/initiating cells

Abstract

Background

The biological phenomenon of cell fusion has been associated with cancer progression since it was determined that normal cell × tumor cell fusion-derived hybrid cells could exhibit novel properties, such as enhanced metastatogenic capacity or increased drug resistance, and even as a mechanism that could give rise to cancer stem/initiating cells (CS/ICs). CS/ICs have been proposed as cancer cells that exhibit stem cell properties, including the ability to (re)initiate tumor growth.

Methods

Five M13HS hybrid clone cells, which originated from spontaneous cell fusion events between M13SV1-EGFP-Neo human breast epithelial cells and HS578T-Hyg human breast cancer cells, and their parental cells were analyzed for expression of stemness and EMT-related marker proteins by Western blot analysis and confocal laser scanning microscopy. The frequency of ALDH1-positive cells was determined by flow cytometry using AldeRed fluorescent dye. Concurrently, the cells' colony forming capabilities as well as the cells' abilities to form mammospheres were investigated. The migratory activity of the cells was analyzed using a 3D collagen matrix migration assay.

Results

M13HS hybrid clone cells co-expressed SOX9, SLUG, CK8 and CK14, which were differently expressed in parental cells. A variation in the ALDH1-positive putative stem cell population was observed among the five hybrids ranging from 1.44% (M13HS-7) to 13.68% (M13HS-2). In comparison to the parental cells, all five hybrid clone cells possessed increased but also unique colony formation and mammosphere formation capabilities. M13HS-4 hybrid clone cells exhibited the highest colony formation capacity and second highest mammosphere formation capacity of all hybrids, whereby the mean diameter of the mammospheres was comparable to the parental cells. In contrast, the largest mammospheres originated from the M13HS-2 hybrid clone cells, whereas these cells' mammosphere formation capacity was comparable to the parental breast cancer cells. All M13HS hybrid clones exhibited a mesenchymal phenotype and, with the exception of one hybrid clone, responded to EGF with an increased migratory activity.

Conclusion

Fusion of human breast epithelial cells and human breast cancer cells can give rise to hybrid clone cells that possess certain CS/IC properties, suggesting that cell fusion might be a mechanism underlying how tumor cells exhibiting a CS/IC phenotype could originate.

http://ift.tt/2uZokau

Retinotopic Organization of Scene Areas in Macaque Inferior Temporal Cortex

Primates have specialized domains in inferior temporal (IT) cortex that are responsive to particular image categories. Though IT traditionally has been regarded as lacking retinotopy, several recent studies in monkeys have shown that retinotopic maps extend to face patches along the lower bank of the superior temporal sulcus (STS) and neighboring regions of IT cortex. Here, we used fMRI to map the retinotopic organization of medial ventral temporal cortex in four monkeys (2 male and 2 female). We confirm the presence of visual field maps within and around the lower bank of the STS and extend these prior findings to scene-selective cortex in the ventral-most regions of IT. Within the occipitotemporal sulcus (OTS), we identified two retinotopic areas, OTS1 and OTS2. The polar angle representation of OTS2 was a mirror reversal of the OTS1 representation. These regions contained representations of the contralateral periphery and were selectively active for scene versus face, body, or object images. The extent of this retinotopy parallels that in humans and shows that the organization of the scene network is preserved across primate species. In addition retinotopic maps were identified in dorsal extrastriate, posterior parietal, and frontal cortex as well as the thalamus, including both the lateral geniculate nucleus and pulvinar. Together, it appears that most, if not all, of the macaque visual system contains organized representations of visual space.

SIGNIFICANCE STATEMENT Primates have specialized domains in inferior temporal (IT) cortex that are responsive to particular image categories. Though retinotopic maps are considered a fundamental organizing principle of posterior visual cortex, IT traditionally has been regarded as lacking retinotopy. Recent imaging studies have demonstrated the presence of several visual field maps within the lateral IT. Using neuroimaging, we found multiple representations of visual space within ventral IT cortex of macaques that included scene-selective cortex. Scene domains were biased toward the peripheral visual field. These data demonstrate the prevalence of visual field maps throughout the primate visual system, including late stages in the ventral visual hierarchy, and support the idea that domains representing different categories are biased toward different parts of the visual field.

http://ift.tt/2u0lOiG

The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release

Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation.

SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these cells remains poorly understood. To provide clarity to this circuit, we made electrophysiological recordings from mouse brain slices and found that AgRP neurons do not contribute spontaneously released GABA onto POMC neurons, although when activated with channelrhodopsin AgRP neurons inhibit POMC neurons through GABA-mediated transmission. These findings indicate that the relevance of AgRP to POMC neuron GABA connectivity depends on the state of AgRP neuron activity and suggest that different types of transmitter release should be considered when circuit mapping.

http://ift.tt/2vp1pYv

Enhanced Excitatory Connectivity and Disturbed Sound Processing in the Auditory Brainstem of Fragile X Mice

Hypersensitivity to sounds is one of the prevalent symptoms in individuals with Fragile X syndrome (FXS). It manifests behaviorally early during development and is often used as a landmark for treatment efficacy. However, the physiological mechanisms and circuit-level alterations underlying this aberrant behavior remain poorly understood. Using the mouse model of FXS (Fmr1 KO), we demonstrate that functional maturation of auditory brainstem synapses is impaired in FXS. Fmr1 KO mice showed a greatly enhanced excitatory synaptic input strength in neurons of the lateral superior olive (LSO), a prominent auditory brainstem nucleus, which integrates ipsilateral excitation and contralateral inhibition to compute interaural level differences. Conversely, the glycinergic, inhibitory input properties remained unaffected. The enhanced excitation was the result of an increased number of cochlear nucleus fibers converging onto one LSO neuron, without changing individual synapse properties. Concomitantly, immunolabeling of excitatory ending markers revealed an increase in the immunolabeled area, supporting abnormally elevated excitatory input numbers. Intrinsic firing properties were only slightly enhanced. In line with the disturbed development of LSO circuitry, auditory processing was also affected in adult Fmr1 KO mice as shown with single-unit recordings of LSO neurons. These processing deficits manifested as an increase in firing rate, a broadening of the frequency response area, and a shift in the interaural level difference function of LSO neurons. Our results suggest that this aberrant synaptic development of auditory brainstem circuits might be a major underlying cause of the auditory processing deficits in FXS.

SIGNIFICANCE STATEMENT Fragile X Syndrome (FXS) is the most common inheritable form of intellectual impairment, including autism. A core symptom of FXS is extreme sensitivity to loud sounds. This is one reason why individuals with FXS tend to avoid social interactions, contributing to their isolation. Here, a mouse model of FXS was used to investigate the auditory brainstem where basic sound information is first processed. Loss of the Fragile X mental retardation protein leads to excessive excitatory compared with inhibitory inputs in neurons extracting information about sound levels. Functionally, this elevated excitation results in increased firing rates, and abnormal coding of frequency and binaural sound localization cues. Imbalanced early-stage sound level processing could partially explain the auditory processing deficits in FXS.

http://ift.tt/2u0aoMa

Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia

Isolated focal dystonia is a debilitating movement disorder of unknown pathophysiology. Early studies in focal dystonias have pointed to segregated changes in brain activity and connectivity. Only recently has the notion that dystonia pathophysiology may lie in abnormalities of large-scale brain networks appeared in the literature. Here, we outline a novel concept of functional connectome-wide alterations that are linked to dystonia phenotype and genotype. Using a neural community detection strategy and graph theoretical analysis of functional MRI data in human patients with the laryngeal form of dystonia (LD) and healthy controls (both males and females), we identified an abnormally widespread hub formation in LD, which particularly affected the primary sensorimotor and parietal cortices and thalamus. Left thalamic regions formed a delineated functional community that highlighted differences in network topology between LD patients with and without family history of dystonia. Conversely, marked differences in the topological organization of parietal regions were found between phenotypically different forms of LD. The interface between sporadic genotype and adductor phenotype of LD yielded four functional communities that were primarily governed by intramodular hub regions. Conversely, the interface between familial genotype and abductor phenotype was associated with numerous long-range hub nodes and an abnormal integration of left thalamus and basal ganglia. Our findings provide the first comprehensive atlas of functional topology across different phenotypes and genotypes of focal dystonia. As such, this study constitutes an important step toward defining dystonia as a large-scale network disorder, understanding its causative pathophysiology, and identifying disorder-specific markers.

SIGNIFICANCE STATEMENT The architecture of the functional connectome in focal dystonia was analyzed in a large population of patients with laryngeal dystonia. Breaking with the empirical concept of dystonia as a basal ganglia disorder, we discovered large-scale alterations of neural communities that are significantly influenced by the disorder's clinical phenotype and genotype.

http://ift.tt/2u07FCn

Mesoscale Mapping of Mouse Cortex Reveals Frequency-Dependent Cycling between Distinct Macroscale Functional Modules

Connectivity mapping based on resting-state activity in mice has revealed functional motifs of correlated activity. However, the rules by which motifs organize into larger functional modules that lead to hemisphere wide spatial-temporal activity sequences is not clear. We explore cortical activity parcellation in head-fixed, quiet awake GCaMP6 mice from both sexes by using mesoscopic calcium imaging. Spectral decomposition of spontaneous cortical activity revealed the presence of two dominant frequency modes (<1 and ~3 Hz), each of them associated with a unique spatial signature of cortical macro-parcellation not predicted by classical cytoarchitectonic definitions of cortical areas. Based on assessment of 0.1–1 Hz activity, we define two macro-organizing principles: the first being a rotating polymodal-association pinwheel structure around which activity flows sequentially from visual to barrel then to hindlimb somatosensory; the second principle is correlated activity symmetry planes that exist on many levels within a single domain such as intrahemispheric reflections of sensory and motor cortices. In contrast, higher frequency activity >1 Hz yielded two larger clusters of coactivated areas with an enlarged default mode network-like posterior region. We suggest that the apparent constrained structure for intra-areal cortical activity flow could be exploited in future efforts to normalize activity in diseases of the nervous system.

SIGNIFICANCE STATEMENT Increasingly, functional connectivity mapping of spontaneous activity is being used to reveal the organization of the brain. However, because the brain operates across multiple space and time domains a more detailed understanding of this organization is necessary. We used in vivo wide-field calcium imaging of the indicator GCaMP6 in head-fixed, awake mice to characterize the organization of spontaneous cortical activity at different spatiotemporal scales. Correlation analysis defines the presence of two to three superclusters of activity that span traditionally defined functional territories and were frequency dependent. This work helps define the rules for how different cortical areas interact in time and space. We provide a framework necessary for future studies that explore functional reorganization of brain circuits in disease models.

http://ift.tt/2vppWMM

Identified Serotonergic Modulatory Neurons Have Heterogeneous Synaptic Connectivity within the Olfactory System of Drosophila

Modulatory neurons project widely throughout the brain, dynamically altering network processing based on an animal's physiological state. The connectivity of individual modulatory neurons can be complex, as they often receive input from a variety of sources and are diverse in their physiology, structure, and gene expression profiles. To establish basic principles about the connectivity of individual modulatory neurons, we examined a pair of identified neurons, the "contralaterally projecting, serotonin-immunoreactive deutocerebral neurons" (CSDns), within the olfactory system of Drosophila. Specifically, we determined the neuronal classes providing synaptic input to the CSDns within the antennal lobe (AL), an olfactory network targeted by the CSDns, and the degree to which CSDn active zones are uniformly distributed across the AL. Using anatomical techniques, we found that the CSDns received glomerulus-specific input from olfactory receptor neurons (ORNs) and projection neurons (PNs), and networkwide input from local interneurons (LNs). Furthermore, we quantified the number of CSDn active zones in each glomerulus and found that CSDn output is not uniform, but rather heterogeneous, across glomeruli and stereotyped from animal to animal. Finally, we demonstrate that the CSDns synapse broadly onto LNs and PNs throughout the AL but do not synapse upon ORNs. Our results demonstrate that modulatory neurons do not necessarily provide purely top-down input but rather receive neuron class-specific input from the networks that they target, and that even a two cell modulatory network has highly heterogeneous, yet stereotyped, pattern of connectivity.

SIGNIFICANCE STATEMENT Modulatory neurons often project broadly throughout the brain to alter processing based on physiological state. However, the connectivity of individual modulatory neurons to their target networks is not well understood, as modulatory neuron populations are heterogeneous in their physiology, morphology, and gene expression. In this study, we use a pair of identified serotonergic neurons within the Drosophila olfactory system as a model to establish a framework for modulatory neuron connectivity. We demonstrate that individual modulatory neurons can integrate neuron class-specific input from their target network, which is often nonreciprocal. Additionally, modulatory neuron output can be stereotyped, yet nonuniform, across network regions. Our results provide new insight into the synaptic relationships that underlie network function of modulatory neurons.

http://ift.tt/2u07OWr

Leptin promotes the migration and invasion of breast cancer cells by upregulating ACAT2

Abstract

Background

Previously, it has been shown that obesity may be considered as a risk factor for breast cancer in postmenopausal women. Leptin, a hormone whose level is elevated in obesity, has been suggested to be involved in the development of breast cancer, and univariate survival analyses have shown that over-expression of ACAT2, an enzyme that is involved in the production of cholesteryl esters, may be associated with a poor prognosis. Here, we aimed to investigate the effect of leptin on the proliferation, migration and invasion of breast cancer cells, as well as to elucidate its underlying mode of action.

Methods

Gene expression changes in leptin treated breast cancer-derived MCF-7, T47D and BT474 cells were assessed using PCR array, qRT-PCR and Western blot analyses. The expression patterns of Ob-R (leptin receptor) and ACAT2 in breast cancer cells and primary breast cancer tissue samples were analyzed using immunofluorescence and immunohistochemistry, respectively. Leptin-induced proliferation of breast cancer cells was assessed using a CCK8 assay, and scratch wound and Transwell assays were used to assess breast cancer cell invasion and migration.

Results

We found that, among the genes tested, ACAT2 expression exhibited the most significant changes in the leptin treated cells. In addition, we found that inhibition of ACAT2 expression using pyripyropene A (PPPA) or siRNA-mediated gene silencing significantly decreased leptin-induced proliferation, migration and invasion of MCF-7 and T47D cells. Subsequent Western blot analyses strongly indicated that the PI3K/AKT/SREBP2 signaling pathway was involved in leptin-induced ACAT2 upregulation in both MCF-7 and T47D cells. Finally, through the analysis of primary breast cancer tissue samples we found that ACAT2 may affect cancer progression through activation of the Ob-R.

Conclusions

Our data indicate that leptin may enhance the proliferation, migration and invasion of breast cancer cells via ACAT2 up-regulation through the PI3K/AKT/SREBP2 signaling pathway. Therefore, the leptin/ACAT2 axis may represent an attractive therapeutic target for breast cancer, particularly in postmenopausal and/or obese women.

http://ift.tt/2w6GWWj

Benefits of marriage on relative and conditional relative cancer survival differ between males and females in the USA

Abstract

Purpose

The purpose of the paper is to assess the influence of marital status on conditional relative survival of cancer according to sex.

Methods

Analyses involved 779,978 males and 1,032,868 females diagnosed with 1 of 13 cancer types between 2000 and 2008, and followed through 2013. Data are from the Surveillance, Epidemiology, and End Results (SEER) Program. Regression models were adjusted for age, sex, race, and tumor stage.

Results

Five-year relative survival conditional on years already survived is higher among married patients with less lethal cancers (oral cavity and pharynx, colon and rectum, breast, urinary bladder, kidney and renal pelvis, melanoma of the skin, thyroid, lymphoma). For more lethal cancers, married patients have similar (liver, lung and bronchus, pancreas, leukemia) or poorer (brain and other nervous system) cancer survival. Separated/divorced or widowed patients have the lowest conditional relative survival rates. For most cancers, 5-year cancer relative survival rates conditional on time already survived through 5 years approach 70 to 90% of that for the general population. The beneficial effect of marriage on survival decreases with years already survived. Superior conditional relative survival rates in females decrease with time already survived and are less pronounced in married patients.

Conclusion

Five-year relative survival rates improve with time already survived. The benefits of marriage on conditional relative survival are greater for less lethal cancers. Greater 5-year conditional relative survival rates in females narrow with time already survived and are less pronounced in married patients.

Implications for Cancer Survivors

Conditional relative survival rates of cancer can lead to more informed decisions and understanding regarding treatment and prognosis.

http://ift.tt/2f8J0Jc

Tuning in the Hippocampal Theta Band In Vitro: Methodologies for Recording from the Isolated Rodent Septohippocampal Circuit

Here, we present a protocol for recording rhythmic neuronal network theta and gamma oscillations from an isolated whole hippocampal preparation. We describe the experimental steps from extraction of the hippocampus to details of field, unitary and whole-cell patch clamp recordings as well as optogenetic pacing of the theta rhythm.

http://ift.tt/2uWKaNh

The 4-vessel Sampling Approach to Integrative Studies of Human Placental Physiology In Vivo

We present a detailed method to study human placental physiology in vivo at term. The method combines blood sampling from the incoming and outgoing vessels on the maternal and fetal sides of the placenta with ultrasound measurements of volume blood flow and placental tissue sampling.

http://ift.tt/2uWCHy1

Survivors of Breast Cancer Differ on Who Should Manage Follow-Up Care

Many survivors of early-stage breast cancer prefer that their oncologist handle aspects of routine medical care usually overseen by primary care practitioners, leading to concerns about gaps in care.

http://ift.tt/2viuNQm

Relationship between day 1 and day 2 Vancomycin area under the curve values and emergence of heterogeneous Vancomycin-intermediate Staphylococcus aureus (hVISA) by Etest® macromethod among patients with MRSA bloodstream infections: a pilot study

In vitro data suggests that suboptimal initial vancomycin exposure may select for heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections. However, no clinical studies have evaluated the re...

http://ift.tt/2uktiN2

The MNK-eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Pain

Injury-induced sensitization of nociceptors contributes to pain states and the development of chronic pain. Inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) pathways blocks the development of nociceptor sensitization. These pathways convergently signal to the eukaryotic translation initiation factor (eIF) 4F complex to regulate the sensitization of nociceptors, but the details of this process are ill defined. Here we investigated the hypothesis that phosphorylation of the 5' cap-binding protein eIF4E by its specific kinase MAPK interacting kinases (MNKs) 1/2 is a key factor in nociceptor sensitization and the development of chronic pain. Phosphorylation of ser209 on eIF4E regulates the translation of a subset of mRNAs. We show that pronociceptive and inflammatory factors, such as nerve growth factor (NGF), interleukin-6 (IL-6), and carrageenan, produce decreased mechanical and thermal hypersensitivity, decreased affective pain behaviors, and strongly reduced hyperalgesic priming in mice lacking eIF4E phosphorylation (eIF4E^S209A). Tests were done in both sexes, and no sex differences were found. Moreover, in patch-clamp electrophysiology and Ca²⁺ imaging experiments on dorsal root ganglion neurons, NGF- and IL-6-induced increases in excitability were attenuated in neurons from eIF4E^S209A mice. These effects were recapitulated in Mnk1/2^–/– mice and with the MNK1/2 inhibitor cercosporamide. We also find that cold hypersensitivity induced by peripheral nerve injury is reduced in eIF4E^S209A and Mnk1/2^–/– mice and following cercosporamide treatment. Our findings demonstrate that the MNK1/2–eIF4E signaling axis is an important contributing factor to mechanisms of nociceptor plasticity and the development of chronic pain.

SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease affecting approximately one in three Americans. Chronic pain is thought to be driven by changes in the excitability of peripheral nociceptive neurons, but the precise mechanisms controlling these changes are not elucidated. Emerging evidence demonstrates that mRNA translation regulation pathways are key factors in changes in nociceptor excitability. Our work demonstrates that a single phosphorylation site on the 5' cap-binding protein eIF4E is a critical mechanism for changes in nociceptor excitability that drive the development of chronic pain. We reveal a new mechanistic target for the development of a chronic pain state and propose that targeting the upstream kinase, MAPK interacting kinase 1/2, could be used as a therapeutic approach for chronic pain.

http://ift.tt/2vp8W9v