Publication date: Available online 20 February 2016
Source:Journal of Oral and Maxillofacial Surgery
Author(s): Achille Tarsitano, Giacomo Del Corso, Claudio Marchetti
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Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Κυριακή 21 Φεβρουαρίου 2016
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Simultaneous identification of abused drugs, benzodiazepines, and new psychoactive substances in urine by liquid chromatography tandem mass spectrometry
Publication date: Available online 20 February 2016
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Hei Hwa Lee, Jong Feng Lee, Shin Yu Lin, Bai Hsiun Chen
A literature search reveals no studies concerning simultaneous identification of commonly abused drugs, benzodiazepines, and new psychoactive substances in urine by liquid chromatography tandem mass spectrometry (LC–MS/MS). We developed and validated an LC–MS/MS method for simultaneous identification of multiple abused drugs, benzodiazepines, and new psychoactive substances in urine from suspected drug abusers. The instrument was operated in multiple-reaction monitoring using an electrospray ionization mode. Chromatograms were separated using an ACE5 C18 column on a gradient of acetonitrile. After liquid–liquid extraction, samples were passed through a 0.22-μm polyvinylidene difluoride filter before injection into the LC–MS/MS. The limits of quantitation ranged from 0.5 ng/mL to 31.3 ng/mL. The linearity ranged from 0.5 ng/mL to 200 ng/mL. The precision results were below 15.4% (intraday) and 18.7% (interday). The intraday accuracy ranged from 85.9% to 121.0%; interday accuracy ranged from 66.1% to 128.7%. The proposed method was applied to 769 urine samples. The most common three drugs identified were ketamine, amphetamine, and opiates. The drug positive rate for one or more drugs was 79.6%. Our results demonstrate the suitability of the LC–MS/MS method for simultaneous identification of multiple abused drugs, benzodiazepines, and new psychoactive substances in urine.
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Anti-HIV seropositivity was related to HBsAg seropositivity among injecting drug users in Taiwan
Publication date: Available online 20 February 2016
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Meng-Hsuan Hsieh, Ming-Yen Hsieh, Chung-Feng Huang, Ming-Lun Yeh, Shu-Chi Wang, Jeng-Fu Yang, Ko Chang, Wei-Ru Lin, Chun-Yu Lin, Tun-Chieh Chen, Jee-Fu Huang, Chia-Yen Dai, Jih-Jin Tsai, Wan-Long Chuang, Ming-Lung Yu
In Taiwan, the number of new cases of human immunodeficiency virus (HIV) infection via drug injection has been increasing since 2003. Due to HIV and hepatitis B virus (HBV) having similar transmission routes, HBV and HIV infections among injecting drug users (IDUs) has become an important public health issue. The aim of this study was explore the prevalence of HBV infection among IDUs with and without HIV infection, and examine whether HIV infection is associated with HBV infection among IDUs in Southern Taiwan. We enrolled 566 IDUs, including 87 anti-HBV positive IDUs and 479 anti-HBV negative IDUs, and also analyzed the results of liver function tests, HBV DNA, anti-HIV, HIV RNA, and CD4 cell count. The results showed that the prevalence of HBV infection among IDUs was 15.4%. The prevalence of hepatitis B surface antigen (HBsAg) was higher among individuals born before 1985 (15.9% vs. 4.0%), but this was not significant. Anti-HIV seropositivity was related to HBsAg seropositivity [odds ratio (OR) = 2.47, 95% confidence interval = 1.26–4.82, p = 0.008). Anti-HCV and anti-HIV were risk factors for abnormal alanine aminotransferase (ALT; OR = 2.11, 95% confidence interval = 1.005–4.42, p = 0.048 and OR = 1.47, 95% confidence interval = 1.02–2.10, p = 0.04, respectively), and HBsAg was not a factor related to abnormal ALT. In conclusion, the prevalence of HBV infection was similar in the general population and in IDUs, and due to anti-HIV seropositivity being significantly related to HBsAg seropositivity, HBV infection among IDUs is still important. We suggest that for IDUs, HBsAg should be monitored closely.
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Heterotopic Renal Autotransplantation in a Porcine Model: A Step-by-Step Protocol
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Evaluation of Planar-Cell-Polarity Phenotypes in Ciliopathy Mouse Mutant Cochlea
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IMPORTANCE OF SERATONIN GENE RELATED PEPTIDE (SGRP) IN MIGRAINE
2016-02-21T11-56-54Z
Source: International Journal of Health and Rehabilitation Sciences (IJHRS)
Sivanandan Ramar, Sankaran Ponnusamy, Salameh Al Dajah.
Migraine is a neurovascular disorder involving trigeminal ganglion characterized by recurrent episodic headache and rise in levels of Serotonin Gene Related Protein (SGRP) in plasma. SGRP is a neuropeptide present in the central and peripheral nervous system that has diverse functions as primary afferent neurotransmitter which is important in nociception. In this study expression of SGRP studied in neurons of trigeminal ganglion in male wistar albino rats. SGRP is expressed in cytoplasm of neurons mainly in the small sized neurons indicating that small sized neurons are mainly involved in nociception. Keyword:.
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Development of a removable head fixation device for longitudinal behavioral and imaging studies in rats
Source:Journal of Neuroscience Methods
Author(s): Yuki Hori, Jun Ogura, Naoki Ihara, Tsunehisa Higashi, Takayuki Tashiro, Manabu Honda, Takashi Hanakawa
BackgroundIn some behavioral neuroscience studies, an attachment is surgically fixed onto the head of an awake animal to allow the animal to perform learning tasks repeatedly in the same position in a task-training system. A recently developed task-training system enables operant conditioning of head-fixed rats within only a few days, and this system has been rigorously applied to record learning-associated neural activity using electrophysiological techniques. However, the head attachment of this device is made of metal and thus is not suitable for simultaneous brain imaging studies with X-ray computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET).New MethodWe developed a novel head fixation device with a removable attachment to position the rat head precisely in both imaging and training devices across different sessions. The device consisted of a removable attachment, a clamp and a stage, all of which were made of PET/MRI compatible acrylic resin. We tested the usefulness of the device with 18F-fluorodeoxyglucose (FDG) PET and CT.ResultsThe new device did not substantially affect 18F-FDG PET images. Repositioning of the rat's head across sessions and experimenters was at a level of submillimeter accuracy.Comparison with Existing MethodThe errors of radioactivity concentration of 18F- FDG in the PET image were lower with the present attachment than with the conventional metal attachment. Repositioning accuracy was considerably improved compared with a visual inspection method.ConclusionsThe developed fixation device is useful for longitudinal behavioral and brain imaging studies in rats.
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Tutoring Trainees to Suture: An Alternative Method for Learning How to Suture and a Way to Compensate for a Lack of Suturing Cases
Publication date: Available online 20 February 2016
Source:Journal of Surgical Education
Author(s): Apinut Wongkietkachorn, Peera Rhunsiri, Pangpoom Boonyawong, Attaporn Lawanprasert, Kasaya Tantiphlachiva
IntroductionTutoring in suturing was developed to compensate for a shortage of suturing cases. The objective of this study was to compare ideal suturing score (ISS; 9 points), suturing time (min:sec), and suture placement error (mm) between medical students completing the suturing tutoring program and medical students attending ordinary medical school training program.MethodsParticipants consisted of 2 groups of medical students who had never performed suturing. The study group had the role of suturing tutor to teach interested high school students. The control group consisted of volunteers from the ordinary medical school program. Skills measurement was performed by having students from both the groups perform 3 vertical mattress sutures on a model. The study group was tested at weeks 1, 9, and 10 to assess improvement. Both the groups were tested at week 10 to compare final learning outcome.ResultsThere were 41 and 40 participants in the study group and the control group, respectively. ISS was significantly improved in the study group from week 1-week 10 (7.0 ± 1.3 vs. 8.2 ± 0.9, p = 0.01). At week 10, the study group had a higher mean ISS than the control group (8.2 ± 0.9 vs. 7.8 ± 1.1, p = 0.68). Mean suturing time and mean placement error were also lower in the study group at the end of suturing training (5:1 ± 1:0 vs. 5:2 ± 1:2, p = 0.13; 7.4 ± 7.4 vs. 8.0 ± 10.8, p = 0.44).ConclusionTutoring trainees to suture can improve a student's ability to learn how to suture.
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Sustained virological response after a 17-day treatment with daclatasvir plus asunaprevir in a cirrhotic patient with hepatitis C virus genotype 1b and null response for peginterferon ribavirin therapy
Abstract
Daclatasvir (DCV) plus asunaprevir (ASV) treatment, an oral therapy for chronic hepatitis C virus (HCV) genotype 1b infection, can achieve a high sustained viral response (SVR) rate within a 24-week treatment period. A 55-year-old Japanese female with cirrhosis and null response for peginterferon plus ribavirin therapy received DCV plus ASV therapy, but she reported a slight fever beginning on treatment day 4. The fever increased to >38.0 °C beginning on treatment day 15 and could not be controlled with antipyretics; thus, the treatment was discontinued on day 17. Although the patient was still positive for HCV RNA 6 days after treatment discontinuation, she achieved an SVR at week 24 after treatment cessation. In some patients with HCV genotype 1b infection, an SVR can be achieved with short-term DCV plus ASV treatment, and HCV RNA positivity at the end of treatment does not always indicate virological failure.
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Practice patterns in the intraoperative use of bispectral index monitoring
Abstract
Assessing the depth of anesthesia and reducing intraoperative awareness has become a focus of much technology development and research in the field of anesthesia. Bispectral index (BIS) is the most widely utilized technology that uses electroencephalogram to provide a measurement of anesthetic depth. There are no definitive guidelines on when BIS should be used. Our aim was to assess actual patterns of intraoperative use of BIS by anesthesia professionals. We retrospectively collected intraoperative data on 55,210 surgical cases at a tertiary care hospital. Variables collected included: age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) physical status, anesthesia provider type and level of training, use of inhalational anesthetics versus total intravenous anesthesia (TIVA), utilization of nitrous oxide, utilization of non-depolarizing neuromuscular blockade, emergency status of surgery, airway type, case duration, and surgical subspecialty. A univariate logistic regression model was fitted. Subsequently, a multivariate logistic regression model was applied. Covariates utilized for the model included age, anesthesia provider level, and length of case. Factors associated with BIS use included increased age, greater ASA physical status, extremes of BMI, use of TIVA, use of a long-acting paralytic agent, use of an endotracheal tube (ETT), emergency surgery, increasing length of case, and certain surgical services. BIS use was associated with previously documented risk factors for intraoperative awareness. These factors are also indicators of case complexity, which may be a major factor among providers deciding when to apply BIS monitoring in the operating room.
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A Review on Animal Models of Stroke: an Update
Source:Brain Research Bulletin
Author(s): Anil Kumar, Aakriti, Varun Gupta
Stroke is one of the major healthcare challenges prevailing across the globe due to its significant rate of mortality and morbidity. Stroke is multifactorial in nature and involves several cellular and molecular signalling cascades that make the pathogenesis complex and treatment difficult. For a deeper understanding of the diverse pathological mechanisms and molecular & cellular cascades during stroke, animal modelling serves as a reliable and an effective tool. This also helps to develop and critically analyse various neuroprotective strategies for the mitigation of this devastating disease. Animal modelling for stroke has been revolutionized with the development of newer and more relevant models or approaches that mimic the clinical setting of stroke to a greater extent. This review analyses experimental models of stroke (ischemic and hemorrhagic) and their reliability in stroke situation. Besides this, the review also stresses upon the use of various preclinical models to understand the pathophysiological mechanisms that operate during stroke and to elucidate new, safe and effective neuroprotective agents to combat this life threatening healthcare concern.
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Pediatric Stroke-MRI
Four old child presented with sudden unconsciousness since 2 days. MRI revealed multifocal T2/FLAIR hyperintense areas in the right thalamic/occipital region-PCA territory, left perisylvian (MCA territory) and left inferior cerebellar hemisphere showing areas of restricted diffusion on DWI and corresponding ADC maps. These findings likely indicate areas of relatively fresh infarction in multifocal vascular territories. Differentials include-causes like hypercoaguable state, vasculitis etc
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The Effectiveness of Manual versus Algometer Pressure Release Techniques for Treating Active Myofascial Trigger Points of the Upper Trapezius
Publication date: Available online 21 February 2016
Source:Journal of Bodywork and Movement Therapies
Author(s): Walaa Abu-Taleb, Aliaa Rehan Youssef, Amir Saleh
Manual pressure release (MPR) is a popular treatment of trigger points. Yet, treatment response may be influenced by inconsistent application of pressure. Further, it may contribute to increased risk of work-related musculoskeletal disorders of the wrist and hand in therapists. Therefore, this study aimed at introducing a novel method to apply pressure using the algometer and to compare its effectiveness to MPR. Forty-five volunteers with active trigger points of the upper trapezius received algometer pressure release (APR), MPR, or sham ultrasound (US). Pain pressure threshold (PPT) and contralateral active and passive neck side-bending ranges were assessed at baseline and immediately after a single session. Results showed no significant differences in post-treatment PPT between the study groups (p>0.05). The APR group showed a significant increase in passive side-bending range compared with the two other groups, whereas active range improved in the APR compared with the US group (p<0.05). Our results show that using APR to apply pressure release to upper trapezius trigger points is more effective compared with manual release and sham US.
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Acute PID-MRI
Clinical Data: Patient presented with 2 days history of pain abdomen and fever. Clinical examination revealed lump in right adnexa.
MRI showed a heterogenous area abutting the uterus on right side extending between uterus & right ovary possibly indicating acute inflammatory tubal lesion. Fluid in POD.
This patient likely requires follow up after a course of intravenous antibiotics.
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CD97/ADGRE5 Inhibits LPS Induced NF-κB Activation through PPAR-γ Upregulation in Macrophages
CD97/ADGRE5 protein is predominantly expressed on leukocytes and belongs to the EGF-TM7 receptors family. It mediates granulocytes accumulation in the inflammatory tissues and is involved in firm adhesion of PMNC on activated endothelial cells. There have not been any studies exploring the role of CD97 in LPS induced NF-κB activation in macrophages. Therefore, we first measured the CD97 expression in LPS treated human primary macrophages and subsequently analyzed the levels of inflammatory factor TNF-α and transcription factor NF-κB in these macrophages that have been manipulated with either CD97 knockdown or overexpression. We found that a reported anti-inflammatory transcription factor, PPAR-γ, was involved in the CD97 mediated NF-κB suppression. Furthermore, by immunofluorescence staining, we established that CD97 overexpression not only inhibited LPS induced p65 expression in the nucleus but also promoted the PPAR-γ expression. Moreover, using CD97 knockout THP-1 cells, we further demonstrated that CD97 promoted PPAR-γ expression and decreased LPS induced NF-κB activation. In conclusion, CD97 plays a negative role in LPS induced NF-κB activation and TNF-α secretion, partly through PPAR-γ upregulation.
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Adsorption Analysis of Lactoferrin to Titanium, Stainless Steel, Zirconia, and Polymethyl Methacrylate Using the Quartz Crystal Microbalance Method
It is postulated that biofilm formation in the oral cavity causes some oral diseases. Lactoferrin is an antibacterial protein in saliva and an important defense factor against biofilm development. We analyzed the adsorbed amount of lactoferrin and the dissociation constant (Kd) of lactoferrin to the surface of different dental materials using an equilibrium analysis technique in a 27 MHz quartz crystal microbalance (QCM) measurement. Four different materials, titanium (Ti), stainless steel (SUS), zirconia (ZrO2) and polymethyl methacrylate (PMMA), were evaluated. These materials were coated onto QCM sensors and the surfaces characterized by atomic force microscopic observation, measurements of surface roughness, contact angles of water, and zeta potential. QCM measurements revealed that Ti and SUS showed a greater amount of lactoferrin adsorption than ZrO2 and PMMA. Surface roughness and zeta potential influenced the lactoferrin adsorption. On the contrary, the Kd value analysis indicated that the adsorbed lactoferrin bound less tightly to the Ti and SUS surfaces than to the ZrO2 and PMMA surfaces. The hydrophobic interaction between lactoferrin and ZrO2 and PMMA is presumed to participate in better binding of lactoferrin to ZrO2 and PMMA surfaces. It was revealed that lactoferrin adsorption behavior was influenced by the characteristics of the material surface.
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Establishment and Characterization of a Telomerase-Immortalized Sheep Trophoblast Cell Line
The primary sheep trophoblast cells (STCs) have a finite lifespan in culture. This feature limits the scope for long-term in vitro studies with STCs. This study was an attempt to establish and characterize a telomerase-immortalized sheep trophoblast cell line. STCs were isolated and purified by using Percoll and specific immunoaffinity purification, respectively. The purified STCs were transfected with a plasmid carrying sequences of human telomerase reverse transcriptase (hTERT) to create immortalized sheep trophoblast cell line (hTERT-STCs). hTERT-STCs showed a stable expression of hTERT gene, serially passaged for a year, and showed active proliferation without signs of senescence. Cytokeratin 7 (CK-7), secreted human chorionic gonadotrophin subunit β (CG-β), placental lactogen (PL), and endogenous jaagsiekte sheep retrovirus (enJSRV) envelope genes were expressed in hTERT-STCs. Transwell cell invasion assay indicated that hTERT-STCs still possessed the same invasive characteristics as normal primary sheep trophoblast cells. hTERT-STCs could not grow in soft agar and did not develop into tumors in nude mice. In this study, we established a strain of immortalized sheep trophoblast cell line which could be gainfully employed in the future as an experimental model to study trophoblast cells with secretory function, invasive features, and probable biological function of enJSRV envelope genes.
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A Simple Allergist-Led Intervention Improves Resident Training in Anaphylaxis
Physicians underrecognize and undertreat anaphylaxis. Effective interventions are needed to improve physician knowledge and competency regarding evidence-based anaphylaxis diagnosis and management (ADAM). We designed and evaluated an educational program to improve ADAM in pediatrics, internal medicine, and emergency medicine residents from two academic medical centers. Anonymous questionnaires queried participants' demographics, prior ADAM clinical experience, competency, and comfort. A pretest assessing baseline knowledge preceded a 45-minute allergist-led evidence-based presentation, including practice with epinephrine autoinjectors, immediately followed by a posttest. A follow-up test assessed long-term knowledge retention twelve weeks later. 159 residents participated in the pretest, 152 participated in the posttest, and 86 participated in the follow-up test. There were no significant differences by specialty or site. With a possible score of 10, the mean pretest score (7.31 ± 1.50) was lower than the posttest score (8.79 ± 1.29) and follow-up score (8.17 ± 1.72) ( for both). Although participants' perceived confidence in diagnosing or managing anaphylaxis improved from baseline to follow-up ( for both), participants' self-reported clinical experience with ADAM or autoinjector use was unchanged. Allergist-led face-to-face educational intervention improves residents' short-term knowledge and perceived confidence in ADAM. Limited clinical experience or reinforcement contributes to the observed decreased knowledge.
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TWiV 377: Chicken with a side of Zika
Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove,
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Potential Effects of Silymarin and Its Flavonolignan Components in Patients with β-Thalassemia Major: A Comprehensive Review in 2015
Major β-thalassemia (β-TM) is one of the most common inherited hemolytic types of anemia which is caused as a result of absent or reduced synthesis of β-globin chains of hemoglobin. This defect results in red blood cells lysis and chronic anemia that can be treated by multiple blood transfusions and iron chelation therapy. Without iron chelation therapy, iron overload will cause lots of complications in patients. Antioxidant components play an important role in the treatment of the disease. Silymarin is an antioxidant flavonoid isolated from Silybum marianum plant. In the present study, we reviewed clinical and experimental studies investigating the use of silymarin prior to September 1, 2015, using PubMed, ISI Web of Knowledge, Science Direct, Scopus, Ovid, and Cochrane Library databases and we evaluated the potential effects of silymarin on controlling the complications induced by iron overload in patients with β-TM. Based on the results of the present study, we can conclude that silymarin may be useful as an adjuvant for improving multiple organ dysfunctions.
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Roles of microRNA-124a and microRNA-30d in breast cancer patients with type 2 diabetes mellitus
Abstract
The aim of the study is to explore roles of microRNA (miR)-124a and miR-30d in breast cancer (BC) patients with type 2 diabetes mellitus (T2DM). A total of 144 cases of confirmed diagnosed BC with T2DM, T2DM, BC, or healthy people were enrolled. Among them, BC patients with T2DM were regarded as the experiment group (n = 36), patients with T2DM as the Dm group (n = 36), patients with BC as the Bc group (n = 36), and healthy subjects as the healthy group (n = 36). The fasting insulin resistance index, glycosylated hemoglobin, and estradiol were measured. MiR-124a and miR-30d expressions were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The insulin resistance index was significantly higher in the experiment group compared to the other three groups (all P < 0.05). The glycated hemoglobin was in a normal range in the Bc group and healthy group, but was higher in the experiment group and the Bc group compared to that in the healthy group (both P < 0.05). The serum estradiol level was obviously higher in the Bc group compared with that in the Dm group and the experiment group (both P < 0.05). The expressions of miR-124a and miR-30d were positively correlated with insulin resistance index, BMI and glycosylated hemoglobin (miR-124a r = 0.659, r = 0.785, and r = 0.862; miR-30d r = 0.742, r = 0.805, r = 0.765; all P < 0.001). Insulin resistance index was an independent factor for expressions of miR124-a and miR-30d. MiR-124a and miR-30d were correlated with insulin resistance and development of BC with T2DM. Although the mechanism is not clear, miR-124a and miR-30d potentially may be used as therapeutic targets and prognostic markers for BC patients with T2DM.
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Rab23 is overexpressed in human astrocytoma and promotes cell migration and invasion through regulation of Rac1
Abstract
Rab23 overexpression has been implicated in several human cancers. However, its biological roles and molecular mechanism in astrocytoma have not been elucidated. The aim of this study is to explore clinical significance and biological roles of Rab23 in astrocytoma. We observed negative Rab23 staining in normal astrocytes and positive staining in 39 out of 86 (45 %) astrocytoma specimens using immunohistochemistry. The positive rate of Rab23 was higher in grades III and IV (56.5 %, 26/46) than grades I + II astrocytomas (32.5 %, 13/40, p < 0.05). Transfection of Rab23 plasmid was performed induced A172 cell proliferation, colony formation, invasion, and migration, while Rab23 depletion with siRNA reduced these abilities of U87 cells. In addition, we found that Rab23 transfection upregulated while its depletion reduced Rac1 activity. Treatment of transfected cells with a Rac1 inhibitor decreased Rac1 activity and invasion. In conclusion, Rab23 serves as an important oncoprotein in human astrocytoma by regulating cell invasion and migration through Rac1 activity.
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A DIVA vaccine for cross-protection against Salmonella
Publication date: 4 March 2016
Source:Vaccine, Volume 34, Issue 10
Author(s): Bradley L. Bearson, Shawn M.D. Bearson, Jalusa D. Kich
Swine are often asymptomatic carriers of Salmonella spp., a leading cause of human bacterial foodborne disease. Vaccination against Salmonella is effective for protecting animal health and enhancing food safety. However, with >2500 Salmonella serovars, current vaccines for swine offer limited cross-protection against heterologous serovars. Also, existing vaccines can interfere with surveillance programs that monitor the Salmonella status of swine herds. To overcome Salmonella vaccine limitations, we rationally designed and constructed an attenuated Salmonella enterica serovar Typhimurium vaccine (BBS 866) by deleting multiple small regulatory RNA (sRNA) genes (omrA, omrB, rybB, micA, and invR) in combination with an rfaH mutation. We vaccinated swine intranasally at 3-weeks of age with PBS (mock-vaccinated), BBS 866 or BBS 202 (S. Typhimurium rfaH, Bearson et al., Front Vet Sci 2014;1:9.) and challenged at 7-weeks of age with virulent S. Choleraesuis, a swine pathogen. Vaccination with BBS 866 enhanced protection against S. Choleraesuis by significantly limiting the duration of fever, weight loss, the levels of circulating INFγ, and the total number of swine with S. Choleraesuis septicemia. Vaccination with either BBS 866 or BBS 202 significantly reduced S. Choleraesuis colonization of both systemic (spleen and liver) and gastrointestinal (Peyer's Patch, Ileocecal lymph nodes, and cecum) tissues. Similar to our earlier report for BBS 202, the BBS 866 vaccine strain can be used in swine without compromising the differentiation of infected from vaccinated animals (DIVA). Therefore, the attenuated S. Typhimurium BBS 866 strain, containing mutations in rfaH and multiple sRNAs, addresses the limitations of current Salmonella vaccines by providing cross-protection against Salmonella serovars in swine without interfering with established monitoring programs for Salmonella surveillance.
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Comparison of the PRNT and an immune fluorescence assay in yellow fever vaccinees receiving immunosuppressive medication
Source:Vaccine, Volume 34, Issue 10
Author(s): Rosanne W. Wieten, Emile F.F. Jonker, Daan K.J. Pieren, Caspar J. Hodiamont, Pieter P.A.M. van Thiel, Eric C.M. van Gorp, Adriëtte W. de Visser, Martin P. Grobusch, Leo G. Visser, Abraham Goorhuis
BackgroundThe 17D-yellow fever (YF) vaccination is considered contraindicated in immune-compromised patients; however, accidental vaccination occurs. In this population, measuring the immune response is useful in clinical practice.MethodsIn this study we compare two antibody tests (the Immune Fluorescence Assay and the Plaque Reduction Neutralization Test) in a group of Dutch immune-compromised travellers with a median of 33 days (IQR [28–49]) after primary YF vaccination.ResultsWe collected samples of 15 immune-compromised vaccinees vaccinated with the 17D yellow fever vaccine between 2004 and 2012. All samples measured in the plaque reduction neutralization test yielded positive results (>80% virus neutralization with a 1:10 serum dilution). Immune Fluorescence Assay sensitivity was 28% (95% CI [0.12–0.49]). No adverse events were reported.ConclusionsAll immune-compromised patients mounted an adequate response with protective levels of virus neutralizing antibodies to the 17-D YF vaccine. No adverse effects were reported. Compared to the plaque reduction neutralization test, the sensitivity of the Immune Fluorescence Assay test was low. Further research is needed to ascertain that 17D vaccination in immune-compromised patients is safe.
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High-throughput characterization of virus-like particles by interlaced size-exclusion chromatography
Source:Vaccine, Volume 34, Issue 10
Author(s): Christopher Ladd Effio, Stefan A. Oelmeier, Jürgen Hubbuch
The development and manufacturing of safe and effective vaccines relies essentially on the availability of robust and precise analytical techniques. Virus-like particles (VLPs) have emerged as an important and valuable class of vaccines for the containment of infectious diseases. VLPs are produced by recombinant protein expression followed by purification procedures to minimize the levels of process- and product-related impurities. The control of these impurities is necessary during process development and manufacturing. Especially monitoring of the VLP size distribution is important for the characterization of the final vaccine product. Currently used methods require long analysis times and tailor-made assays. In this work, we present a size-exclusion ultra-high performance liquid chromatography (SE-UHPLC) method to characterize VLPs and quantify aggregates within 3.1min per sample applying interlaced injections. Four analytical SEC columns were evaluated for the analysis of human B19 parvo-VLPs and murine polyoma-VLPs. The optimized method was successfully used for the characterization of five recombinant protein-based VLPs including human papillomavirus (HPV) VLPs, human enterovirus 71 (EV71) VLPs, and chimeric hepatitis B core antigen (HBcAg) VLPs pointing out the generic applicability of the assay. Measurements were supported by transmission electron microscopy and dynamic light scattering. It was demonstrated that the iSE-UHPLC method provides a rapid, precise and robust tool for the characterization of VLPs. Two case studies on purification tools for VLP aggregates and storage conditions of HPV VLPs highlight the relevance of the analytical method for high-throughput process development and process monitoring of virus-like particles.
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Editorial Board/Aims and Scope
Source:Vaccine, Volume 34, Issue 10
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Activation of cross-reactive mucosal T and B cell responses in human nasopharynx-associated lymphoid tissue in vitro by Modified Vaccinia Ankara-vectored influenza vaccines
Source:Vaccine
Author(s): Jennifer Mullin, Muhammed S. Ahmed, Ravi Sharma, Navdeep Upile, Helen Beer, Priya Achar, Suttida Puksuriwong, Francesca Ferrara, Nigel Temperton, Paul McNamara, Teresa Lambe, Sarah C. Gilbert, Qibo Zhang
Recent efforts have been focused on the development of vaccines that could induce broad immunity against influenza virus, either through T cell responses to conserved internal antigens or B cell response to cross-reactive haemagglutinin (HA). We studied the capacity of Modified Vaccinia Ankara (MVA)-vectored influenza vaccines to induce cross-reactive immunity to influenza virus in human nasopharynx-associated lymphoid tissue (NALT) in vitro. Adenotonsillar cells were isolated and stimulated with MVA vaccines expressing either conserved nucleoprotein (NP) and matrix protein 1 (M1) (MVA-NP-M1) or pandemic H1N1 HA (MVA-pdmH1HA). The MVA vaccine uptake and expression, and T and B cell responses were analyzed. MVA-vectored vaccines were highly efficient infecting NALT and vaccine antigens were highly expressed by B cells. MVA-NP-M1 elicited T cell response with greater numbers of IFNγ-producing CD4+ T cells and tissue-resident memory T cells than controls. MVA-pdmH1HA induced cross-reactive anti-HA antibodies to a number of influenza subtypes, in an age-dependent manner. The cross-reactive antibodies include anti-avian H5N1 and mainly target HA2 domain. Conclusion: MVA vaccines are efficient in infecting NALT and the vaccine antigen is highly expressed by B cells. MVA vaccines expressing conserved influenza antigens induce cross-reactive T and B cell responses in human NALT in vitro, suggesting the potential as mucosal vaccines for broader immunity against influenza.
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Venom conjugated polylactide applied as biocompatible material for passive and active immunotherapy against scorpion envenomation
Source:Vaccine
Author(s): Sana Ayari-Riabi, Thomas Trimaille, Kamel Mabrouk, Denis Bertin, Didier Gigmes, Zakaria Benlasfar, Ahlem Zaghmi, Balkiss Bouhaouala-Zahar, Mohamed Elayeb
Scorpion envenoming represents a public health issue in subtropical regions of the world. Treatment and prevention needs to promote antitoxin immunity. Preserving antigenic presentation while removing toxin effect remains a major challenge in toxin vaccine development. Among particulate adjuvant, particles prepared with poly (d,l-lactide) polymer are the most extensively investigated due to their excellent biocompatibility and biodegradability. The aim of this study is to develop surfactant-free PLA nanoparticles that safely deliver venom toxic fraction to enhance specific immune response. PLA nanoparticles are coated with AahG50 (AahG50/PLA) and BotG50 (BotG50/PLA): a toxic fraction purified from Androctonus australis hector and Buthus occitanus tunetanus venoms, respectively. Residual toxicities are evaluated following injections of PLA-containing high doses of AahG50 (or BotG50). Immunization trials are performed with the detoxified fraction administered alone without adjuvant. A comparative study of the effect of Freund is also included. The neutralizing capacity of sera is determined in naive mice. Six months later, immunized mice are challenged subcutaneously, with increased doses of AahG50.Subcutaneous lethal dose 50 (LD50) of AahG50 and BotG50 is of 575μg/kg and 1300μg/kg respectively. By comparison, BotG50/PLA is totally innocuous while 50% of tested mice survive 2875μg AahG50/kg. Alhydrogel and Freund are not able to detoxify such a high dose. Cross-antigenicity between particulate and soluble fraction is also, ensured. AahG50/PLA and BotG50/PLA induce high antibody levels in mice serum. The neutralizing capacity per mL of anti-venom was 258μg/mL and 186μg/mL calculated for anti-AahG50/PLA and anti-BotG50/PLA sera, respectively. Animals immunized with AahG50/PLA are protected against AahG50 injected dose of 3162μg/kg as opposed all non-immunized mice died at this dose. We find that the detoxification approach based PLA nanoparticles, benefit the immunogenicity and protective efficacy of venom immunogen.
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Effect of change in sequence of administration of DTwP and Hepatitis B vaccines on perception of pain in infants: A randomized control trial
Source:Vaccine
Author(s): Mithilesh Kumar, Amit Upadhyay, Jeevika Singh, Manika Chhabra, Abhishek Singh, Navratan Kumar Gupta, Aditya Bhat, C.P. Yadav
ObjectiveThis study was designed with objective to study pain response of infants to change in sequence of administration of Hepatitis B and DTwP vaccines.MethodsThis was a randomized parallel control trial. The study was carried out in the immunization clinic of the Department of Pediatrics, LLRM Medical College, Meerut. One hundred and thirty healthy term infants up to 4 months of age were injected either DTwP vaccine first or Hepatitis B vaccine first, followed one minute later by the other vaccine.ResultBaseline characteristics did not differ between the groups. The mean (SD) of AUC of MFCS and NIPS was significantly more in DF group as compared to HF group (for MFCS 25.5±5.4 versus 22.5±5.5, p<0.01; for NIPS 31.77±5.5 versus 27.64±6.9, p<0.01). Similarly mean (SD) of AUC of Heart rate and saturation of oxygen showed significant variation in DF group as compared to HF group (for heart rate 591.6±55 versus 559.6±49, p<0.01; for SpO2 326.4±12 versus 335±8, p<0.01).ConclusionThese results showed that infant experienced lesser pain when Hepatitis B was administered first than when DTwP vaccine was given first.
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Astragaloside IV improves the isoproterenol-induced vascular dysfunction via attenuating eNOS uncoupling-mediated oxidative stress and inhibiting ROS-NF-κB pathways
Publication date: April 2016
Source:International Immunopharmacology, Volume 33
Author(s): Chonghua Xu, Futian Tang, Meili Lu, Jing Yang, Ronghui Han, Meng Mei, Jin Hu, Mingsheng Zhou, Hongxin Wang
ObjectiveOxidative stress and inflammation are regarded as two important triggers of endothelial dysfunction and play pivotal role in progression of vascular damage associated with cardiac hypertrophy. Our previous studies demonstrated that astragaloside IV (AsIV) could protect against cardiac hypertrophy in rats induced by isoproterenol (Iso), but its effects on the aorta are not known. In present study, we aimed to assess the effects of AsIV on Isoinduced vascular dysfunction.MethodsSprague-Dawley (SD) rats were treated with Iso (10mg/kg/d) alone or in combination with AsIV (50mg/kg/d).ResultsCompared with Isotreated alone, AsIV significantly reduced the ratios of heart weight/body weight and left ventricular weight/body weight. AsIV ameliorated the increased vasoconstriction response to phenylephrine induced by Iso and suppressed superoxide anion generation in rat aorta, increased endothelial nitric oxide synthase (eNOS) dimer/monomer ratio and its critical cofactor tetrahydrobiopterin (BH4) content in aorta as well as the NO production in the serum, reduced the plasmatic peroxynitrite (ONOO–). Moreover, in contrast with Isotreatment alone, AsIV decreased the ratio of nuclear-to-cytosolic protein expression of the NF-κB p65 subunit while enhanced its inhibited protein expression of IκB-α, down-regulated mRNA expression of IL-1β, IL-6 and TNF-α of the aorta.ConclusionsThe present study suggested that AsIV protects against Isoinduced vascular dysfunction probably via attenuating eNOS uncoupling-mediated oxidative stress and inhibiting ROS-NF-κB pathways.
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Carnitine and/or Acetylcarnitine Deficiency as a Cause of Higher Levels of Ammonia
Blood carnitine and/or acetylcarnitine deficiencies are postulated in the literature as possible causes of higher ammonia levels. The aim of this study was to investigate if the use of valproic acid, the age of the patients, or certain central nervous system pathologies can cause carnitine and/or acetylcarnitine deficiency leading to increased ammonia levels. Three groups of patients were studied: (A) epileptic under phenytoin monotherapy (); (B) with bipolar disorder under valproic acid treatment (); (C) elderly (). Plasma valproic acid and blood carnitine and acyl carnitine profiles were determined using a validated HPLC and LC-MS/MS method, respectively. Blood ammonia concentration was determined using an enzymatic automated assay. Higher ammonia levels were encountered in patients under valproic acid treatment and in the elderly. This may be due to the lower carnitine and/or acetylcarnitine found in these patients. Patients with controlled seizures had normal carnitine and acetylcarnitine levels. Further studies are necessary in order to conclude if the uncontrolled bipolar disorder could be the cause of higher carnitine and/or acetylcarnitine levels.
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Microelectrical Impedance Spectroscopy for the Differentiation between Normal and Cancerous Human Urothelial Cell Lines: Real-Time Electrical Impedance Measurement at an Optimal Frequency
Purpose. To distinguish between normal (SV-HUC-1) and cancerous (TCCSUP) human urothelial cell lines using microelectrical impedance spectroscopy (μEIS). Materials and Methods. Two types of μEIS devices were designed and used in combination to measure the impedance of SV-HUC-1 and TCCSUP cells flowing through the channels of the devices. The first device (μEIS-OF) was designed to determine the optimal frequency at which the impedance of two cell lines is most distinguishable. The μEIS-OF trapped the flowing cells and measured their impedance at a frequency ranging from 5 kHz to 1 MHz. The second device (μEIS-RT) was designed for real-time impedance measurement of the cells at the optimal frequency. The impedance was measured instantaneously as the cells passed the sensing electrodes of μEIS-RT. Results. The optimal frequency, which maximized the average difference of the amplitude and phase angle between the two cell lines (), was determined to be 119 kHz. The real-time impedance of the cell lines was measured at 119 kHz; the two cell lines differed significantly in terms of amplitude and phase angle (). Conclusion. The μEIS-RT can discriminate SV-HUC-1 and TCCSUP cells by measuring the impedance at the optimal frequency determined by the μEIS-OF.
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One of the most well-established age-related changes in neural activity disappears after controlling for visual acuity
Source:NeuroImage, Volume 130
Author(s): Fábio H.G. Porto, Erich S. Tusch, Anne M. Fox, Brittany R. Alperin, Phillip J. Holcomb, Kirk R. Daffner
Numerous studies using a variety of imaging techniques have reported age-related differences in neural activity while subjects carry out cognitive tasks. Surprisingly little attention has been paid to the potential impact of age-associated changes in sensory acuity on these findings. Studies in the visual modality frequently report that their subjects had "normal or corrected- to-normal vision." However, in most cases, there is no indication that visual acuity was actually measured, and it is likely that the investigators relied largely on self-reported visual status of subjects, which is often inaccurate. We investigated whether differences in visual acuity influence one of the most commonly observed findings in the event-related potentials literature on cognitive aging, a reduction in posterior P3b amplitude, which is an index of cognitive decision-making/updating. Well-matched young (n=26) and old adults (n=29) participated in a visual oddball task. Measured visual acuity with corrective lenses was worse in old than young adults. Results demonstrated that the robust age-related decline in P3b amplitude to visual targets disappeared after controlling for visual acuity, but was unaffected by accounting for auditory acuity. Path analysis confirmed that the relationship between age and diminished P3b to visual targets was mediated by visual acuity, suggesting that conveyance of suboptimal sensory data due to peripheral, rather than central, deficits may undermine subsequent neural processing. We conclude that until the relationship between age-associated differences in visual acuity and neural activity during experimental tasks is clearly established, investigators should exercise caution attributing results to differences in cognitive processing.
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Quantitative analysis of MRI-guided attenuation correction techniques in time-of-flight brain PET/MRI
Publication date: 15 April 2016
Source:NeuroImage, Volume 130
Author(s): Abolfazl Mehranian, Hossein Arabi, Habib Zaidi
PurposeIn quantitative PET/MR imaging, attenuation correction (AC) of PET data is markedly challenged by the need of deriving accurate attenuation maps from MR images. A number of strategies have been developed for MRI-guided attenuation correction with different degrees of success. In this work, we compare the quantitative performance of three generic AC methods, including standard 3-class MR segmentation-based, advanced atlas-registration-based and emission-based approaches in the context of brain time-of-flight (TOF) PET/MRI.Materials and methodsFourteen patients referred for diagnostic MRI and 18F-FDG PET/CT brain scans were included in this comparative study. For each study, PET images were reconstructed using four different attenuation maps derived from CT-based AC (CTAC) serving as reference, standard 3-class MR-segmentation, atlas-registration and emission-based AC methods. To generate 3-class attenuation maps, T1-weighted MRI images were segmented into background air, fat and soft-tissue classes followed by assignment of constant linear attenuation coefficients of 0, 0.0864 and 0.0975cm−1 to each class, respectively. A robust atlas-registration based AC method was developed for pseudo-CT generation using local weighted fusion of atlases based on their morphological similarity to target MR images. Our recently proposed MRI-guided maximum likelihood reconstruction of activity and attenuation (MLAA) algorithm was employed to estimate the attenuation map from TOF emission data. The performance of the different AC algorithms in terms of prediction of bones and quantification of PET tracer uptake was objectively evaluated with respect to reference CTAC maps and CTAC-PET images.ResultsQualitative evaluation showed that the MLAA-AC method could sparsely estimate bones and accurately differentiate them from air cavities. It was found that the atlas-AC method can accurately predict bones with variable errors in defining air cavities. Quantitative assessment of bone extraction accuracy based on Dice similarity coefficient (DSC) showed that MLAA-AC and atlas-AC resulted in DSC mean values of 0.79 and 0.92, respectively, in all patients. The MLAA-AC and atlas-AC methods predicted mean linear attenuation coefficients of 0.107 and 0.134cm−1, respectively, for the skull compared to reference CTAC mean value of 0.138cm−1. The evaluation of the relative change in tracer uptake within 32 distinct regions of the brain with respect to CTAC PET images showed that the 3-class MRAC, MLAA-AC and atlas-AC methods resulted in quantification errors of −16.2±3.6%, −13.3±3.3% and 1.0±3.4%, respectively. Linear regression and Bland–Altman concordance plots showed that both 3-class MRAC and MLAA-AC methods result in a significant systematic bias in PET tracer uptake, while the atlas-AC method results in a negligible bias.ConclusionThe standard 3-class MRAC method significantly underestimated cerebral PET tracer uptake. While current state-of-the-art MLAA-AC methods look promising, they were unable to noticeably reduce quantification errors in the context of brain imaging. Conversely, the proposed atlas-AC method provided the most accurate attenuation maps, and thus the lowest quantification bias.
Graphical abstract
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Primary motor cortex changes after amputation correlate with phantom limb pain and the ability to move the phantom limb
Source:NeuroImage, Volume 130
Author(s): Estelle Raffin, Nathalie Richard, Pascal Giraux, Karen T. Reilly
A substantial body of evidence documents massive reorganization of primary sensory and motor cortices following hand amputation, the extent of which is correlated with phantom limb pain. Many therapies for phantom limb pain are based upon the idea that plastic changes after amputation are maladaptive and attempt to normalize representations of cortical areas adjacent to the hand area. Recent data suggest, however, that higher levels of phantom pain are associated with stronger local activity and more structural integrity in the missing hand area rather than with reorganization of neighbouring body parts. While these models appear to be mutually exclusive they could co-exist, and one reason for the apparent discrepancy between them might be that no single study has examined the organisation of lip, elbow, and hand movements in the same participants. In this study we thoroughly examined the 3D anatomy of the central sulcus and BOLD responses during movements of the hand, elbow, and lips using MRI techniques in 11 upper-limb amputees and 17 healthy control subjects. We observed different reorganizational patterns for all three body parts as the former hand area showed few signs of reorganization, but the lip and elbow representations reorganized and shifted towards the hand area. We also found that poorer voluntary control and higher levels of pain in the phantom limb were powerful drivers of the lip and elbow topological changes. In addition to providing further support for the maladaptative plasticity model, we demonstrate for the first time that motor capacities of the phantom limb correlate with post-amputation reorganization, and that this reorganization is not limited to the face and hand representations but also includes the proximal upper-limb.
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Human habenula segmentation using myelin content
Publication date: 15 April 2016
Source:NeuroImage, Volume 130
Author(s): Joo-won Kim, Thomas P. Naidich, Benjamin A. Ely, Essa Yacoub, Federico De Martino, Mary E. Fowkes, Wayne K. Goodman, Junqian Xu
The habenula consists of a pair of small epithalamic nuclei located adjacent to the dorsomedial thalamus. Despite increasing interest in imaging the habenula due to its critical role in mediating subcortical reward circuitry, in vivo neuroimaging research targeting the human habenula has been limited by its small size and low anatomical contrast. In this work, we have developed an objective semi-automated habenula segmentation scheme consisting of histogram-based thresholding, region growing, geometric constraints, and partial volume estimation steps. This segmentation scheme was designed around in vivo 3T myelin-sensitive images, generated by taking the ratio of high-resolution T1w over T2w images. Due to the high myelin content of the habenula, the contrast-to-noise ratio with the thalamus in the in vivo 3T myelin-sensitive images was significantly higher than the T1w or T2w images alone. In addition, in vivo 7T myelin-sensitive images (T1w over T2*w ratio images) and ex vivo proton density-weighted images, along with histological evidence from the literature, strongly corroborated the in vivo 3T habenula myelin contrast used in the proposed segmentation scheme. The proposed segmentation scheme represents a step toward a scalable approach for objective segmentation of the habenula suitable for both morphological evaluation and habenula seed region selection in functional and diffusion MRI applications.
Graphical abstract
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New tissue priors for improved automated classification of subcortical brain structures on MRI
Publication date: 15 April 2016
Source:NeuroImage, Volume 130
Author(s): S. Lorio, S. Fresard, S. Adaszewski, F. Kherif, R. Chowdhury, R.S. Frackowiak, J. Ashburner, G. Helms, N. Weiskopf, A. Lutti, B. Draganski
Despite the constant improvement of algorithms for automated brain tissue classification, the accurate delineation of subcortical structures using magnetic resonance images (MRI) data remains challenging. The main difficulties arise from the low gray-white matter contrast of iron rich areas in T1-weighted (T1w) MRI data and from the lack of adequate priors for basal ganglia and thalamus. The most recent attempts to obtain such priors were based on cohorts with limited size that included subjects in a narrow age range, failing to account for age-related gray-white matter contrast changes. Aiming to improve the anatomical plausibility of automated brain tissue classification from T1w data, we have created new tissue probability maps for subcortical gray matter regions. Supported by atlas-derived spatial information, raters manually labeled subcortical structures in a cohort of healthy subjects using magnetization transfer saturation and R2* MRI maps, which feature optimal gray-white matter contrast in these areas. After assessment of inter-rater variability, the new tissue priors were tested on T1w data within the framework of voxel-based morphometry. The automated detection of gray matter in subcortical areas with our new probability maps was more anatomically plausible compared to the one derived with currently available priors. We provide evidence that the improved delineation compensates age-related bias in the segmentation of iron rich subcortical regions. The new tissue priors, allowing robust detection of basal ganglia and thalamus, have the potential to enhance the sensitivity of voxel-based morphometry in both healthy and diseased brains.
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Frequent Flyers: Rookie dinner duties
See all of Lenwood Brown's comics.
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Electrospun pH-sensitive core-shell polymer nanocomposites fabricated using a tri-axial process
Publication date: Available online 20 February 2016
Source:Acta Biomaterialia
Author(s): Chen Yang, Deng-Guang Yu, Deng Pan, Xin-Kuan Liu, Xia Wang, S.W. Annie Bligh, Gareth R. Williams
A modified tri-axial electrospinning process was developed for the generation of a new type of pH-sensitive polymer/lipid nanocomposite. The systems produced are able to promote both dissolution and permeation of a model poorly water-soluble drug. First, we show that it is possible to run a tri-axial procress with only one of the three fluids being electrospinnable. Using an electrospinnable middle fluid of Eudragit S100 (ES100) with pure ethanol as the outer solvent and an unspinnable lecithin-diclofenac sodium (PL-DS) core solution, nanofibers with linear morphology and clear core/shell structures can be fabricated continuously and smoothly. X-ray diffraction proved that these nanofibers are structural nanocomposites with the drug present in an amorphous state. In vitro dissolution tests demonstrated that the formulations could preclude release in acidic conditions, and that the drug was released from the fibers in two successive steps at neutral pH. The first step is the dissolution of the shell ES100 and the conversion of the core PL-DS into sub-micron sized particles. This frees some DS into solution, and later the remaining DS is gradually released from the PL-DS particles through diffusion. Ex vivo permeation results showed that the composite nanofibers give a more than two-fold uplift in the amount of DS passing through the colonic membrane as compared to pure DS; 74% of the transmitted drug was in the form of PL-DS particles. The new tri-axial electrospinning process developed in this work provides a platform to fabricate structural nanomaterials, and the core-shell polymer-PL nanocomposites we have produced have significant potential applications for oral colon-targeted drug delivery.Statement of SignificanceA modified tri-axial electrospinning is demonstrated to create a new type of core-shell pH-sensitive polymer/lipid nanocomposites, in which an electrospinnable middle fluid is exploited to support the un-spinnable outer and inner fluids. The structural nanocomposites are able to provide a colon-targeted sustained release and an enhanced permeation performance of diclofenac sodium. The developed tri-axial process can provide a platform for fabricating new structural nanomaterials with high quality. The strategy of a combined usage of polymeric excipients and phosphilipid in a core-shell format should provide new possibilities of developing novel drug delivery systems for efficacious oral administration of poorly-water soluble drugs.
Graphical abstract
Highlights
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TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial
Abstract
Background
Cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Whereas not all high grade CIN lesions progress to cervical cancer, the natural history and risk of progression of individual lesions remain unpredictable. Therefore, high-grade CIN is currently treated by surgical excision: large loop excision of the transformation zone (LLETZ). This procedure has potential complications, such as acute haemorrhage, prolonged bleeding, infection and preterm birth in subsequent pregnancies. These complications could be prevented by development of a non-invasive treatment modality, such as topical imiquimod treatment.
The primary study objective is to investigate the efficacy of topical imiquimod 5 % cream for the treatment of high-grade CIN and to develop a biomarker profile to predict clinical response to imiquimod treatment. Secondary study objectives are to assess treatment side-effects, disease recurrence and quality of life during and after different treatment modalities.
Methods/design
The study design is a randomized controlled trial. One hundred forty women with a histological diagnosis of high-grade CIN (CIN 2–3) will be randomized into two arms: imiquimod treatment during 16 weeks (experimental arm) or immediate LLETZ (standard care arm). Treatment efficacy will be evaluated by colposcopy with diagnostic biopsies at 20 weeks for the experimental arm. Successful imiquimod treatment is defined as regression to CIN 1 or less, successful LLETZ treatment is defined as PAP 1 after 6 months. Disease recurrence will be evaluated by cytology at 6, 12 and 24 months after treatment. Side-effects will be evaluated using a standardized report form. Quality of life will be evaluated using validated questionnaires at baseline, 20 weeks and 1 year after treatment. Biomarkers, reflecting both host and viral factors in the pathophysiology of CIN, will be tested at baseline with the aim of developing a predictive biomarker profile for the clinical response to imiquimod treatment.
Discussion
Treatment of high-grade CIN lesions with imiquimod in a selected patient population may diminish complications as a result of surgical intervention. More knowledge on treatment efficacy, side effects and long-term recurrence rates after treatment is necessary.
Trial registration
EU Clinical Trials Register EU-CTR2013-001260-34. Registered 18 March 2013.
Medical Ethical Committee approval number: NL44336.068.13 (Medical Ethical Committee Maastricht University Hospital, University of Maastricht).
Affiliation: Maastricht University Hospital.
Registration number ClinicalTrials.gov: NCT02329171.
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Foregut Duplication Cyst of the Stomach: A Case Report and Review of the Literature
Duplication cyst of the stomach is a rare congenital malformation, typically diagnosed in the first year of life. In most adult cases the cyst remains asymptomatic, but patients may present with abdominal symptoms including epigastric discomfort or pain. We present a case of a 65-year-old male with an asymptomatic gastric tumor diagnosed incidentally during initial workup of his esophageal adenocarcinoma. Computed tomography revealed a low density soft tissue tumor near the gastroesophageal junction. Endoscopic ultrasonography demonstrated a cystic lesion as a hypoechoic round mass with well-defined borders. Following complete laparoscopic resection, microscopic review revealed a cyst lined with respiratory pseudostratified ciliated columnar epithelium and layers of smooth muscle with an outermost thin fibrous capsule consistent with a foregut duplication cyst.
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De Novo Transcriptome Sequencing of Olea europaea L. to Identify Genes Involved in the Development of the Pollen Tube
In olive (Olea europaea L.), the processes controlling self-incompatibility are still unclear and the molecular basis underlying this process are still not fully characterized. In order to determine compatibility relationships, using next-generation sequencing techniques and a de novo transcriptome assembly strategy, we show that pollen tubes from different olive plants, grown in vitro in a medium containing its own pistil and in combination pollen/pistil from self-sterile and self-fertile cultivars, have a distinct gene expression profile and many of the differentially expressed sequences between the samples fall within gene families involved in the development of the pollen tube, such as lipase, carboxylesterase, pectinesterase, pectin methylesterase, and callose synthase. Moreover, different genes involved in signal transduction, transcription, and growth are overrepresented. The analysis also allowed us to identify members in actin and actin depolymerization factor and fibrin gene family and member of the Ca2+ binding gene family related to the development and polarization of pollen apical tip. The whole transcriptomic analysis, through the identification of the differentially expressed transcripts set and an extended functional annotation analysis, will lead to a better understanding of the mechanisms of pollen germination and pollen tube growth in the olive.
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Effect of TENS on stimulation of saliva in postmenopausal women with or without oral dryness – An interventional study
Publication date: Available online 20 February 2016
Source:Journal of Oral Biology and Craniofacial Research
Author(s): Aravinda Konidena, Dheeraj Sharma, Gagan Puri, Avani Dixit, Deepa Jatti, Rajesh Gupta
BackgroundDecreased estrogen levels in postmenopausal women may cause an increase in oral symptoms including dry mouth, burning sensation of the mouth, and taste alterations. Management of salivary gland hypofunction by various modalities had been tried with variable results and associated side effects or discomfort.AimTo evaluate the effects of transcutaneous electric nerve stimulation (TENS) on whole salivary flow rate in postmenopausal females with and without oral dryness.MethodsFifty postmenopausal women, based on their response to Xerostomia Inventory, were divided into 2 groups of 25 each; group 1 were postmenopausal women with oral dryness (PMD+OD) and group 2 were postmenopausal women without oral dryness (PMD−OD). Unstimulated whole saliva collection was done by low forced spitting method. External salivary stimulation of parotid gland by electrodes of TENS unit was done and sialometry was repeated. The salivary flow rates were compared within both groups before and after stimulation and between the two groups.ResultsThe mean salivary flow rates at baseline were statistically significantly lower in the PMD+OD group than the PMD−OD group. There was a mean increase of 0.33ml and 0.46ml with TENS stimulation in PMD+OD and PMD−OD groups, respectively.ConclusionPostmenopausal women with perception of oral dryness had lower salivary flow rates. 90% of the subjects, irrespective of oral dryness status, responded to TENS therapy. TENS stimulation resulted in a statistically significant increase in the quantity of whole saliva flow rate in postmenopausal women with or without oral dryness.
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Role of Transforming Growth Factor-β1 and Smads Signaling Pathway in Intrauterine Adhesion
The aim of the study was to evaluate the role of Smad3, Smad7, and TGF-β1 in intrauterine adhesion (IUA) patients and experimental rabbit models. 60 IUA patients, 30 control participants, and 18 female rabbits were enrolled in this study. We found that the plasma concentrations and protein expressions of TGF-β1 were significantly increased in patients and experimental rabbits compared to those in controls (). Furthermore, the mRNA and protein expression levels of Smad3 were significantly elevated, while Smad7 level was markedly decreased in the patients and experimental rabbits compared with controls (). This altered ratio recommended that IUA was positively correlated to the mRNA and protein expression levels of Smad3, Smad7, and TGF-β1 in blood and uterine tissue. Moreover, we used the specific inhibitor of Smad3 (SIS3) in experimental rabbit. SIS3 obviously reduced the mRNA and protein expression of smad3 and TGF-β1, while it increased Smad7 expression in the treatment groups as compared with IUA rabbits (). Our study suggested that TGF-β1/Smad3/smad7 is a major pathway which plays an important role in the regulation of the IUA and specific inhibitor of Smad3 (SIS3) may provide a new therapeutic strategy for IUA.
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Altered Resting-State Amygdala Functional Connectivity after Real-Time fMRI Emotion Self-Regulation Training
Real-time fMRI neurofeedback (rtfMRI-nf) is a promising tool for enhancing emotion regulation capability of subjects and for the potential alleviation of neuropsychiatric disorders. The amygdala is composed of structurally and functionally distinct nuclei, such as the basolateral amygdala (BLA) and centromedial amygdala (CMA), both of which are involved in emotion processing, generation, and regulation. However, the effect of rtfMRI-nf on the resting-state functional connectivity (rsFC) of BLA and CMA remains to be elucidated. In our study, participants were provided with ongoing information on their emotion states by using real-time multivariate voxel pattern analysis. Results showed that participants presented significantly increased rsFC of BLA and CMA with prefrontal cortex, rostral anterior cingulate cortex, and some others related to emotion after rtfMRI-nf training. The findings provide important evidence for the emotion regulation effectiveness of rtfMRI-nf training and indicate its usefulness as a tool for the self-regulation of emotion.
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Pacemaker Created in Human Ventricle by Depressing Inward-Rectifier K+ Current: A Simulation Study
Cardiac conduction disorders are common diseases which cause slow heart rate and syncope. The best way to treat these diseases by now is to implant electronic pacemakers, which, yet, have many disadvantages, such as the limited battery life and infection. Biopacemaker has been expected to replace the electronic devices. Automatic ventricular myocytes (VMs) could show pacemaker activity, which was induced by depressing inward-rectifier K+ current (). In this study, a 2D model of human biopacemaker was created from the ventricular endocardial myocytes. We examined the stability of the created biopacemaker and investigated its driving capability by finding the suitable size and spatial distribution of the pacemaker for robust pacing and driving the surrounding quiescent cardiomyocytes. Our results suggest that the rhythm of the pacemaker is similar to that of the single cell at final stable state. The driving force of the biopacemaker is closely related to the pattern of spatial distribution of the pacemaker.
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THYROSIM App for Education and Research Predicts Potential Health Risks of Over-the-Counter (OTC) Thyroid Supplements.
THYROSIM App for Education and Research Predicts Potential Health Risks of Over-the-Counter (OTC) Thyroid Supplements.
Thyroid. 2016 Feb 19;
Authors: Han SX, Eisenberg M, Larsen PR, DiStefano Iii JJ
Abstract
BACKGROUND: Computer simulation tools for education and research are making increasingly effective use of the internet and personal devices. To facilitate these activities in endocrinology and metabolism, we developed and further validated a mechanistically-based simulator of human thyroid hormone and thyrotropin regulation dynamics, implementing it as a facile and freely accessible web-based and personal device application (the THYROSIM app). We elucidate and demonstrate its utility here in a research context by exploring key physiological effects of over-the-counter thyroid supplements.
METHODS: THYROSIM has a simple and intuitive user interface for teaching and conducting simulated "what-if" experiments. User-selectable "experimental" test-input dosages (oral, IV-pulses, IV-infusions) are represented by animated graphical icons integrated with a cartoon of the hypothalamic-pituitary-thyroid axis. Simulations of familiar T3, T4 and TSH temporal dynamic responses to these exogenous stimuli are reported graphically along with normal ranges on the same single interface page; and multiple sets of simulated experimental results are superimposable, to facilitate comparative analyses.
RESULTS AND CONCLUSIONS: We show that THYROSIM accurately reproduces a wide range of published clinical study data reporting hormonal kinetic responses to large and small oral hormone challenges. Simulation examples of partial-thyroidectomies and malabsorption illustrate typical usage, by optionally changing thyroid gland secretion and/or gut absorption rates - expressed as percentages of normal - as well as additions of oral hormone dosing, all directly on the interface, and visualizing the kinetic responses to these challenges. Classroom and patient education usage - with public health implications - is illustrated by predictive simulated responses to nonprescription thyroid health supplements analyzed previously for T3 and T4 content. Notably, we found T3 in supplements has potentially more serious pathological effects than does T4 - concomitant with low-normal TSH levels. Some preparations contain enough T3 to generate thyrotoxic conditions, with supernormal serum T3-spiking and subnormal serum T4 and TSH levels and, in some cases, with normal or low-normal range TSH levels due to thyroidal axis negative feedback. These results suggest that appropriate regulation of these products is needed.
PMID: 26895744 [PubMed - as supplied by publisher]
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WEIGHT LOSS AND VARIATION OF LEVOTHYROXINE (L-T4) REQUIREMENTS IN HYPOTHYROID OBESE PATIENTS AFTER BARIATRIC SURGERY.
WEIGHT LOSS AND VARIATION OF LEVOTHYROXINE (L-T4) REQUIREMENTS IN HYPOTHYROID OBESE PATIENTS AFTER BARIATRIC SURGERY.
Thyroid. 2016 Feb 19;
Authors: Fierabracci P, Martinelli S, Tamberi A, Piaggi P, Basolo A, Pelosini C, Ricco I, Magno S, Querci G, Ceccarini G, Scartabelli G, Salvetti G, Vitti P, Santini F
Abstract
BACKGROUND: Obesity and hypothyroidism are both common disorders within the general population. Obese hypothyroid subjects require higher doses of L-T4 as compared to normal weight individuals. Previous studies on the effects of bariatric surgery on L-T4 dose requirements in hypothyroid subjects provided conflicting results. The aim of this study was to evaluate the L-T4 requirements in a group of obese subjects with acquired hypothyroidism, before and after weight loss achieved by bariatric surgery.
METHODS: Ninety-three obese hypothyroid subjects (age: 48 ± 9 yrs, BMI: 45.9 ± 5.6 kg/m2), were evaluated before and 28 ± 8 months after bariatric surgery. Changes in the L-T4 dose, anthropometric measures, and hormone values were evaluated. In 20 patients data of body composition, assessed by dual energy X-ray absorptiometry, were also analyzed.
RESULTS: On average, after weight loss, a significant reduction of the total dose of L-T4 was documented (from 130.6 ± 48.5 to 116.2 ± 38.6 µg/day, p<0.001). The L-T4 dose had to be reduced in 47 patients, it was unchanged in 34 while it had to be increased in 12 patients affected by autoimmune thyroiditis. Reduction of the L-T4 dose was proportional to reduction of the lean mass.
CONCLUSIONS: The weight loss that is achieved with modern surgical bariatric procedures is associated with a reduction of L-T4 requirements in most hypothyroid subjects, which appears related to a decrease of the lean mass. Occasionally, a concurrent decline of residual thyroid function, as it occurs in autoimmune thyroiditis, can counteract this phenomenon and eventually produce an increase of L-T4 needs. We believe that during the weight loss phase that follows bariatric surgery there is no need for preventive adjustments of the L-T4 dose, but serum thyroid hormones and TSH should be periodically monitored, to detect possible variations of L-T4 requirements and to allow proper corrections of the therapy.
PMID: 26895690 [PubMed - as supplied by publisher]
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Characterization of IXINITY® (Trenonacog Alfa), a Recombinant Factor IX with Primary Sequence Corresponding to the Threonine-148 Polymorph
The goal of these studies was to extensively characterize the first recombinant FIX therapeutic corresponding to the threonine-148 (Thr-148) polymorph, IXINITY (trenonacog alfa [coagulation factor IX (recombinant)]). Gel electrophoresis, circular dichroism, and gel filtration were used to determine purity and confirm structure. Chromatographic and mass spectrometry techniques were used to identify and quantify posttranslational modifications. Activity was assessed as the ability to activate factor X (FX) both with and without factor VIIIa (FVIIIa) and in a standard clotting assay. All results were consistent across multiple lots. Trenonacog alfa migrated as a single band on Coomassie-stained gels; activity assays were normal and showed 97%γ-carboxylation and underwent the appropriate structural change upon binding calcium ions. Trenonacog alfa was activated normally with factor XIa (FXIa); once activated it bound to FVIIIa and FXa. When activated to FIXa, it was inhibited efficiently by antithrombin. Glycosylation patterns were similar to plasma-derived FIX with sialic acid content consistent with the literature reports of good pharmacokinetic performance. These studies have shown that trenonacog alfa is a highly pure product with a primary sequence and posttranslational modifications consistent with the common Thr-148 polymorphism of plasma-derived FIX.
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