Managing mechanical ventilation in patient with bronchopleural fistula with coexisting acute respiratory distress syndrome is a challenging situation for the intensivist. We are reporting a case of a pregnant patient with systemic lupus erythematosus on immunosuppressive medications who developed methicillin-resistant Staphylococcus aureus necrotizing pneumonia complicated by bronchopleural fistula and acute respiratory distress syndrome.
http://ift.tt/2refgw2
Σάββατο 13 Μαΐου 2017
Ventilator Management of Bronchopleural Fistula Secondary to Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia in a Pregnant Patient with Systemic Lupus Erythematosus
Perceptions of Painful Diabetic Peripheral Neuropathy in South-East Asia: Results from Patient and Physician Surveys
Abstract
There are no data on physician–patient communication in painful diabetic peripheral neuropathy (pDPN) in the Asia–Pacific region. The objective of this study was to examine patient and physician perceptions of pDPN and clinical practice behaviors in five countries in South-East Asia. Primary care physicians and practitioners, endocrinologists, diabetologists, and patients with pDPN completed separate surveys on pDPN diagnosis, impact, management, and physician–patient interactions in Hong Kong, Malaysia, the Philippines, Taiwan, and Thailand. Data were obtained from 100 physicians and 100 patients in each country. The majority of physicians (range across countries, 30–85%) were primary care physicians and practitioners. Patients were mostly aged 18–55 years and had been diagnosed with diabetes for >5 years. Physicians believed pDPN had a greater impact on quality of life than did patients (ranges 83–92% and 39–72%, respectively), but patients believed pDPN had a greater impact on items such as sleep, anxiety, depression, and work than physicians. Physicians considered the diagnosis and treatment of pDPN a low priority, which may be reflected in the generally low incidence of screening (range 12–65%) and a lack of awareness of pDPN. Barriers to treatment included patients' lack of awareness of pDPN. Both physicians and patients agreed that pain scales and local language descriptions were the most useful tools in helping to describe patients' pain. Most patients were monitored upon diagnosis of pDPN (range 55–97%), but patients reported a shorter duration of monitoring compared with physicians. Both physicians and patients agreed that it was patients who initiated conversations on pDPN. Physicians most commonly referred to guidelines from the American Diabetes Association or local guidelines for the management of pDPN. This study highlights important differences between physician and patient perceptions of pDPN, which may impact on its diagnosis and treatment. For a chronic and debilitating complication like pDPN, the physician–patient dialogue is central to maximizing patient outcomes. Strategies, including education of both groups, need to be developed to improve communication.
Funding
Pfizer.
http://ift.tt/2rcvzc7
Prospective Observational Post-Marketing Study of Tafluprost for Glaucoma and Ocular Hypertension: Effectiveness and Treatment Persistence
Abstract
Introduction
The aim of this study was to investigate the long-term intraocular pressure (IOP)-lowering effect and safety of tafluprost, a prostaglandin analogue, in actual clinical practice and to determine persistency of tafluprost as an indicator of its benefit–risk balance.
Methods
This was a large-scale, post-marketing, multicenter, non-interventional, open-label, long-term study. Patients with glaucoma or ocular hypertension who initiated tafluprost treatment were registered and prospectively observed over a 2-year period in the real-world setting in Japan. Long-term IOP and safety data were collected.
Results
Of the 4502 patients registered from 553 medical institutions, 4265 patients were analyzed. The majority of patients had normal-tension glaucoma (44.4%) and primary open-angle glaucoma (37.8%), and patients with ocular hypertension constituted 7.0%. Treatment patterns with tafluprost during the study period were as follows: naïve monotherapy (48.1%), switching monotherapy (18.4%), and concomitant therapy (33.5%). In all patients analyzed, mean IOP was significantly reduced from 18.6 ± 5.9 mmHg (month 0) to 15 mmHg or below throughout the 2-year observation period after initiation of tafluprost. Significant IOP-lowering effects were shown in various treatment patterns and disease types. Adverse reactions were observed in 795 patients (18.64%). Major adverse reactions included eyelid pigmentation, ocular hyperemia, eyelash changes, eyelid hypertrichosis, and iris hyperpigmentation. Kaplan–Meier curves showed that 84.6% and 76.1% of patients were persistent on tafluprost for 1 and 2 years, respectively, when discontinuation due to insufficient efficacy or adverse events was defined as a treatment failure event. Furthermore, among treatment-naïve patients (n = 2304), the persistency rates on tafluprost monotherapy were 77.0% for 1 year and 67.0% for 2 years.
Conclusion
Tafluprost showed significant long-term IOP-lowering effects regardless of treatment patterns or diagnosis, with minimum safety concerns in the actual clinical practice. The observed treatment persistence suggests that tafluprost can be used long term owing to its benefit–risk profile.
Funding
Santen Pharmaceutical Co., Ltd., Osaka, Japan.
http://ift.tt/2qdS0QQ
Possible involvement of the lipoxygenase and leukotriene signaling pathways in cisplatin-mediated renal toxicity
Abstract
Purpose
The present study examined the possible involvement of the lipoxygenase (LOX) pathway in cisplatin (CPT)-induced nephrotoxicity.
Methods
Wistar albino rats were challenged with CPT IP injection (7.5 mg/kg) and were sacrificed after one week. Signs of renal dysfunction, including urea and creatinine clearance levels and renal histological structure, were investigated. Gene and protein expression levels of different LOX pathway enzymes and products, including 5-LOX, 12-LOX, 15-LOX, 5-LOX activating protein (FLAP), leukotriene A4 hydrolase (LTA4 hydrolase), leukotriene C4 synthase (LTC4 synthase), LTB4 receptor, and cysteinyl (cys) LT receptor types 1 and 2, were also determined in the kidneys using real-time PCR and western blotting, respectively. The serum and kidney levels of LTB4 and inflammatory markers were also estimated.
Results
CPT renal toxicity was established as the creatinine and urea clearance levels were significantly reduced, while the serum levels of creatinine and urea were markedly increased. We reported a considerable up-regulation in the mRNA and protein expression levels of 5-LOX, FLAP, 12-LOX, LTA4 hydrolase, LTC4 synthase, LTB4 receptor, and Cys LT receptor types 1 and 2, while 15-LOX expression did not significantly change in the CPT group. Additionally, LTB4 and inflammatory indicators in serum and renal levels were elevated significantly in the CPT group. Histopathological examination clearly showed the nephrotoxic changes in the renal tissues of CPT-challenged animals.
Conclusions
Our findings suggested, for the first time, the participation of LOX enzymes and products in the signaling pathway leading to CPT-associated nephrotoxicity, which could be the foundation stone for combining LOX pathway attenuators with CPT therapy to decrease CPT-associated renal toxicity.
http://ift.tt/2qgu7pv
UGT1A1 polymorphisms with irinotecan-induced toxicities and treatment outcome in Asians with Lung Cancer: a meta-analysis
Abstract
Previous studies of irinotecan pharmacogenetics have shown that the UGT1A1*28 polymorphism has an effect on irinotecan (IRI)-induced toxicities in Caucasians. Yet compared with the UGT1A1*6 mutation, the UGT1A1*28 occurs at a much lower frequency in the Asians. Whether UGT1A1*6 and UGT1A1*28 are associated with IRI-induced neutropenia, diarrhea and IRI-based chemotherapy tumor response (TR) in Asians with lung cancer remains controversial. In this meta-analysis, we found a higher risk of neutropenia and diarrhea with IRI-based chemotherapy in Asians with lung cancer carrying the UGT1A1*6 polymorphism. However, UGT1A1*28 showed a weak correlation with diarrhea, but no significant correlation with neutropenia. Neither UGT1A1*6 nor UGT1A1*28 is associated with IRI-based chemotherapy TR. These data suggest that the UGT1A1*28 polymorphism may not be a suitable biomarker to predict IRI-induced toxicities and chemotherapy TR in Asians, while UGT1A*6 polymorphism is associated with a higher risk of IRI-induced neutropenia and diarrhea, but not IRI-based chemotherapy TR.
http://ift.tt/2pvSXF5
Systematic Review of Animal Models Used in Research of Origins and Treatments of Fecal Incontinence
BACKGROUND: Fecal incontinence is a common disorder, but its pathophysiology is not completely understood. OBJECTIVE: The aim of this review is to present animal models that have a place in the study of fecal incontinence. DATA SOURCES: A literature review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines performed in August 2016 revealed 50 articles of interest. Search terms included fecal/faecal incontinence and animal model or specific species. STUDY SELECTION: Articles not describing an animal model, in vitro studies, veterinary literature, reviews, and non-English articles were excluded. MAIN OUTCOME MEASURES: The articles described models in rats (n = 31), dogs (n = 8), rabbits (n = 7), and pigs (n = 4). RESULTS: Different fecal incontinence etiologies were modeled, including anal sphincter lesions (33 articles) ranging from a single anal sphincter cut to destruction of 50% of the anal sphincter by sharp dissection, electrocautery, or diathermy. Neuropathic fecal incontinence (12 articles) was achieved by complete or incomplete pudendal, pelvic, or inferior rectal nerve damage. Mixed fecal incontinence (5 articles) was modeled either by the inflation of pelvic balloons or an array of several lesions including nervous and muscular damage. Anal fistulas (2 articles), anal sphincter resection (3 articles), and diabetic neuropathy (2 articles) were studied to a lesser extent. LIMITATIONS: Bias may have arisen from the authors' own work on fecal incontinence and the absence of blinding to the origins of articles. CONCLUSIONS: Validated animal models representing the main etiologies of fecal incontinence exist, but no animal model to date represents the whole pathophysiology of fecal incontinence. Therefore, the individual research questions still dictate the choice of model and species.http://ift.tt/2qEYMQz
Selected Techniques of Anal Fistula Surgery from Antiquity Through the Early 20th Century Illustrated
This article highlights surgical approaches to the surgical treatment of anal fistula from antiquity to the early 20th century. Primary translations and other authoritative commentaries on the subject are included. Selected surgical techniques have been reconstructed and illustrated in contemporary interpreted images.http://ift.tt/2re9MRX
Physician Burnout and Well-Being: A Systematic Review and Framework for Action
BACKGROUND: Physician burnout in the United States has reached epidemic proportions and is rising rapidly, although burnout in other occupations is stable. Its negative impact is far reaching and includes harm to the burned-out physician, as well as patients, coworkers, family members, close friends, and healthcare organizations. OBJECTIVE: The purpose of this review is to provide an accurate, current summary of what is known about physician burnout and to develop a framework to reverse its current negative impact, decrease its prevalence, and implement effective organizational and personal interventions. DATA SOURCES: I completed a comprehensive MEDLINE search of the medical literature from January 1, 2000, through December 28, 2016, related to medical student and physician burnout, stress, depression, suicide ideation, suicide, resiliency, wellness, and well-being. In addition, I selectively reviewed secondary articles, books addressing the relevant issues, and oral presentations at national professional meetings since 2013. STUDY SELECTION: Healthcare organizations within the United States were studied. RESULTS: The literature review is presented in 5 sections covering the basics of defining and measuring burnout; its impact, incidence, and causes; and interventions and remediation strategies. CONCLUSIONS: All US medical students, physicians in training, and practicing physicians are at significant risk of burnout. Its prevalence now exceeds 50%. Burnout is the unintended net result of multiple, highly disruptive changes in society at large, the medical profession, and the healthcare system. Both individual and organizational strategies have been only partially successful in mitigating burnout and in developing resiliency and well-being among physicians. Two highly effective strategies are aligning personal and organizational values and enabling physicians to devote 20% of their work activities to the part of their medical practice that is especially meaningful to them. More research is needed.http://ift.tt/2qEXLI3
Bowel Sounds Are Not Associated With Flatus, Bowel Movement, or Tolerance of Oral Intake in Patients After Major Abdominal Surgery
BACKGROUND: Auscultation for bowel sounds has been advocated by some clinicians as a method to determine the resolution of postoperative ileus. OBJECTIVE: Our primary aim was to prospectively evaluate the relationships between bowel sounds and the ability to tolerate oral intake in patients after major abdominal surgery. Secondarily we aimed to evaluate relationships among bowel sounds, flatus and bowel movement, and oral intake. DESIGN: This was a prospective, blinded observational study. SETTINGS: The study was conducted at Western Pennsylvania Hospital. PATIENTS: A total of 124 adult patients undergoing major abdominal surgery were included. MAIN OUTCOME MEASURES: Data were collected by medical students blinded to the purpose of the study for 10 days postoperatively or until discharge, including the presence of bowel sounds (auscultation for 1 minute), flatus, bowel movement, and tolerance of oral intake (defined as ingestion of ≥1000 mL/24 h and each subsequent day without vomiting). Associations between paired variables were determined using ϕ coefficient testing. RESULTS: The study population consisted of 51 men and 73 women, with a mean age of 64 years (range, 20–92 y). The majority of patients (78/124 (63%)) underwent colorectal resection. The median length of hospital was 6 days. Bowel sounds were not associated with flatus, bowel movement, or tolerance of oral intake throughout the study period. The positive predictive value of bowel sounds in predicting flatus and bowel movement was low in the early postoperative period and remainedhttp://ift.tt/2qERCfa
What To Do With Lateral Nodal Disease in Low Locally Advanced Rectal Cancer? A Call for Further Reflection and Research
BACKGROUND: There remains a lack of international consensus on the appropriate management of lateral nodal disease. Although the East manages this more aggressively with lateral lymph node dissections, the West aims to eradicate small-volume disease with neoadjuvant chemoradiotherapy and lateral nodal disease is not considered for routine surgical treatment. However, recent studies have shown that, despite neoadjuvant treatment, a significant number of patients with lateral nodal disease develop local recurrence in the lateral compartment after total mesorectal excision. OBJECTIVE: The aim of this study is to assess the role of the pretreatment features of lateral nodes on MRI in regard to local recurrence. DESIGN: All patients operated on for low locally advanced rectal cancer over a 5-year period were evaluated retrospectively. SETTINGS: This study was conducted at a single expert center. PATIENTS: The MRIs of a total of 313 patients were reviewed, and only those with rectal cancers up to 8 cm from the anorectal junction, measured on MRI, were selected. This left 185 patients; of these, 58 patients had clinical T1 or T2 tumors as assessed on MRI, identifying 127 patients who had cT3/T4 tumors that were included in this study. MAIN OUTCOME MEASURES: The primary outcomes measured were lateral local recurrence and multivariate analyses. RESULTS: The lateral local recurrence rate was significantly higher (33.3% 4-year rate) in patients with nodes larger than 10 mm than in patients with smaller nodes (10.1%, p = 0.03), despite patients being irradiated in the lateral compartment. LIMITATIONS: Because this is a relatively uncommon disease, patient numbers are low, and a multicenter study is needed to further address lateral nodal disease in low rectal cancer. CONCLUSIONS: Chemoradiotherapy with total mesorectal excision might not be sufficient in a selected group of patients. Further research is needed about which pretreatment features of the lateral nodes predict local recurrence and what is needed to prevent these from developing. See Video Abstract at http://ift.tt/2qc4Cb2 .http://ift.tt/2qF1tBs
The Evolution of Pelvic Exenteration Practice at a Single Center: Lessons Learned from over 500 Cases
Considerable progress has been made in the management of patients with locally advanced or recurrent cancers of the pelvis over the past 60 years since the inception of pelvic exenteration. Early progress in pelvic exenteration was marred by the high surgical mortality and morbidity, which drew scepticism from the broader surgical community. Subsequent evolution in the procedure hinged on establishing surgical safety and a better understanding of outcome predictors. Surgical mortality from pelvic exenteration is now comparable to that of elective resection for primary colorectal cancers. The importance of a clear resection margin is also now well established in providing durable local control and predicting long-term survival that, in turn, has driven the development of novel surgical techniques for pelvic side wall resection, en bloc sacrectomy, and pubic bone resection. A tailored surgical approach depending on the location of the tumor with resection of contiguously involved organs, yet preserving uninvolved organs to minimize unnecessary surgical morbidity, is paramount. Despite improved surgical and oncological outcomes, surgical morbidity following pelvic exenteration remains high with reported complication rates ranging between 20% and 80%. Extended antibiotic prophylaxis and preemptive parenteral nutrition in the immediate postoperative period may reduce septic and nutritional complications. A high index of suspicion is needed in the early diagnosis and management of complications that may avoid prolonged duration of hospitalization. An acceptable quality of life has been reported among patients after pelvic exenteration. Further research into novel chemotherapy, immunotherapy, and reconstructive options are currently underway and are needed to further improve outcomes.http://ift.tt/2qEXPaL
Baseline T Classification Predicts Early Tumor Regrowth After Nonoperative Management in Distal Rectal Cancer After Extended Neoadjuvant Chemoradiation and Initial Complete Clinical Response
BACKGROUND: Selected patients with rectal cancer and complete clinical response after neoadjuvant chemoradiation have been managed nonoperatively with acceptable outcomes. However, ≈20% of these patients will develop early tumor regrowth. Identification of these patients could select candidates for more intensive follow-up. OBJECTIVE: The purpose of this study was to investigate the influence of baseline radiological T classification on recurrences after a complete clinical response managed nonoperatively after chemoradiation. DESIGN: This was a retrospective review of a prospective collected database. SETTINGS: The study was conducted at a single center. PATIENTS: Patients with distal rectal cancer (cT2-4N0-2M0) undergoing extended chemoradiation (54 Gy + 5-fluorouracil–based chemotherapy) were eligible. Patients were reassessed for tumor response at 10 weeks after radiation completion. Patients with complete clinical response (clinical, radiological, and endoscopic) were managed nonoperatively and strictly followed. MAIN OUTCOMES MEASURES: Complete clinical response rates, early tumor regrowth rates (http://ift.tt/2qELS4U
The Rationale for and Reality of the New National Accreditation Program for Rectal Cancer
BACKGROUND: The treatment of rectal cancer has greatly evolved because of numerous diagnostic and therapeutic advances. More accurate staging by MRI has allowed more appropriate use of neoadjuvant therapy as well as more standardized high-quality total mesorectal excision. Lower rates of perioperative morbidity, permanent colostomy creation, and improved rates of oncologically acceptable rectal excision have led to lower recurrence and greater disease-free survival rates. The recognition of the need for pathologic assessment of the quality of total mesorectal excision, the status of the circumferential resection margins, and the finding of a minimum of 12 lymph nodes as well as identification of extramural vascular invasion has improved staging. These evolutions in imaging, surgical management, and pathologic specimen assessment are interdependent and have been repeatedly shown on national levels to be best operationalized in a multidisciplinary team environment. OBJECTIVE: The aim of this article is to evaluate the evidence leading to these important changes, including the imminent launch of the National Accreditation Program for Rectal Cancer. DESIGN AND SETTING: Based on the myriad confirmatory experiences in Europe and in the United Kingdom, a multidisciplinary team rectal cancer program was designed by the Consortium for Optimizing Surgical Treatment of Rectal Cancer and subsequently endorsed and accepted by the American College of Surgeons Commission on Cancer. MAIN OUTCOME MEASURES: The primary outcome measured is the adherence to the new program standards. RESULTS: Surgical treatment of rectal cancer consortium membership rapidly increased from 14 centers in August 2011 to more than 350 centers in April 2017. LIMITATIONS: The multidisciplinary team rectal cancer program has not yet launched; thus, its impact cannot yet be assessed. CONCLUSIONS: It is our hope and expectation that the outstanding improvement in quality outcomes repeatedly demonstrated within Europe, and extensively shown as much needed in the United States, will be rapidly achieved.http://ift.tt/2relsE7
Paradoxical Impact of Ileal Pouch-Anal Anastomosis on Male and Female Fertility in Patients With Ulcerative Colitis
BACKGROUND: Birth rates in males with ulcerative colitis and ileal pouch-anal anastomosis have not been studied. OBJECTIVE: This study aimed to estimate birth rates in males and females with ulcerative colitis and study the impact of ileal pouch-anal anastomosis. DESIGN: This was a retrospective registry-based cohort study that was performed over a 30-year period. SETTINGS: Records for parenting a child from the same period were cross-linked with patient records, and birth rates were calculated using 15 through 49 years as age limits. All data were prospectively registered. PATIENTS: All patients with ulcerative colitis and ulcerative colitis with ileal pouch-anal anastomosis between 1980 and 2010 were identified in Danish national databases. MAIN OUTCOME MEASURES: The primary outcomes measured were birth rates in females and males with ulcerative colitis and ulcerative colitis with ileal pouch-anal anastomosis. RESULTS: We included 27,379 patients with ulcerative colitis (12,812 males and 14,567 females); 1544 had ileal pouch-anal anastomosis (792 males and 752 females). Patients with ulcerative colitis have slightly reduced birth rates (males at 40.8 children/1000 years, background population 43.2, females at 46.2 children/1000 years, background population 49.1). After ileal pouch-anal anastomosis, males had increased birth rates at 47.8 children/1000 years in comparison with males with ulcerative colitis without ileal pouch-anal anastomosis (40.5 children/1000 years), whereas females had reduced birth rates at 27.6 children/1000 years in comparison with females with ulcerative colitis without ileal pouch-anal anastomosis (46.8 children/1000 years). LIMITATIONS: Only birth rates were investigated and not fecundability. Furthermore, there is a question about misattributed paternity, but this has previously been shown to be less than 5%. CONCLUSIONS: Ulcerative colitis per se has little impact on birth rates in both sexes, but ileal pouch-anal anastomosis surgery leads to a reduction in birth rates in females and an increase in birth rates in males. This has clinical impact when counseling patients before ileal pouch-anal anastomosis surgery.http://ift.tt/2qFdC9A
siRNA Targeting Net1 Reduces the Angiogenesis and Tumor Growth of in vivo Cervical Squamous Cell Carcinoma through VEGF down-regulation
Net1, a guanine nucleotide exchange factor, is implicated in cancer cell invasion through activation of RhoA. However, there is still no report on the association between Net1 and cancer angiogenesis. The current study was designed to explore the roles of Net1 in the angiogenesis of cervical squamous cell carcinoma (CSCC) and further observe the effects of Net1 siRNA on the tumor growth. Net1 was overexpressed in CSCC samples (n=80), correlated to the cancer microvessel density (MVD, r=0.223, P=.026) and related to aggressive clinical behaviors, including depth of cervical wall invasion (P=.041), parametrial involvement (P=.037), lymph node metastasis (P=.021) and vascular invasion (P=.018).
http://ift.tt/2remcJA
Asymmetric Dimethylarginine Induced Apoptosis and Dysfunction of Endothelial Progenitor Cells: Role of Endoplasmic Reticulum Stress Pathway
Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, is a novel risk factor of cardiovascular disease. Endothelial progenitor cells (EPCs) bear typical endothelial characteristics and are thought to contribute to neovascularization by providing new endothelial cells (ECs) after arterial injury. Many studies have shown that ADMA can induce EPC apoptosis and dysfunction, but the underlying mechanism is not well understood. EPCs from umbilical cord blood were cultured in EGM-2 medium with particular growth factors and supplemented with 10% fetal bovine serum. The cells were treated with different concentrations of ADMA (5, 10, and 50 μmol/L). Endoplasmic reticulum (ER) stress marker levels were examined by western blot analysis. After 24-hour incubation, ADMA induced apoptosis of EPCs and significantly decreased the proliferation, migration, and vasculogenesis capacity of EPCs. We also found that ADMA treatment activated phosphorylated protein kinase RNA-activated-like ER kinase (PERK), a stress sensor protein in the endoplasmic reticulum (ER). The activated PERK induced 78 kDa glucose-regulated protein (GRP-78) and C/EBP homologous protein (CHOP) expression. Additionally, the inhibition of the ER stress pathway by Salubrinal (a specific ER stress inhibitor) can attenuate ADMA-induced apoptosis of EPCs. Overall, these observations indicate that ADMA may induce the apoptosis and dysfunction of EPCs through the ER stress pathway.
http://ift.tt/2qEu5uK
The Association of Chemokine Gene Polymorphisms with VKH and Behcet’s Disease in a Chinese Han Population
To investigate the association of chemokine gene polymorphisms and Behcet's disease (BD) and Vogt Koyanagi Harada (VKH) disease in a Chinese Han population. A case-control study was performed. Three hundred and seventy-one BD patients, 371 VKH disease patients, and 605 healthy controls were recruited to determine genetic variants of 26 SNPs in 12 chemokine genes with iPLEX Gold genotyping assay and Sequenom MassARRAY or TaqMan SNP assays. In this study, values showed a weak association of five SNPs of five genes in BD and three SNPs of three genes in VKH disease. However, after Bonferroni correction, the 26 investigated SNPs showed no significant differences in genetic variants, including genotype and allele frequencies, between BD or VKH disease patients and healthy individuals. Haplotype analysis for the chemokine genes showed a significant association with the TC haplotype of CXCL12 in VKH. Stratified gender analysis and genotype-phenotype analysis were conducted to analyze the association of the 26 SNPs of 12 chemokine genes with BD and VKH disease. However, no significant association was observed after Bonferroni correction. This study showed no association of 26 SNPs in 12 chemokine genes with both BD and VKH disease in a Chinese Han population.
http://ift.tt/2qERdtj
Dexamethasone Modulates Nonvisual Opsins, Glucocorticoid Receptor, and Clock Genes in Danio rerio ZEM-2S Cells
Here we report, for the first time, the differential cellular distribution of two melanopsins (Opn4m1 and Opn4m2) and the effects of GR agonist, dexamethasone, on the expression of these opsins and clock genes, in the photosensitive D. rerio ZEM-2S embryonic cells. Immunopositive labeling for Opn4m1 was detected in the cell membrane whereas Opn4m2 labeling shows nuclear localization, which did not change in response to light. opn4m1, opn4m2, gr, per1b, and cry1b presented an oscillatory profile of expression in LD condition. In both DD and LD condition, dexamethasone (DEX) treatment shifted the peak expression of per1b and cry1b transcripts to ZT16, which corresponds to the highest opn4m1 expression. Interestingly, DEX promoted an increase of per1b expression when applied in LD condition but a decrease when the cells were kept under DD condition. Although DEX effects are divergent with different light conditions, the response resulted in clock synchronization in all cases. Taken together, these data demonstrate that D. rerio ZEM-2S cells possess a photosensitive system due to melanopsin expression which results in an oscillatory profile of clock genes in response to LD cycle. Moreover, we provide evidence that glucocorticoid acts as a circadian regulator of D. rerio peripheral clocks.
http://ift.tt/2reqvEM
Native Valve Endocarditis due to Veillonella Species: A Case Report and Review of the Literature
Veillonella species are fastidious bacteria that have been isolated from skin, dental, and respiratory tract infections and rarely have been implicated in serious infections like meningitis, endocarditis, and osteomyelitis. A 76-year-old woman presented to our hospital with fever, vomiting, and generalized weakness for 3 days. A transthoracic echocardiogram showed a mobile structure on anterior mitral valve leaflet measuring 0.9 cm suggestive of vegetation. Empiric therapy with vancomycin and piperacillin-tazobactam was started with clinical resolution of her symptoms. On day 6, the blood culture drawn at admission grew Veillonella species. A transesophageal echocardiogram confirmed a 1.2 0.4 cm echo dense structure attached to the left ventricular side of the anterior mitral leaflet. The patient was discharged home after 10 days of inpatient antibiotic therapy and completed 4 weeks of IV ceftriaxone at home without any adverse events. She was reevaluated in the clinic after completion of treatment and repeat blood cultures remained negative. We report the first case of successful treatment of endocarditis due to Veillonella species with once daily ceftriaxone.
http://ift.tt/2qEILtL
The Acoustic Habitat Hypothesis: An Ecoacoustics Perspective on Species Habitat Selection
Abstract
Sound is an inherent component of the environment that provides conditions and information necessary for many animal activities. Soniferous species require specific acoustic and physical conditions suitable for their signals to be transmitted, received, and effectively interpreted to successfully identify and utilize resources in their environment and interact with conspecifics and other heterospecific organisms. We propose the Acoustic Habitat Hypothesis to explain how the acoustic environment influences habitat selection of sound-dependent species. We postulate that sound-dependent species select and occupy habitats with unique acoustic characteristics that are essential to their functional needs and conducive to the threshold of sound frequency they produce and detect. These acoustic habitats are based on the composition of biophony, geophony, and technophony in the soundscape and on the biosemiotics mechanisms described in the eco-field hypothesis. The Acoustic Habitat Hypothesis initiates questions of habitat selection that go beyond the physical attributes of the environment by applying ecoacoustics theory. We outline the theoretical basis of the Acoustic Habitat Hypothesis and provide examples from the literature to support its assumptions. The concept of acoustic habitats has been documented in the literature for many years but here, we accurately and extensively define acoustic habitat and we put this concept into a unified theory. We also include perspectives on how the Acoustic Habitat Hypothesis can stimulate a paradigm shift in conservation strategies for threatened and endangered species.
http://ift.tt/2qEuaPc
Mechanisms of Resistance to JAK2 Inhibitors in Myeloproliferative Neoplasms
Myeloproliferative neoplasms are driven by activated JAK2 signaling due to somatic mutations in JAK2, the thrombopoietin receptor MPL or the chaperone calreticulin in hematopoietic stem/progenitor cells. JAK2 inhibitors have been developed, but despite clinical benefits, they do not signficantly reduce the mutant clone. Loss of response to JAK2 inhibitors occurs and several mechanisms of resistance, genetic and functional, have been identified. Resistance mutations have not been reported in MPN patients suggesting incomplete target inhibition. Alternative targeting of JAK2 by HSP90 inhibitors or type II JAK2 inhibition overcomes resistance to current JAK2 inhibitors. Additional combined therapy approaches are currently being evaluated.
http://ift.tt/2qebogA
Clinical Review: Loperamide Toxicity
Loperamide is a nonprescription opioid widely used for the treatment of diarrhea. Although it is relatively safe at therapeutic doses, increasing reports describe its misuse and abuse at very high doses either for euphoric effects or to attenuate symptoms of opioid withdrawal. Life-threatening loperamide toxicity can result from the relatively new clinical syndrome of loperamide-induced cardiac toxicity. These patients are often young and may present in cardiac arrest or with unheralded, recurrent syncope in conjunction with ECG abnormalities, including marked QT-interval prolongation, QRS-interval widening, and ventricular dysrhythmias.
http://ift.tt/2rdSy75
Tacit knowledge
Abstract
Information that is not made explicit is nonetheless embedded in most of our standard procedures. In its simplest form, embedded information may take the form of prior knowledge held by the researcher and presumed to be agreed to by consumers of the research product. More interesting are the settings in which the prior information is held unconsciously by both researcher and reader, or when the very form of an "effective procedure" incorporates its creator's (unspoken) understanding of a problem. While it may not be productive to exhaustively detail the embedded or tacit knowledge that manifests itself in creative scientific work, at least at the beginning, we may want to routinize methods for extracting and documenting the ways of thinking that make "experts" expert. We should not back away from both expecting and respecting the tacit knowledge the pervades our work and the work of others.
http://ift.tt/2qhqmAx
Pseudomyxoma peritonei due to low-grade appendiceal mucinous neoplasm with symptoms of inguinal hernia and uterine prolapse: a case report and review of the literature
Abstract
Pseudomyxoma peritonei (PMP) is an unusual condition in which massive amounts of mucinous ascites in conjunction with mucinous peritoneal and omental implants occur. We herein report a case of PMP due to low-grade appendiceal neoplasm (LAMN) and a literature review to clarify the clinical features of PMP. A 68-year-old female suffered from anorexia and abdominal distension and was referred to the emergency department of our hospital. Right-side inguinal hernia and uterine prolapse were revealed by a physical examination. Abdominal computed tomography at admission indicated massive ascites and a ruptured cystic mass in the lower-right abdomen. We diagnosed the patient with a ruptured appendiceal mucinous adenoma and PMP and scheduled a laparotomy. We performed an appendectomy containing the cystic mass, bilateral oophorectomy, and a biopsy for the peritoneum. We irrigated the abdominal cavity using 3000 ml of dextran solution. The macroscopic findings showed a ruptured cystic mass measuring 5 × 4 cm arising from the middle of the appendix. The bilateral ovaries and peritoneum were also covered with yellow mucin. The pathologic findings revealed the presence of low-grade atypical cells inside the capsule. However, no tumor cells were found on the surface of the ovary or peritoneum. A literature review revealed that the prognosis of PMP due to LAMN is relatively good, with a 5-year survival rate of 80%, and hernia is occasionally caused by PMP. According to this literature review, we knew this case might be a typical case. However, PMP is very rare; we need further follow-up data to select an optimal treatment for preventing the relapse of PMP.
http://ift.tt/2pJLM7s
A case report of Muir-Torre syndrome in a woman with breast cancer and MSI-Low skin squamous cell carcinoma
Abstract
Background
The tumor spectrum in the Lynch syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch syndrome spectrum. Hence, the real link between Lynch syndrome, or Muir-Torre syndrome, and these tumors remains difficult to assess.
Case presentation
We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma.
Conclusion
Squamous cell carcinomas have been described in Lynch syndrome and Muir-Torre syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch syndrome and squamous cell carcinoma.
http://ift.tt/2qfdTyM
Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2 + γδ T cell cytotoxicity in a perforin-dependent manner
Abstract
Vδ2+ T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2+ T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2+ T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C–C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2+ T cell cytotoxicity. Vδ2+ T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive—at least in part—to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2+ T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy.
http://ift.tt/2rc2jlC
Paracrine release of IL-2 and anti-CTLA-4 enhances the ability of artificial polymer antigen-presenting cells to expand antigen-specific T cells and inhibit tumor growth in a mouse model
Abstract
Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology. Here, a novel biodegradable aAPC platform for active immunotherapy was developed by co-encapsulating IL-2 and anti-CTLA-4 inside cell-sized polylactic-co-glycolic acid microparticles (PLGA-MPs) while co-coupling an H-2Kb/TRP2-Ig dimer and anti-CD28 onto the surface. Cytokines (activating signal) and antibodies (anti-inhibition signal) were efficiently co-encapsulated in PLGA-MP-based aAPCs and co-released without interfering with each other. The targeted, sustained co-release of IL-2 and anti-CTLA-4 achieved markedly enhanced, synergistic effects in activating and expanding tumor antigen-specific T cells both in vitro and in vivo, as well as in inhibiting tumor growth in a mouse melanoma model, as compared with conventional two-signal aAPCs and IL-2 or anti-CTLA-4 single-released aAPCs. These data revealed the feasibility and importance of the paracrine release of multiple costimulatory molecules and cytokines from biodegradable aAPCs and thus provide a proof of principle for the future use of polymeric aAPCs for active immunotherapy of tumors and infectious diseases.
http://ift.tt/2qdcuZJ
Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high-grade glioma cell lines derived from glioblastoma
Abstract
We have reported that calcitonin receptor (CTR) is widely expressed in biopsies from the lethal brain tumour glioblastoma by malignant glioma and brain tumour-initiating cells (glioma stem cells) using anti-human CTR antibodies. A monoclonal antibody against an epitope within the extracellular domain of CTR was raised (mAb2C4) and chemically conjugated to either plant ribosome-inactivating proteins (RIPs) dianthin-30 or gelonin, or the drug monomethyl auristatin E (MMAE), and purified. In the high-grade glioma cell line (HGG, representing glioma stem cells) SB2b, in the presence of the triterpene glycoside SO1861, the EC50 for mAb2C4:dianthin was 10.0 pM and for mAb2C4:MMAE [antibody drug conjugate (ADC)] 2.5 nM, 250-fold less potent. With the cell line U87MG, in the presence of SO1861, the EC50 for mAb2C4:dianthin was 20 pM, mAb2C4:gelonin, 20 pM, compared to the ADC (6.3 nM), which is >300 less potent. Several other HGG cell lines that express CTR were tested and the efficacies of mAb2C4:RIP (dianthin or gelonin) were similar. Co-administration of the enhancer SO1861 purified from plants enhances lysosomal escape. Enhancement with SO1861 increased potency of the immunotoxin (>3 log values) compared to the ADC (1 log). The uptake of antibody was demonstrated with the fluorescent conjugate mAb2C4:Alexa Fluor 568, and the release of dianthin-30:Alexa Fluor488 into the cytosol following addition of SO1861 supports our model. These data demonstrate that the immunotoxins are highly potent and that CTR is an effective target expressed by a large proportion of HGG cell lines representative of glioma stem cells and isolated from individual patients.
http://ift.tt/2rc0SU8
Expression of PD-L1 in keratoacanthoma and different stages of progression in cutaneous squamous cell carcinoma
Abstract
Background
Programmed cell death 1 (PD-1) and its ligands (PD-L1) play a major role in the immune responses of a variety of cancers.
Objectives
To investigate the expression of PD-L1 in different progression forms of cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA).
Methods
We performed immunohistochemical staining of 21 KA, 26 actinic keratoses (AK), 20 Bowen´s diseases (BD), and 26 high-risk cSCC. The staining patterns were assessed using the tumour proportion score and staining intensity evaluation. Immunohistology scores were statistically analysed.
Results
PD-L1 expression of tumour cells as well as tumour-infiltrating cells (TILs) was significantly higher in KA and cSCC when compared to AK and BD (P = 0.00028 and P = 0.00033, respectively). We observed a very strong positive correlation between the PD-L1 protein expression of tumour cells of KA and the PD-L1 protein expression of TILs (r = 0.97; P < 0.0001). A similar correlation was also found for cSCC (r = 0.86; P < 0.0001). The percentage of PD-L1 + tumours was 33.3% for KA and 26.9% for cSCC. Similarly, the percentage of PD-L1 + TILs in KA and cSCC was 33.3 and 34.6%, respectively.
Conclusions
PD-L1 is differently expressed in cSCC and closely related non-melanoma skin cancer. cSCC exhibit PD-L1 expression in a fourth of cases, indicating that PD1/PD-L1 inhibitors might be beneficial in a proportion of patients with an inoperable or metastatic cSCC. Unlike AK and BD, TILs and tumour cells of KA and cSCC present very similar PD-L1 expression profiles indicating a common immune escape mechanism.
http://ift.tt/2qd0SGa
Common extracellular matrix regulation of myeloid cell activity in the bone marrow and tumor microenvironments
Abstract
The complex interaction between cells undergoing transformation and the various stromal and immunological cell components of the tumor microenvironment (TME) crucially influences cancer progression and diversification, as well as endowing clinical and prognostic significance. The immunosuppression characterizing the TME depends on the recruitment and activation of different cell types including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Less considered is the non-cellular component of the TME. Here, we focus on the extracellular matrix (ECM) regulatory activities that, within the TME, actively contribute to many aspects of tumor progression, acting on both tumor and immune cells. Particularly, ECM-mediated regulation of tumor-associated immunosuppression occurs through the modulation of myeloid cell expansion, localization, and functional activities. Such regulation is not limited to the TME but occurs also within the bone marrow, wherein matricellular proteins contribute to the maintenance of specialized hematopoietic stem cell niches thereby regulating their homeostasis as well as the generation and expansion of myeloid cells under both physiological and pathological conditions. Highlighting the commonalities among ECM-myeloid cell interactions in bone marrow and TME, in this review we present a picture in which myeloid cells might sense and respond to ECM modifications, providing different ECM-myeloid cell interfaces that may be useful to define prognostic groups and to tailor therapeutic interventions.
http://ift.tt/2rc0Snm
Pediatric Gynecologic Cancers
Abstract
Purpose of Review
Three primary categories of gynecologic cancer are found in pediatric and adolescent patients: stromal carcinomas including juvenile granulosa cell tumors and Sertoli-Leydig cell tumors, rhabdomyosarcomas arising from the vagina and cervix (sarcoma botryoides), and ovarian germ cell tumors which comprise a wide range of histologies. These entities are rare and treatment approaches have focused on decreasing late effects of chemotherapy treatment. Here, we review presentation, histologic classifications, diagnosis, and treatment recommendations for pediatric gynecologic cancers.
Recent Findings
Event-free and overall survival for these cancers is high, and the goals of treatment are minimization of morbidity and preservation of fertility with unilateral salpingo-oophorectomies and limited staging. Surveillance of tumor markers after surgery is helpful in monitoring for disease progression and adjuvant chemotherapy is often reserved for patients at recurrence.
Summary
Recent literature supports avoiding chemotherapy even in high-grade germ cell tumors in the pediatric population.
http://ift.tt/2rc6TAe
Are Family Routines Modifiable Determinants of Preschool Children’s Eating, Dietary Intake, and Growth? A Review of Intervention Studies
Abstract
Purpose of Review
Children's eating behaviors are critical determinants of their dietary intake and, hence, childhood growth. Nutritional interventions among families with young children are focused on parents as agents of change, with interventions increasingly targeting family routines as drivers of children's eating and health outcomes. This review describes studies that have acted on family routines in the context of preschoolers' eating and growth, summarizes their findings, and discusses the limitations of current approaches to studying family routines and the implications for future research.
Recent Findings
We found that food availability and parental offering of foods have been modified by several interventions and linked to positive changes in child outcomes. Parent interventions have had success in reducing controlling feeding practices and improving self-efficacy related to child feeding, but these have not been associated with long-term change in child outcomes.
Summary
We conclude that opportunities exist to strengthen the definition, operationalization, and measurement of family routine variables. Improvements in fidelity and process evaluation measures will be important for more efficacious intervention development and dissemination.
http://ift.tt/2r4Y2UJ
Current status of superficial pharyngeal squamous cell carcinoma in Japan
Abstract
Background
To investigate the status and treatment of superficial pharyngeal squamous cell carcinoma in Japan.
Methods
We analyzed all cases diagnosed between 2011 and 2013, as recorded in the national database of hospital-based cancer registries. We extracted data on patient sex, age, tumor locations, histology, presentation routes, initial treatments, and TNM stages. Additionally, we compared the characteristics of pharyngeal carcinoma to those of esophageal cancer.
Results
A total of 16,521 oropharyngeal and hypopharyngeal cancers from 409 institutions were included. Diagnosis of Tis tumors was infrequent, and both cancers were likely to be diagnosed at an advanced stage (n = 866, 5.3%). Tis diseases were the most commonly detected during follow-up examinations for other diseases (n = 608, 70%). While more oropharyngeal Tis patients were men compared to T1–4 patients (88 vs 82%, respectively), hypopharyngeal cancer patients comprised an equally high proportion of men (94 vs 92%, respectively). The most common location of oropharyngeal Tis tumors was the posterior wall (32%), whereas T1–4 tumors were most commonly found on the lateral wall (36%). In hypopharyngeal cancer, both Tis and T1–4 were most commonly located in the pyriform sinus (62%). The proportion of Tis tumors diagnosed at individual institutions showed a positive correlation with the number of endoscopic treatments (r = 0.32, P < 0.001) and the number of esophageal cancer cases (r = 0.37, P < 0.001).
Conclusion
Our national database study elucidated the current characteristics of superficial pharyngeal squamous cell carcinoma patients in Japan. Further improvements in early diagnosis and standardized treatments are warranted.
http://ift.tt/2pw9M2I
Isolation and identification Candida vulvovaginitis in women referred to health centers of Arak City and antifungal activity of Equisetum arvense and Quercus on Candida albicans
Abstract
Among the vulvovaginal infections, the second prevalent infection is vulvovaginal candidiasis which is created due to abnormal growth of Candida species in genital system of the women. Equisetum arvense is regarded as an effective drug in treatment of wounds. Quercus has been also used for treatment of many diseases. This study investigated 152 patients suspicious of vulvovaginal candidiasis. Seventy-five isolates were identified from 152 isolates of Candida albicans, and 55 yeast isolates were identified as non-albicans (Candida krusei, Candida glabrata, and Candida tropicalis), and 22 yeast isolates were unidentified. In broth microdilution method, MIC 50 was reported as 12.5 μl/ml in Candida albicans for Equisetum arvense and Quercus, and MFC was reported as 25 μl/ml for both plants. In this research, isolation of Candida albicans species is more than that of non-albicans species.
http://ift.tt/2rdw06C
Topical co-administration of Pistacia atlantica hull and Quercus infectoria gall hydroethanolic extract improves wound-healing process
Abstract
Pistacia atlantica hulls and Quercus infectoria galls have been used in traditional medicine for treatment of many disorders. In the current study, excision wound model was used for the assessment of wound-healing activity of topical co-administration of hydroethanolic extracts of Pistacia atlantica hulls (P. atlantica) and Quercus infectoria galls (Q. infectoria) in streptozotocin-induced diabetic mice. Four groups of diabetic mouse model were used; control group (received soft yellow paraffin), treated groups P. atlantica 5%; Q. infectoria 5% and Q. infectoria 5% + P. atlantica 5% mixed soft yellow paraffin. Two circular, full-thickness skin wounds with 5 mm diameter were created on the back of each of the mice. During the healing time, wound rate was measured and wound sample was obtained at the end of days 3, 7, and 14 for histopathological evaluation. Moreover, immunohistochemistry staining for GLUT-1 and GPC3 was done. According to the results, topical application of each hydroethanolic extract of pistachio and quercus extract alone and co-administrated together cause improved wound-healing activity in diabetic mice via decrease in inflammation phases with decrease of edema and immune cell migration scores, and proliferation stage with increase in new vessels formation, fibroblast infiltration, collagen synthesis scores, and GLUT-1- and GPC3-positive cells in diabetic mice. These results suggest that the topical application of P. atlantica hulls and Q. infectoria galls hydroethanolic extracts has beneficial effect on full-thickness wound-healing activity in diabetic mice and it might be useful for treating various types of chronic wounds.
http://ift.tt/2qDZjC7
High Precision FRET at Single-molecule Level for Biomolecule Structure Determination
http://ift.tt/2pJsizO
Expression, Purification, and Antimicrobial Activity of S100A12
http://ift.tt/2qDKZK3
Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2 + γδ T cell cytotoxicity in a perforin-dependent manner
Abstract
Vδ2+ T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2+ T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2+ T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C–C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2+ T cell cytotoxicity. Vδ2+ T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive—at least in part—to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2+ T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy.
http://ift.tt/2rc2jlC
Paracrine release of IL-2 and anti-CTLA-4 enhances the ability of artificial polymer antigen-presenting cells to expand antigen-specific T cells and inhibit tumor growth in a mouse model
Abstract
Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology. Here, a novel biodegradable aAPC platform for active immunotherapy was developed by co-encapsulating IL-2 and anti-CTLA-4 inside cell-sized polylactic-co-glycolic acid microparticles (PLGA-MPs) while co-coupling an H-2Kb/TRP2-Ig dimer and anti-CD28 onto the surface. Cytokines (activating signal) and antibodies (anti-inhibition signal) were efficiently co-encapsulated in PLGA-MP-based aAPCs and co-released without interfering with each other. The targeted, sustained co-release of IL-2 and anti-CTLA-4 achieved markedly enhanced, synergistic effects in activating and expanding tumor antigen-specific T cells both in vitro and in vivo, as well as in inhibiting tumor growth in a mouse melanoma model, as compared with conventional two-signal aAPCs and IL-2 or anti-CTLA-4 single-released aAPCs. These data revealed the feasibility and importance of the paracrine release of multiple costimulatory molecules and cytokines from biodegradable aAPCs and thus provide a proof of principle for the future use of polymeric aAPCs for active immunotherapy of tumors and infectious diseases.
http://ift.tt/2qdcuZJ
Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high-grade glioma cell lines derived from glioblastoma
Abstract
We have reported that calcitonin receptor (CTR) is widely expressed in biopsies from the lethal brain tumour glioblastoma by malignant glioma and brain tumour-initiating cells (glioma stem cells) using anti-human CTR antibodies. A monoclonal antibody against an epitope within the extracellular domain of CTR was raised (mAb2C4) and chemically conjugated to either plant ribosome-inactivating proteins (RIPs) dianthin-30 or gelonin, or the drug monomethyl auristatin E (MMAE), and purified. In the high-grade glioma cell line (HGG, representing glioma stem cells) SB2b, in the presence of the triterpene glycoside SO1861, the EC50 for mAb2C4:dianthin was 10.0 pM and for mAb2C4:MMAE [antibody drug conjugate (ADC)] 2.5 nM, 250-fold less potent. With the cell line U87MG, in the presence of SO1861, the EC50 for mAb2C4:dianthin was 20 pM, mAb2C4:gelonin, 20 pM, compared to the ADC (6.3 nM), which is >300 less potent. Several other HGG cell lines that express CTR were tested and the efficacies of mAb2C4:RIP (dianthin or gelonin) were similar. Co-administration of the enhancer SO1861 purified from plants enhances lysosomal escape. Enhancement with SO1861 increased potency of the immunotoxin (>3 log values) compared to the ADC (1 log). The uptake of antibody was demonstrated with the fluorescent conjugate mAb2C4:Alexa Fluor 568, and the release of dianthin-30:Alexa Fluor488 into the cytosol following addition of SO1861 supports our model. These data demonstrate that the immunotoxins are highly potent and that CTR is an effective target expressed by a large proportion of HGG cell lines representative of glioma stem cells and isolated from individual patients.
http://ift.tt/2rc0SU8
Expression of PD-L1 in keratoacanthoma and different stages of progression in cutaneous squamous cell carcinoma
Abstract
Background
Programmed cell death 1 (PD-1) and its ligands (PD-L1) play a major role in the immune responses of a variety of cancers.
Objectives
To investigate the expression of PD-L1 in different progression forms of cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA).
Methods
We performed immunohistochemical staining of 21 KA, 26 actinic keratoses (AK), 20 Bowen´s diseases (BD), and 26 high-risk cSCC. The staining patterns were assessed using the tumour proportion score and staining intensity evaluation. Immunohistology scores were statistically analysed.
Results
PD-L1 expression of tumour cells as well as tumour-infiltrating cells (TILs) was significantly higher in KA and cSCC when compared to AK and BD (P = 0.00028 and P = 0.00033, respectively). We observed a very strong positive correlation between the PD-L1 protein expression of tumour cells of KA and the PD-L1 protein expression of TILs (r = 0.97; P < 0.0001). A similar correlation was also found for cSCC (r = 0.86; P < 0.0001). The percentage of PD-L1 + tumours was 33.3% for KA and 26.9% for cSCC. Similarly, the percentage of PD-L1 + TILs in KA and cSCC was 33.3 and 34.6%, respectively.
Conclusions
PD-L1 is differently expressed in cSCC and closely related non-melanoma skin cancer. cSCC exhibit PD-L1 expression in a fourth of cases, indicating that PD1/PD-L1 inhibitors might be beneficial in a proportion of patients with an inoperable or metastatic cSCC. Unlike AK and BD, TILs and tumour cells of KA and cSCC present very similar PD-L1 expression profiles indicating a common immune escape mechanism.
http://ift.tt/2qd0SGa
Common extracellular matrix regulation of myeloid cell activity in the bone marrow and tumor microenvironments
Abstract
The complex interaction between cells undergoing transformation and the various stromal and immunological cell components of the tumor microenvironment (TME) crucially influences cancer progression and diversification, as well as endowing clinical and prognostic significance. The immunosuppression characterizing the TME depends on the recruitment and activation of different cell types including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Less considered is the non-cellular component of the TME. Here, we focus on the extracellular matrix (ECM) regulatory activities that, within the TME, actively contribute to many aspects of tumor progression, acting on both tumor and immune cells. Particularly, ECM-mediated regulation of tumor-associated immunosuppression occurs through the modulation of myeloid cell expansion, localization, and functional activities. Such regulation is not limited to the TME but occurs also within the bone marrow, wherein matricellular proteins contribute to the maintenance of specialized hematopoietic stem cell niches thereby regulating their homeostasis as well as the generation and expansion of myeloid cells under both physiological and pathological conditions. Highlighting the commonalities among ECM-myeloid cell interactions in bone marrow and TME, in this review we present a picture in which myeloid cells might sense and respond to ECM modifications, providing different ECM-myeloid cell interfaces that may be useful to define prognostic groups and to tailor therapeutic interventions.
http://ift.tt/2rc0Snm
Patient buys ballistic vests for paramedics who saved him
The man said he hopes his gift plants the seed for others to step up and help equip paramedics
http://ift.tt/2qdhrC5
Don't Label Me: A Qualitative Study of Patients’ Perceptions and Experiences of Sedation during Behavioral Emergency in the Emergency Department
Abstract
Objectives
Behavioral emergencies are commonly seen in emergency departments. Acutely agitated patients can be difficult to manage and sedation may be required to decrease dangerous behavior and to ensure the safety of both the patient and staff. While the experience of staff caring for this population has been reported, patients' experiences with their overall management remains unknown. We aimed to describe the perceptions and experiences of patients regarding the use of sedation during acute behavioral emergencies.
Methods
Face-to-face semi-structured interviews were conducted with adults aged 18 years or older, who had received parenteral sedative medication for the management of a behavioral emergency and were deemed capable to participate. The participants were asked about their experiences of receiving care in the emergency department during the episode and their perceptions of sedation. All interviews were transcribed verbatim and analyzed thematically.
Results
Data saturation was reached after 13 interviews. Two broad themes emerged: trusting relationships; and needs or wants following sedation. A trusting relationship is built through (i) confidence in care; (ii) sedation as an appropriate treatment; (iii) insight into own behavior; and (iv) humane treatment. Four subthemes of needs or wants were identified: (i) empathy; (ii) debrief; (iii) addressing concerns; and (iv) follow up.
Conclusions
A trusting relationship was identified as crucial to minimize the negative impact of coercive measures used to manage behavioral emergencies. Participants expressed similar needs to patients presenting with medical problems. This study illustrates their needs for compassionate communication, adequate information about the treatment provided, and follow-up care.
This article is protected by copyright. All rights reserved.
http://ift.tt/2qg5DwE
A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH.
A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH.
PLoS Negl Trop Dis. 2017 May 12;11(5):e0005527
Authors: Osman M, Mistry A, Keding A, Gabe R, Cook E, Forrester S, Wiggins R, Di Marco S, Colloca S, Siani L, Cortese R, Smith DF, Aebischer T, Kaye PM, Lacey CJ
Abstract
BACKGROUND: Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells.
METHODS: We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry.
FINDINGS: ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects.
CONCLUSION: The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.
TRIAL REGISTRATION: This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).
PMID: 28498840 [PubMed - as supplied by publisher]
http://ift.tt/2pIC6KZ
Nifuroxazide prompts antitumor immune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma.
Nifuroxazide prompts antitumor immune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma.
Oncol Rep. 2017 May 05;:
Authors: Zhao T, Jia H, Cheng Q, Xiao Y, Li M, Ren W, Li C, Feng Y, Feng Z, Wang H, Zheng J
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and high mortality. At present, vaccination with tumor cell lysate (TCL) loaded dendritic cells (DC) has been shown to be an effective therapy against HCC. However, the ability of promoting the specific T cell immune response is rather weak, influencing the antitumor response. Thus, it is necessary to find a strategy to improve the antitumor effect of TCL-loaded DC. Activation of signal transducer and activator of transcription 3 (STAT3) significantly inhibits antitumor immune response and DC maturity. Nifuroxazide, an antidiarrheal agent, has been proved to directly inhibit STAT3 activation. Thus, we investigated whether nifuroxazide could improve the antitumor immune response in mice vaccinated with TCL-loaded DC. The study provides the theoretical and experimental basis for developing an effective adjuvant for DC vaccine to treat HCC. Our results showed that the administration of nifuroxazide and DC-loaded TCL could significantly improve the survival rate, inhibit the tumor growth, and prompt the antitumor immune responses in mice with orthotopically implanted hepatocarcinomas, thus, possibly providing a new combination strategy to treat HCC.
PMID: 28498414 [PubMed - as supplied by publisher]
http://ift.tt/2r3g75C
Vaccine-based immunotherapeutic approaches to gliomas and beyond.
Vaccine-based immunotherapeutic approaches to gliomas and beyond.
Nat Rev Neurol. 2017 May 12;:
Authors: Weller M, Roth P, Preusser M, Wick W, Reardon DA, Platten M, Sampson JH
Abstract
Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.
PMID: 28497804 [PubMed - as supplied by publisher]
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Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations.
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Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations.
J Neurooncol. 2017 May 11;:
Authors: Balendran S, Liebmann-Reindl S, Berghoff AS, Reischer T, Popitsch N, Geier CB, Kenner L, Birner P, Streubel B, Preusser M
Abstract
Ovarian cancer represents the most common gynaecological malignancy and has the highest mortality of all female reproductive cancers. It has a rare predilection to develop brain metastases (BM). In this study, we evaluated the mutational profile of ovarian cancer metastases through Next-Generation Sequencing (NGS) with the aim of identifying potential clinically actionable genetic alterations with options for small molecule targeted therapy. Library preparation was conducted using Illumina TruSight Rapid Capture Kit in combination with a cancer specific enrichment kit covering 94 genes. BRCA-mutations were confirmed by using TruSeq Custom Amplicon Low Input Kit in combination with a custom-designed BRCA gene panel. In our cohort all eight sequenced BM samples exhibited a multitude of variant alterations, each with unique molecular profiles. The 37 identified variants were distributed over 22 cancer-related genes (23.4%). The number of mutated genes per sample ranged from 3 to 7 with a median of 4.5. The most commonly altered genes were BRCA1/2, TP53, and ATM. In total, 7 out of 8 samples revealed either a BRCA1 or a BRCA2 pathogenic mutation. Furthermore, all eight BM samples showed mutations in at least one DNA repair gene. Our NGS study of BM of ovarian carcinoma revealed a significant number of BRCA-mutations beside TP53, ATM and CHEK2 mutations. These findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian cancer metastasizing to the brain. Based on these findings, pharmacological PARP inhibition could be one potential targeted therapeutic for brain metastatic ovarian cancer patients.
PMID: 28497333 [PubMed - as supplied by publisher]
http://ift.tt/2qCXBB3
Excessively delayed maternal reaction after their perception of decreased fetal movements in stillbirths: Population-based study in Japan
Publication date: Available online 12 May 2017
Source:Women and Birth
Author(s): Shigeki Koshida, Tetsuo Ono, Shunichiro Tsuji, Takashi Murakami, Hisatomi Arima, Kentaro Takahashi
BackgroundFetal movement is the most common method to evaluate fetal well-being. Furthermore, maternal perception of decreased fetal movements is associated with perinatal demise. Previously, we showed that perception of decreased fetal movements was the most common reason for mothers visiting the outpatient department among those who had stillbirths in our region. Further investigation of stillbirths with decreased fetal movements is essential to find a possible way of preventing stillbirth.AimTo investigate maternal reaction time after their perceiving decreased fetal movements among stillbirths in our region of Japan.MethodsThis is a population-based study of stillbirths in Shiga Prefecture, Japan conducted from 2007 to 2011. We sent a questionnaire to each obstetrician who had submitted the stillbirth certificate. We reviewed and evaluated the questionnaires returned from the obstetricians.FindingsThere were 66 cases (35%) with decreased fetal movements among 188 stillbirths in Shiga during the study period. The number of maternal visits to outpatient department after perception of decreased fetal movements within 24h was only seven (11%) among 64 stillbirths diagnosed at outpatient department.ConclusionWe conclude that delayed maternal visit after perceiving decreased fetal movements is frequently observed in stillbirths. Promoting more thorough maternal education on fetal movements, including emphasizing earlier visitation after perceiving decreased fetal movements, may prevent stillbirths.
http://ift.tt/2qcySm9
A 0h/1h protocol for safe early discharge of chest pain patients
Abstract
Objectives
Guidelines recommend a 0h/1h high-sensitivity cardiac troponin T (hs-cTnT) diagnostic strategy in acute chest pain patients. There is however little data on the performance of this strategy when combined with clinical risk stratification. We aimed to evaluate the diagnostic accuracy of an accelerated diagnostic protocol (ADP) using the 0h/1h hs-cTnT strategy together with an adapted Thrombolysis In Myocardial Infarction (TIMI) score and ECG for ruling out major adverse cardiac events (MACE) within 30 days.
Methods
This prospective observational study enrolled consecutive emergency department (ED) chest pain patients. TIMI score variables, ED physicians' assessments of the ECG, and 0 and 1h hs-cTnT were collected. 30-day MACE was defined as acute myocardial infarction, unstable angina (UA), cardiogenic shock, ventricular arrhythmia, atrioventricular-block, cardiac arrest or death of cardiac or unknown cause.
Results
A total of 1020 patients were included in the final analysis. The combination of an adapted TIMI score ≤1, a non-ischemic ECG, and either a 0h hs-cTnT <5 ng/L, or a 0h hs-cTnT <12 ng/L combined with a 1h increase <3 ng/L, identified 432 (42.4%) patients as very low risk with a negative predictive value of 99.5% (95% CI: 98.3 – 99.9) and a negative likelihood ratio of 0.04 (95% CI: 0.01 – 0.14) for 30-day MACE. The ADP missed only 2 patients with UA and no patients with AMI or other forms of MACE.
Conclusion
An ADP using the guideline recommended 0h/1h hs-cTnT strategy rapidly identified patients with a very low risk of 30-day MACE including UA where no further cardiac testing would be needed. This could potentially allow safe early discharge of about 40% of ED chest pain patients.
This article is protected by copyright. All rights reserved.
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Red tattoos, ultraviolet radiation and skin cancer in mice
Abstract
Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and red tattoos may be associated with increased risk of skin cancer due to potential carcinogens in tattoo inks. This combination has not been studied previously.
Immunocompetent C3.Cg/TifBomTac hairless mice (n=99) were tattooed on their back with a popular red tattoo ink. This often used ink is banned for use on humans because of high content of the potential carcinogen 2-anisidine. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured.
All UV-irradiated mice developed SCCs. The time to the onset of the first and second tumour was identical in the red tattooed group compared with the control group (182 vs. 186 days and 196 vs. 203 days, p=ns). Statistically, the third tumour appeared slightly faster in the red tattooed group than in the controls (214 vs 224 days, p=0.043). For the second and third tumour the growth rate was faster in the red tattooed group compared with the control (31 vs 49 days, p=0.009 and 30 vs 38 days, p=0.036).
In conclusion, no spontaneous cancers were observed in skin tattooed with a red ink containing 2-anisidine. However, red tattoos exposed to UVR showed faster tumour onset regarding the third tumour, and faster growth rate of the second and third tumour indicating red ink acts as a co-carcinogen with UVR. The co-carcinogenic effect was weak and may not be clinically relevant.
This article is protected by copyright. All rights reserved.
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Analysis of serum markers of cellular immune activation in patients with bullous pemphigoid
Abstract
Experimental models of bullous pemphigoid (BP), the most frequent subepidermal autoimmune bullous disease, revealed that the immune response leading to blister formation represents an incompletely understood complex process involving different inflammatory cells. In contrast to previous reports commonly focusing on limited molecular and cellular phenotypes of the disease, the aim of this study was to investigate a broad spectrum of markers of cellular immune activation in patients with BP. We found that serum levels of soluble CD4, myeloperoxidase, S100A12, eosinophil cationic protein, and soluble P-selectin were significantly elevated in patients with active BP compared with normal controls. Mast cell tryptase and neopterin serum levels significantly decreased at the time of clinical remission of the patients. Additionally, serum concentrations of soluble IL-2 receptor, mast cell tryptase, and soluble P-selectin were significantly associated with levels of circulating anti-BP180 autoantibodies. Our findings confirm and extend previous reports suggesting some concomitant involvement of a panel of molecules representative for a wide spectrum of cellular players (T cells, mast cells, neutrophils, eosinophils, macrophages, and platelets) orchestrating the inflammatory reaction in BP. These data may favor the employment of broad-spectrum or combined immunosuppressants, potentially together with an anticoagulant treatment, over cell- or molecule-specific targeted therapy in patients with this disorder.
This article is protected by copyright. All rights reserved.
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Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer
Abstract
Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3), and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17, and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL, miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from <HSIL cytology using at least one assay. Overall, SOX1, DCC, and EPB41L3 showed the best discrimination with AUC values of ≥0.80, irrespective of methylation detection assay. In addition to verifying candidate markers from the literature (e.g., SOX1 and EPB41L3), we identified novel markers that may be considered for detection of cervical precancer and cancer and warrant further validation in prospective studies. This article is protected by copyright. All rights reserved.
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Simultaneous inhibition of NMDA and mGlu1/5 receptors by levo-Corydalmine in rat spinal cord attenuates bone cancer pain
Abstract
Bone cancer pain is a challenge for its not completely clarified mechanism and broad clinical morbidity. Therefore, novel and more effective drugs are urgent needed for improvement of patients' quality of life. Glutamate receptors have been associated with the development of the central sensitization of chronic pain. Inhibition of N-methyl-D-aspartate (NMDA) and metabotropic glutamate (mGlu) receptors can effectively attenuate bone cancer pain respectively. Herein, our results indicated that levo-Corydalmine (l-CDL), a compound from Corydalis yanhusuo W.T. Wang, which has been used in traditional Chinese medicine for pain relief could effectively attenuate bone cancer pain induced by tibia bone cavity tumor cell implantation (TCI) through simultaneously inhibiting the NMDA and mGlu1/5 receptors in rat spinal cord without notable side effects. Both intragastric and intrathecal administration of l-CDL significantly alleviated the mechanical hypersensitivity induced by TCI in rats, and the analgesic effect of l-CDL could be reversed by intrathecal administration of NMDA receptor agonist NMDA and mGlu1/5 receptor agonist DHPG but not AMPA receptor agonist AMPA. l-CDL could also selectively suppress NMDA and DHPG induced rapid rise in Ca2+ oscillations in primary cultures neurons of spinal cord in vitro. The antinociception of l-CDL were partially mediated by the reduced phosphorylation of PKC γ and ERK1/2 in spinal cord of TCI rats in a NMDA and mGlu1/5 dependent manner. In conclusion, these results suggested that l-CDL attenuates TCI induced bone cancer pain through simultaneously inhibiting the NMDA and mGlu1/5 receptors and the downstream PKC γ, ERK1/2 signaling pathways in the spinal cord. This article is protected by copyright. All rights reserved.
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TOTAL FATTY ACID CONTENT, ANTIOXIDANT COMPOSITION, ANTIOXIDANT ACTIVITY AND CONTENT OF OIL FROM CRAMBE SEEDS CULTIVATED WITH PHOSPHORUS
Abstract
The objective of this study was to determine parameters of crambe oil culvtived with phosphorus (P), with respect to oil content, fatty acid composition, minor compounds and total antioxidant activity. The experiment followed a randomized block design, with five doses of P (0, 40, 80, 120 and 160 kg P ha−1) and four replications. All results were subjected to analysis of covariance (ANCOVA) 5% significance. The P dose had a negative linear association with δ-tocopherol and total antioxidant activity and a positive association with stigmasterol and total carotenoids. P influenced the concentrations of β-sitosterol and campesterol, whereas the remaining variables (content, α-tocopherol, β+γ-tocopherol, fatty acids, total phenolic compounds and chlorophyll a) were not affected. This study show a positive effect the concentrations of compounds that act as antioxidants in crambe oil, which can influence with its oxidation stability.
Practical applications: Is relevant the studies concerning the oxidative stability of inedible vegetable oils, such as crambe, in terms of the composition of antioxidants and fatty acids, as this affects the conservation, storage and refining costs, and the quality of the products, considering the many uses of this oil, such as biodiesel, lubricants, corrosion inhibitors, synthetic rubber, plastic films, nylon and adhesives, among other products.
http://ift.tt/2qfH573
Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory
The reason why Cystic Fibrosis (CF) is the most common fatal genetic disease among Caucasians has been incompletely studied. We aimed at deepening the hypothesis that CF carriers have a relative protection aga...
http://ift.tt/2raKYtm
Early morning urine collection to improve urinary lateral flow LAM assay sensitivity in hospitalised patients with HIV-TB co-infection
Urine LAM testing has been approved by the WHO for use in hospitalised patients with advanced immunosuppression. However, sensitivity remains suboptimal. We therefore examined the incremental diagnostic sensit...
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Identification of a major Listeria monocytogenes outbreak clone linked to soft cheese in Northern Italy – 2009-2011
Molecular subtyping and enhanced surveillance in Lombardy region identified a cluster of possibly related listeriosis cases from 2006 to 2010. This cluster grouped 31 isolates that belonged to serotype 1/2a an...
http://ift.tt/2rb3DoJ
Total delay in treatment among tuberculous meningitis patients in China: a retrospective cohort study
Currently, there is limited data on the risk factors associated with treatment delay in tuberculous meningitis (TBM). This study aimed to assess the duration of delay in the treatment TBM and to investigate it...
http://ift.tt/2qcfSEw
BGG492 as an adjunctive treatment in patients with partial-onset seizures: A 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study with an open-label extension
Summary
Objectives
To evaluate dose–response relationship of BGG492 as add-on therapy to 1–3 antiepileptic drugs in patients with partial-onset seizures and to investigate safety and tolerability of BGG492.
Methods
This was a 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study (core study) with a 30-week, flexible-dose, open-label extension. In the core study, patients were randomized (1:2) to placebo or BGG492 100 mg t.i.d. in cohort 1, and in cohort 2 patients were randomized (1:4) to placebo or BGG492 150 mg t.i.d. On completion of the core study, eligible patients entered the extension study. Primary outcome measures were total partial seizure frequency per 28 days (core study) and safety and tolerability (extension study).
Results
Overall, 93 patients were randomized (150 mg [n = 44]; 100 mg [n = 24]; placebo [n = 25]), and 81 (87.1%) completed the core study. Fifty-one patients entered and 43 (84.3%) completed the extension study. In the core study, no statistically significant dose–response trend among the BGG492 treatment groups (100 and 150 mg) was observed at the 4-week double-blind maintenance period (weeks 7–10); however, there was higher percent reduction in total partial seizure frequency in the BGG492 150 mg over placebo groups (37.32%; 95% confidence interval [CI] −18.90, 66.95). Dizziness, somnolence, and fatigue were the most common adverse events (AEs), higher in the BGG492 150 mg group than in the 100 mg and placebo groups (dizziness: 14 [31.8%] vs. 3 [12.5%] and 1 [4.0%]; somnolence: 7 [15.9%] vs. 1 [4.2%] and 1 [4.0%]; fatigue: 5 [11.4%] vs. 1 [4.2%] and 1 [4.0%]). During the open-label extension study, 39 (76.5%) patients on BGG492 had AEs, and the most commonly experienced AEs were dizziness (14 [27.5%]) and somnolence (9 [17.6%]).
Significance
There was no significant dose–response trend in the BGG492 treatment groups (100 and 150 mg); however, higher percent reduction over placebo was observed in the BGG492 150 mg group. Safety and tolerability data were consistent with the known safety profile for BGG492, and no new safety risks were identified.
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Novel glycolipid agents for killing cisplatin-resistant human epithelial ovarian cancer cells
Abstract
Background
Chemotherapy resistance is one of the major factors contributing to mortality from human epithelial ovarian cancer (EOC). Identifying drugs that can effectively kill chemotherapy-resistant EOC cells would be a major advance in reducing mortality. Glycosylated antitumour ether lipids (GAELs) are synthetic glycolipids that are cytotoxic to a wide range of cancer cells. They appear to induce cancer cell death in an apoptosis-independent manner.
Methods
Herein, the effectiveness of two GAELs, GLN and MO-101, in killing chemotherapy-sensitive and –resistant EOC cells lines and primary cell samples was tested using monolayer, non-adherent aggregate, and non-adherent spheroid cultures.
Results
Our results show that EOC cells exhibit a differential sensitivity to the GAELs. Strikingly, both GAELs are capable of inducing EOC cell death in chemotherapy-sensitive and –resistant cells grown as monolayer or non-adherent cultures. Mechanistic studies provide evidence that apoptotic-cell death (caspase activation) contributes to, but is not completely responsible for, GAEL-induced cell killing in the A2780-cp EOC cell line, but not primary EOC cell samples.
Conclusions
Studies using primary EOC cell samples supports previously published work showing a GAEL-induced caspase-independent mechanism of death. GAELs hold promise for development as novel compounds to combat EOC mortality due to chemotherapy resistance.
http://ift.tt/2pIhtxF
MicroRNAs for Detection of Pancreatic Neoplasia: Biomarker Discovery by Next-generation Sequencing and Validation in 2 Independent Cohorts
Objective: The aim of our study was to analyze the miRNome of pancreatic ductal adenocarcinoma (PDAC) and its preneoplastic lesion intraductal papillary mucinous neoplasm (IPMN), to find new microRNA (miRNA)-based biomarkers for early detection of pancreatic neoplasia. Objective: Effective early detection methods for PDAC are needed. miRNAs are good biomarker candidates. Methods: Pancreatic tissues (n = 165) were obtained from patients with PDAC, IPMN, or from control individuals (C), from Hospital Clínic of Barcelona. Biomarker discovery was done using next-generation sequencing in a discovery set of 18 surgical samples (11 PDAC, 4 IPMN, 3 C). MiRNA validation was carried out by quantitative reverse transcriptase PCR in 2 different set of samples. Set 1—52 surgical samples (24 PDAC, 7 IPMN, 6 chronic pancreatitis, 15 C), and set 2—95 endoscopic ultrasound-guided fine-needle aspirations (60 PDAC, 9 IPMN, 26 C). Results: In all, 607 and 396 miRNAs were significantly deregulated in PDAC and IPMN versus C. Of them, 40 miRNAs commonly overexpressed in both PDAC and IPMN were selected for further validation. Among them, significant up-regulation of 31 and 30 miRNAs was confirmed by quantitative reverse transcriptase PCR in samples from set 1 and set 2, respectively. Conclusions: miRNome analysis shows that PDAC and IPMN have differential miRNA profiles with respect to C, with a large number of deregulated miRNAs shared by both neoplastic lesions. Indeed, we have identified and validated 30 miRNAs whose expression is significantly increased in PDAC and IPMN lesions. The feasibility of detecting these miRNAs in endoscopic ultrasound-guided fine-needle aspiration samples makes them good biomarker candidates for early detection of pancreatic cancer.http://ift.tt/2r0TAmi
High-frame rate vector flow imaging of the carotid bifurcation
Abstract
Carotid artery atherosclerotic disease is still a significant cause of cerebrovascular morbidity and mortality. A new angle-independent technique, measuring and visualizing blood flow velocities in all directions, called vector flow imaging (VFI) is becoming available from several vendors. VFI can provide more intuitive and quantitative imaging of vortex formation, which is not clearly distinguishable in the color Doppler image. VFI, as quantitative method assessing disturbed flow patterns of the carotid bifurcation, has the potential to allow better understanding of the diagnostic value of complex flow and to enhance risk stratification. This pictorial review article will show which new information VFI adds for the knowledge of hemodynamics in comparison to the conventional ultrasound techniques.
Teaching points
• VFI is an angle-independent technique measuring flow velocities in all directions.
• This kind of VFI is based on a plane wave multidirectional excitation technique.
• VFI allows quantitative assessment of carotid streamlines progression and visualizes vorticity.
• VFI does not allow a precise comprehension of streamlines' 3D shape.
• VFI allows a better understanding of carotid artery complex flows.
http://ift.tt/2qBurCn
Tips and tricks for a safe and effective image-guided percutaneous renal tumour ablation
Abstract
Image-guide thermal ablations are nowadays increasingly used to provide a minimally invasive treatment to patients with renal tumours, with reported good clinical results and low complications rate. Different ablative techniques can be applied, each with some advantages and disadvantages according to the clinical situation. Moreover, percutaneous ablation of renal tumours might be complex in cases where there is limited access for image guidance or a close proximity to critical structures, which can be unintentionally injured during treatment. In the present paper we offer an overview of the most commonly used ablative techniques and of the most important manoeuvres that can be applied to enhance the safety and effectiveness of percutaneous image-guided renal ablation. Emphasis is given to the different technical aspects of cryoablation, radiofrequency ablation, and microwave ablation, on the ideal operating room setting, optimal image guidance, application of fusion imaging and virtual navigation, and contrast enhanced ultrasound in the guidance and monitoring of the procedure. Moreover, a series of protective manoeuvre that can be used to avoid damage to surrounding sensitive structures is presented. A selection of cases of image-guided thermal ablation of renal tumours in which the discussed technique were used is presented and illustrated.
Teaching points
• Cryoablation, radiofrequency and microwave ablation have different advantages and disadvantages.
• US, CT, fusion imaging, and CEUS increase an effective image-guidance.
• Different patient positioning and external compression may increase procedure feasibility.
• Hydrodissection and gas insufflation are useful to displace surrounding critical structures.
• Cold pyeloperfusion can reduce the thermal damage to the collecting system.
http://ift.tt/2raSipr
A confirmed case of sugammadex-induced anaphylaxis in a UK hospital
We report the first published case of confirmed anaphylaxis to sugammadex in a UK hospital. The patient was given a bolus of sugammadex at the end of surgery. Four minutes later, he developed hypotension and a widespread erythematous rash. Multiple epinephrine boluses were administered and a continuous intravenous infusion of epinephrine commenced. The patient later reported auditory awareness, which occurred while the diagnosis of anaphylaxis was being made and initial treatment initiated. Serial serum tryptase levels were consistent with a type I hypersensitivity reaction. Skin prick and intradermal testing were performed 6 months later confirming allergy to sugammadex. This case restates the potential for hypersensitivity reactions to develop following the administration of sugammadex and makes clinicians aware that such reactions may require prolonged treatment with intravenous infusions of epinephrine. Finally, this case highlights the importance of maintaining or re-establishing anaesthesia while managing the emergent situation in order to avoid unintentional awareness.
http://ift.tt/2qccd9B
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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