Publications by authors named "Anna-Maria Costa"

42 Publications

Adding saliva testing to oropharyngeal and deep nasal swab testing increases PCR detection of SARS-CoV-2 in primary care and children.

Med J Aust 2021 Jul 20. Epub 2021 Jul 20.

The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC.

Objective: To compare the concordance and acceptability of saliva testing with standard-of-care oropharyngeal and bilateral deep nasal swab testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in children and in general practice.

Design: Prospective multicentre diagnostic validation study.

Setting: Royal Children's Hospital, and two general practices (cohealth, West Melbourne; Cirqit Health, Altona North) in Melbourne, July-October 2020.

Participants: 1050 people who provided paired saliva and oropharyngeal-nasal swabs for SARS-CoV-2 testing.

Main Outcome Measures: Numbers of cases in which SARS-CoV-2 was detected in either specimen type by real-time polymerase chain reaction; concordance of results for paired specimens; positive percent agreement (PPA) for virus detection, by specimen type.

Results: SARS-CoV-2 was detected in 54 of 1050 people with assessable specimens (5%), including 19 cases (35%) in which both specimens were positive. The overall PPA was 72% (95% CI, 58-84%) for saliva and 63% (95% CI, 49-76%) for oropharyngeal-nasal swabs. For the 35 positive specimens from people aged 10 years or more, PPA was 86% (95% CI, 70-95%) for saliva and 63% (95% CI, 45-79%) for oropharyngeal-nasal swabs. Adding saliva testing to standard-of-care oropharyngeal-nasal swab testing increased overall case detection by 59% (95% CI, 29-95%). Providing saliva was preferred to an oropharyngeal-nasal swab by most participants (75%), including 141 of 153 children under 10 years of age (92%).

Conclusion: In children over 10 years of age and adults, saliva testing alone may be suitable for SARS-CoV-2 detection, while for children under 10, saliva testing may be suitable as an adjunct to oropharyngeal-nasal swab testing for increasing case detection.
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http://dx.doi.org/10.5694/mja2.51188DOI Listing
July 2021

COVID-19 public health measures and respiratory viruses in children in Melbourne.

J Paediatr Child Health 2021 Jun 3. Epub 2021 Jun 3.

Department of Microbiology, Royal Children's Hospital, Melbourne, Victoria, Australia.

Aim: To describe the epidemiology of respiratory viruses in children before and during the 2020 SARS-CoV-2 pandemic and the relationship to public health measures instituted by the Victorian government.

Methods: Retrospective audit of respiratory viruses at a tertiary paediatric hospital in Melbourne from January 2015 up to week 47, 2020 in children under 18 years of age. The proportion of positive cases in weeks 1-47 in 2015-2019 (period 1) were compared to weeks 1-47, 2020 (period 2), and reviewed in the context of public health restrictions in Victoria.

Results: An annual average of 4636 tests were performed in period 1 compared to 3659 tests in period 2. Proportions of positive influenza A virus, influenza B virus, respiratory syncytial virus (RSV) and human parainfluenza virus were significantly reduced in period 2 compared to period 1: 77.3, 89.4, 68.6 and 66.9% reductions, respectively (all P < 0.001). From week 12-47, 2020, 28 893 SARS-CoV-2 tests were performed with a 0.64% positivity rate. Influenza viruses were not detected after week 17, RSV was not detected after week 35.

Conclusions: Strict public health measures and border closures were successful in eliminating community transmission of SARS-CoV-2 in Melbourne. This was associated with a significant reduction in other respiratory virus infections in children. Identifying sustainable and effective ongoing public health interventions to reduce transmission of RSV and influenza could result in reduced morbidity and mortality in children and requires further research.
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http://dx.doi.org/10.1111/jpc.15601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242487PMC
June 2021

Rapid detection of human respiratory syncytial virus A and B by duplex real-time RT-PCR.

J Virol Methods 2021 08 10;294:114171. Epub 2021 May 10.

WHO Collaborating Centre for Reference and Research on Influenza, Victoria Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Elizabeth Street, Melbourne, VIC, Australia. Electronic address:

Respiratory syncytial virus (RSV) is a common cause of acute respiratory disease worldwide, especially in young children. The World Health Organization (WHO) has initiated an RSV Surveillance Pilot program that aims to perform worldwide RSV surveillance, requiring the development of reliable and rapid molecular methods to detect and identify RSV. A duplex real-time RT-PCR assay developed for simultaneous detection of both A and B subtypes of RSV was included as part of this program. This duplex assay targeted a conserved region of the RSV polymerase gene and was validated for analytical sensitivity, specificity, reproducibility and clinical performance with a wide range of respiratory specimens. The assay was highly specific for RSV and did not react with non-RSV respiratory pathogens, including the SARS-CoV-2 virus.
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http://dx.doi.org/10.1016/j.jviromet.2021.114171DOI Listing
August 2021

Evaluation of E-Health Applications for Paediatric Patients with Refractory Epilepsy and Maintained on Ketogenic Diet.

Nutrients 2021 Apr 9;13(4). Epub 2021 Apr 9.

Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

E-health technologies improve healthcare quality and disease management. The aim of this study was to develop a ketogenic diet management app as well as a website about this dietary treatment and to evaluate the benefits of giving caregivers access to various web materials designed for paediatric patients with refractory epilepsy. Forty families participated in the questionnaire survey, from January 2016 to March 2016. All caregivers were exposed to paper-based materials about the ketogenic diet, whereas only 22 received the app, called KetApp, and videos produced by dieticians. Caregivers with free access to web materials were more satisfied than the others with the informative material provided by the centre ( 0.001, Mann-Whitney test). Indeed, they showed a better attitude towards treatment, and they became more aware of dietary management in comparison to the control group ( 0.001). Moreover, caregivers provided with web materials were stimulated to pursue the treatment ( 0.002) and to introduce it to their children and other people ( 0.001). Additionally, caregivers supplied with web materials were more willing to help other families in choosing the ketogenic diet ( 0.004). Overall, these findings indicate that web materials are beneficial for caregivers of paediatric patients with refractory epilepsy in our centres. Thus, the use of e-health applications could be a promising tool in the daily aspects of ketogenic diet management, and it is especially of value in the attempt to start or maintain the diet during the ongoing COVID-19 pandemic crisis.
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http://dx.doi.org/10.3390/nu13041240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069190PMC
April 2021

and prevalence and associated factors among women presenting to a pregnancy termination and contraception clinic, 2009-2019.

Sex Transm Infect 2021 Mar 29. Epub 2021 Mar 29.

Centre for Women's Infectious Diseases, Royal Women's Hospital, Parkville, Victoria, Australia

Background: Risk of pelvic inflammatory disease associated with and is increased after termination of pregnancy (TOP) and may be increased after insertion of intrauterine devices (IUDs). Screening prior to these procedures is recommended only for . We examined and prevalence and associated factors among women presenting to a pregnancy termination and contraception service over 10 years.

Methods: Retrospective analysis of clinical data collected from 17 573 women aged 15-45 years in 2009-2019 and for 266 . positive women tested for macrolide resistance-associated mutations in 2016-2019.

Results: and prevalence was 3.7% and 3.4%, respectively. In multivariable analyses, shared risk factors were younger age (p<0.001, for both and ), socioeconomic disadvantage (p=0.045 and p=0.008, respectively) and coinfection (p<0.001, for both sexually transmitted infections), with 10.1% of positive women also positive for . Additional risk factors were earlier year of visit (p=0.001) for and for residing outside a major city (p=0.013). The proportion of infections tested between 2016 and 2019 with macrolide resistance-associated mutations was 32.7%.

Conclusions: Given the high level of antimicrobial resistance and the prevalence of coinfection, testing positive women for could be considered in this setting to prevent further spread of resistant infections. Further research is required into the causal link between and pelvic inflammatory disease in women undergoing TOP and IUD insertion.
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http://dx.doi.org/10.1136/sextrans-2020-054695DOI Listing
March 2021

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect.

Pharmaceuticals (Basel) 2021 Feb 6;14(2). Epub 2021 Feb 6.

Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Abrupt withdrawal from antiepileptic drugs is followed by increased occurrence of epileptic seizures, a phenomenon known as the "rebound effect". By stopping treatment with levetiracetam (LEV 300 mg/kg/day, = 15; vs. saline, = 15), we investigated the rebound effect in adult male Sprague-Dawley rats. LEV was continuously administered using osmotic minipumps, 7 weeks after the intraperitoneal administration of kainic acid (15 mg/kg). The effects of LEV were determined by comparing time intervals, treatments, and interactions between these main factors. Seizures were evaluated by video-electrocorticographic recordings and power band spectrum analysis. Furthermore, we assessed endogenous neurosteroid levels by liquid chromatography-electrospray-tandem mass spectrometry. LEV significantly reduced the percentage of rats experiencing seizures, reduced the seizure duration, and altered cerebral levels of neurosteroids. In the first week of LEV discontinuation, seizures increased abruptly up to 700% ( = 0.002, Tukey's test). The power of delta band in the seizure postictal component was related to the seizure occurrence after LEV withdrawal ( = 0.73, < 0.001). Notably, allopregnanolone hippocampal levels were positively related to the seizure occurrence ( = 0.51, = 0.02) and to the power of delta band ( = 0.67, = 0.004). These findings suggest a role for the seizure postictal component in the rebound effect, which involves an imbalance of hippocampal neurosteroid levels.
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http://dx.doi.org/10.3390/ph14020127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914513PMC
February 2021

Augmentation of endogenous neurosteroid synthesis alters experimental status epilepticus dynamics.

Epilepsia 2020 09 14;61(9):e129-e134. Epub 2020 Sep 14.

Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Neurosteroids can modulate γ-aminobutyric acid type A receptor-mediated inhibitory currents. Recently, we discovered that the neurosteroids progesterone, 5α-dihydroprogesterone, allopregnanolone, and pregnanolone are reduced in the cerebrospinal fluid of patients with status epilepticus (SE). However, it is undetermined whether neurosteroids influence SE. For this reason, first we evaluated whether the inhibitor of adrenocortical steroid production trilostane (50 mg/kg) could modify the levels of neurosteroids in the hippocampus and neocortex, and we found a remarkable increase in pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone levels using liquid chromatography tandem mass spectrometry. Second, we characterized the dynamics of SE in the presence of the varied neurosteroidal milieu by a single intraperitoneal kainic acid (KA; 15 mg/kg) injection in trilostane-treated rats and their controls. Convulsions started in advance in the trilostane group, already appearing 90 minutes after the KA injection. In contrast to controls, convulsions prevalently developed as generalized seizures with loss of posture in the trilostane group. However, this effect was transient, and convulsions waned 2 hours before the control group. Moreover, electrocorticographic traces of convulsions were shorter in trilostane-treated rats, especially at the 180-minute (P < .001) and 210-minute (P < .01) time points. These findings indicate that endogenous neurosteroids remarkably modulate SE dynamics.
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http://dx.doi.org/10.1111/epi.16654DOI Listing
September 2020

Allopregnanolone and Pregnanolone Are Reduced in the Hippocampus of Epileptic Rats, but Only Allopregnanolone Correlates with Seizure Frequency.

Neuroendocrinology 2021 3;111(6):536-541. Epub 2020 Jun 3.

Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy,

Background: Neurosteroids modulate epileptic activity by interacting with the γ-aminobutyric acid type A receptor, but their brain levels are still undetermined.

Objectives: We aimed to establish neurosteroid levels in the neocortex and hippocampus by liquid chromatography/mass spectrometry in epileptic rats.

Methods: Kainic acid-treated rats were continuously monitored up to 9 weeks to determine seizure frequency by video electrocorticography (n = 23) and compared to age-matched controls monitored in the same manner (n = 11).

Results: Decreased allopregnanolone (-50%; p < 0.05, Mann-Whitney test) and pregnanolone levels (-64%; p < 0.01) were found in the hippocampus, whereas pregnenolone sulfate, pregnenolone, progesterone, and 5α-dihydroprogesterone were nonsignificantly reduced. No changes were found in the neocortex. Moreover, allopregnanolone (but not pregnanolone) levels were positively correlated with seizure frequency (r2 = 0.4606, p < 0.01).

Conclusion: These findings indicate a selective reduction in hippocampal levels of 3α-reduced neurosteroids. This reduction was partially mitigated by seizures in the case of allopregnanolone.
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http://dx.doi.org/10.1159/000509093DOI Listing
June 2020

Status Epilepticus Dynamics Predicts Latency to Spontaneous Seizures in the Kainic Acid Model.

Cell Physiol Biochem 2020 May;54(3):493-507

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy,

Background/aims: Status epilepticus (SE) might be followed by temporal lobe epilepsy (TLE), a common neurologic disorder characterized by spontaneous recurrent seizures (SRSs). However, the relationship between SE and TLE is still incompletely characterized. For this reason, in a model of TLE we evaluated the lesion extent and the onset of SRSs to determine if they were influenced by the SE dynamics.

Methods: Sixty-two adult male Sprague-Dawley rats were implanted for video-electrocorticographic (v-ECoG) monitoring and intraperitoneally treated with saline or kainic acid (KA, 15 mg/kg) at 8 weeks of age. v-ECoG recordings were obtained during SE, in the following 9 weeks, and assessed by amplitude or power band spectrum. Rats were euthanized 3 or 64 days after SE to evaluate the lesion.

Results: SE lasted about 10 h during which the mean duration of convulsive seizures (CSs) increased from 39 s, at 30 min, to 603 s at 4 h. The gamma power peaked 30 min after the SE onset and its peak was correlated (r²=0.13, p=0.042) with the overall SE duration. Subsequently, the gamma power was reduced under the baseline until the end of SE. The theta power increased at approximately 150% of basal levels 3 h after KA injection, but it went back to basal levels with the full development of CSs. Interestingly, the timing of the first SRS in chronic epilepsy was correlated with the latency to develop the first CS with loss of posture during SE (r²=0.60, p<0.001). Additionally, the overall duration of CSs observed during SE was related to the number of damaged brain regions (r²=0.60, p=0.005), but it did not influence the timing of the first SRS in chronic epilepsy.

Conclusion: Overall, our results show that the onset of chronic epilepsy is modulated by SE dynamics, whereas brain damage is related to prolonged convulsions in SE.
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http://dx.doi.org/10.33594/000000232DOI Listing
May 2020

Monitoring human papillomavirus prevalence among young Australian women undergoing routine chlamydia screening.

Vaccine 2020 01 22;38(5):1186-1193. Epub 2019 Nov 22.

Centre for Women's Infectious Diseases, The Royal Women's Hospital, Melbourne, Victoria, Australia; Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Melbourne School of Population and Global Health, University of Melbourne, Victoria, Australia. Electronic address:

Introduction: Australia has recently implemented major changes in cervical cancer prevention policies including introduction of primary human papillomavirus (HPV) screening starting at age 25, and replacement of the quadrivalent HPV vaccine with the nonavalent vaccine in the national school-based program. We assessed the feasibility and utility of conducting HPV testing in residual clinical specimens submitted for routine Chlamydia trachomatis screening, as a means of tracking HPV vaccine program impact among young sexually active women.

Methods: De-identified residual specimens from women aged 16-24 years submitted for chlamydia testing were collected from three pathology laboratories in Victoria and New South Wales. Limited demographic information, and chlamydia test results were also collected. Patient identifiers were sent directly from the laboratories to the National HPV Vaccination Program Register, to obtain HPV vaccination histories. Samples underwent HPV genotyping using Seegene Anyplex II HPV 28 assay.

Results: Between April and July 2018, 362 residual samples were collected, the majority (60.2%) of which were cervical swabs. Demographic data and vaccination histories were received for 357 (98.6%) women (mean age 21.8, SD 2.0). Overall, 65.6% of women were fully vaccinated, 9.8% partially, and 24.7% unvaccinated. The majority (86.0%) resided in a major city, 35.9% were classified in the upper quintile of socioeconomic advantage and chlamydia positivity was 7.8%.The prevalence of quadrivalent vaccine-targeted types (HPV6/11/16/18) was 2.8% (1.5-5.1%) overall with no differences by vaccination status (p = 0.729). The prevalence of additional nonavalent vaccine-targeted types (HPV31/33/45/52/58) was 19.3% (15.6-23.8%). One or more oncogenic HPV types were detected in 46.8% (95% CI 41.6-52.0%) of women.

Conclusions: HPV testing of residual chlamydia specimens provides a simple, feasible method for monitoring circulating genotypes. Applied on a larger scale this method can be utilised to obtain a timely assessment of nonavalent vaccine impact among young women not yet eligible for cervical screening.
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http://dx.doi.org/10.1016/j.vaccine.2019.11.019DOI Listing
January 2020

STAT-ART: The Promise and Practice of a Rapid Palliative Single Session of MR-Guided Online Adaptive Radiotherapy (ART).

Front Oncol 2019 22;9:1013. Epub 2019 Oct 22.

Department of Human Oncology, UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States.

This work describes a novel application of MR-guided online adaptive radiotherapy (MRgoART) in the management of patients whom urgent palliative care is indicated using statum-adaptive radiotherapy (STAT-ART). The implementation of STAT-ART, as performed at our institution, is presented including a discussion of the advantages and limitations compared to the standard of care for palliative radiotherapy on conventional c-arm linacs. MR-based treatment planning techniques of STAT-ART for density overrides and deformable image registration (DIR) of diagnostic CT to the treatment MR are also addressed.
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http://dx.doi.org/10.3389/fonc.2019.01013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817496PMC
October 2019

Ghrelin Plasma Levels After 1 Year of Ketogenic Diet in Children With Refractory Epilepsy.

Front Nutr 2019 24;6:112. Epub 2019 Jul 24.

Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

The ketogenic diet (KD) is a high-fat, low carbohydrate nutritional treatment adopted in several countries for refractory epilepsy. However, the use of KD is limited by adverse events including growth retardation. In a previous investigation, we demonstrated that ghrelin is reduced in children maintained on KD for 3 months. As ghrelin regulates growth hormone (GH) secretion, it can be hypothesized that growth retardation depends on the reduced ghrelin availability. To assess this hypothesis, in this study we evaluate ghrelin and growth during 1 year of KD. We examined a small cohort of 6 children (2 males and 4 females, age range 3-10.4 years) affected by refractory epilepsy, who received the KD as add-on treatment. All patients were on drug polytherapy. Endpoints of the study were: (i) ghrelin plasma levels at 0, 15, 30, 90, and 365 days from KD onset, (ii) growth, and (iii) seizure control by ketogenesis. Ghrelin levels were -53 and -47% of basal levels, respectively, at 90 and 365 days ( < 0.05 for both). Mean height index scores were reduced, but not significantly, by comparing basal values with those at the end of observation. Instead, body mass index scores slightly increased. Ketosis induced by the KD was within 2-5 mmol/L and satisfactorily reduced the seizure frequency (>50%) in all patients. We show that ghrelin plasma levels are consistently reduced in children with refractory epilepsy and maintained on the KD. This change was associated with low growth indexes in the majority of patients.
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http://dx.doi.org/10.3389/fnut.2019.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668051PMC
July 2019

Analysis of Infection Loads in Mycoplasma genitalium Clinical Specimens by Use of a Commercial Diagnostic Test.

J Clin Microbiol 2019 09 26;57(9). Epub 2019 Aug 26.

Centre for Women's Infectious Disease, Royal Women's Hospital, Parkville, Victoria, Australia.

is a common sexually transmitted infection with a propensity to acquire resistance to commonly used antimicrobial therapies. Bacterial load has been linked to patient symptoms and the success of treatment. In this study, we demonstrate methodology to estimate load from routine diagnostic assays using the ResistancePlus MG test (SpeeDx Pty Ltd., Australia). The method gave comparable quantitation to an -specific 16S rRNA quantitative PCR (qPCR; Spearman  = 0.94) for the samples analyzed ( = 499, including urine and swab types as detailed below) and was, therefore, employed to analyze typical load levels for samples in a diagnostic laboratory (total of 1,012 tests). When stratified by sample type, female urine (median, 826 genomes/ml) had the lowest load. This was significantly lower than median loads for all other sample types (male urine [6.91 × 10 genomes/ml], anal swabs [5.50 × 10], cervical swabs [8.15 × 10], endocervical swabs [3.97 × 10], and vaginal swabs [6.95 × 10]) ( < 0.0001). There were no significant differences in load estimates between the other sample types. Reproducibility of load estimates conducted on the same samples was high (r > 0.85). In conclusion, this methodology to provide load estimates for can be easily integrated into routine diagnostic laboratory workflow. Given the association between organism load, symptoms, and treatment success, load assessment has future diagnostic potential.
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http://dx.doi.org/10.1128/JCM.00344-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711907PMC
September 2019

Pharmacological restoration of gut barrier function in stressed neonates partially reverses long-term alterations associated with maternal separation.

Psychopharmacology (Berl) 2019 May 23;236(5):1583-1596. Epub 2019 May 23.

Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France.

Rationale: Intestinal permeability plays an important role in gut-brain axis communication. Recent studies indicate that intestinal permeability increases in neonate pups during maternal separation (MS).

Objectives: The present study aims to determine whether pharmacological inhibition of myosin light chain kinase (MLCK), which regulates tight junction contraction and controls intestinal permeability, in stressed neonates, protects against the long-term effects of MS.

Methods: Male Wistar rats were exposed to MS (3 h per day from post-natal day (PND)2 to PND14) or left undisturbed and received daily intraperitoneal injection of a MLCK inhibitor (ML-7, 5 mg/kg) or vehicle during the same period. At adulthood, emotional behaviors, corticosterone response to stress, and gut microbiota composition were analyzed.

Results: ML-7 restored gut barrier function in MS rats specifically during the neonatal period. Remarkably, ML-7 prevented MS-induced sexual reward-seeking impairment and reversed the alteration of corticosterone response to stress at adulthood. The effects of ML-7 were accompanied by the normalization of the abundance of members of Lachnospiraceae, Clostridiales, Desulfovibrio, Bacteroidales, Enterorhabdus, and Bifidobacterium in the feces of MS rats at adulthood.

Conclusions: Altogether, our work suggests that improvement of intestinal barrier defects during development may alleviate some of the long-term effects of early-life stress and provides new insight on brain-gut axis communication in a context of stress.
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http://dx.doi.org/10.1007/s00213-019-05252-wDOI Listing
May 2019

Development of a pilot proficiency program for human papillomavirus DNA detection.

Pathology 2018 Oct 20;50(6):659-664. Epub 2018 Aug 20.

Department of Microbiology and Infectious Diseases, Royal Women's Hospital and Department of Microbiology, Royal Children's Hospital, Vic, Australia; Murdoch Children's Research Institute, Vic, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Vic, Australia.

Human papillomavirus (HPV) DNA testing has become routine in many diagnostic laboratories, particularly with changes from cervical cytology to HPV DNA as primary screening as of 1 December 2017 in Australia. External quality assurance (EQA) is essential for assessment of laboratory performance once HPV testing is implemented. The aim of this study was to develop a pilot program to evaluate and determine stability of material that could be utilised in an ongoing external quality assurance program (EQAP). Two sample types were evaluated: cells in PreservCyt solution (ThinPrep) from stored clinical specimens and HPV-seeded swabs. Two panels sent 5 months apart were distributed to 18 Australian and two New Zealand laboratories (participants) for testing by Hybrid Capture 2 (HC2) or alternative molecular methods. Participants were given 1 month to test specimens. Eight ThinPrep specimens in Panel 1 were reported correctly by 73% (11/15) of HC2 participants and 40% (2/5) of participants performing alternative methods. Of eight dry swab specimens, 58% (23/40) and 78% (25/32) were correctly identified by HC2 and alternative methods, respectively. Panel 2 included four ThinPrep and two swab specimens. ThinPrep specimens were reported correctly by 100% (60/60) of participants utilising HC2 and 95% (19/20) utilising alternative methods. Dry swab specimens were reported correctly by 89% (25/28) of participants utilising HC2 and 100% (10/10) of participants utilising alternative methods. These results indicate that both specimen types are suitable for utilisation in an EQAP and outline some issues of EQAP for ongoing assessment of HPV molecular methods in diagnostic molecular laboratories.
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http://dx.doi.org/10.1016/j.pathol.2018.05.005DOI Listing
October 2018

The new screening program to prevent cervical cancer using HPV DNA: getting the balance right in maintaining quality.

J Pathol Clin Res 2018 10 11;4(4):207-212. Epub 2018 Sep 11.

Microbiology and Infectious Disease, South Australia Pathology, North Terrace, Australia.

Along with the reduction in human papillomavirus (HPV) infection and cervical abnormalities as a result of the successful HPV vaccination program, Australia is adopting a new screening strategy. This involves a new paradigm moving from cervical cytological screening to molecular nucleic acid technology (NAT), using HPV DNA assays as primary screening methodology for cervical cancer prevention. These assays must strike a balance between sufficient clinical sensitivity to detect or predict high-grade cervical intraepithelial lesions, the precursor to cervical cancer, without being too sensitive and detecting transient infection not destined for disease. Ensuring the highest quality HPV NAT is thus a priority in order to reduce the possibility of falsely negative screens and manage the risk associated with false positive HPV NAT test results. How to do this needs informed discussion and on-going refinement of the screening algorithm. This is of relevance as more countries move to more sensitive HPV NAT tests for secondary prevention of cervical cancer and as more HPV assays become available.
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http://dx.doi.org/10.1002/cjp2.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175713PMC
October 2018

A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both and Optic Nerve Crush Animal Models.

Int J Mol Sci 2018 Jul 25;19(8). Epub 2018 Jul 25.

Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood⁻brain barrier (BBB) leakage and subsequent neuronal cell death that follows (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss.
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http://dx.doi.org/10.3390/ijms19082178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121268PMC
July 2018

Novel use of ViewRay MRI guidance for high-dose-rate brachytherapy in the treatment of cervical cancer.

Brachytherapy 2018 Jul - Aug;17(4):680-688. Epub 2018 Jun 7.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Carbone Comprehensive Cancer Center, Madison, WI. Electronic address:

Purpose: To characterize image quality and feasibility of using ViewRay MRI (VR)-guided brachytherapy planning for cervical cancer.

Methods And Materials: Cervical cancer patients receiving intracavitary brachytherapy with tandem and ovoids, planned using 0.35T VR MRI at our institution, were included in this series. The high-risk clinical target volume (HR-CTV), visible gross tumor volume, bladder, sigmoid, bowel, and rectum contours for each fraction of brachytherapy were evaluated for dosimetric parameters. Typically, five brachytherapy treatments were planned using the T2 sequence on diagnostic MRI for the first and third fractions, and a noncontrast true fast imaging with steady-state precession sequence on VR or CT scan for the remaining fractions. Most patients received 5.5 Gy × 5 fractions using high-dose-rate Ir-192 following 45 Gy of whole-pelvis radiotherapy. The plan was initiated at 5.5 Gy to point A and subsequently optimized and prescribed to the HR-CTV. The goal equivalent dose in 2 Gy fractions for the combined external beam and brachytherapy dose was 85 Gy. Soft-tissue visualization using contrast-to-noise ratios to distinguish normal tissues from tumor at their interface was compared between diagnostic MRI, CT, and VR.

Results: One hundred and forty-two fractions of intracavitary brachytherapy were performed from April 2015 to January 2017 on 29 cervical cancer patients, ranging from stages IB1 to IVA. The median HR-CTV was 27.78 cc, with median D HR-CTV of 6.1 Gy. The median time from instrument placement to start of treatment using VR was 65 min (scan time 2 min), compared to 105 min using diagnostic MRI (scan time 11 min) (t-test, p < 0.01). The contrast-to-noise ratio of tumor to cervix in both diagnostic MRI and VR had significantly higher values compared to CT (ANOVA and t-tests, p < 0.01).

Conclusions: We report the first clinical use of VR-guided brachytherapy. Time to treatment using this approach was shorter compared to diagnostic MRI. VR also provided significant advantage in visualizing the tumor and cervix compared to CT. This presents a feasible and reliable manner to image and plan gynecologic brachytherapy.
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http://dx.doi.org/10.1016/j.brachy.2018.04.005DOI Listing
March 2019

Clinical implementation of a novel Double-Balloon single-entry breast brachytherapy applicator.

Brachytherapy 2017 Nov - Dec;16(6):1239-1245. Epub 2017 Aug 24.

Department of Human Oncology, University of Wisconsin, Madison, WI.

Purpose: The purpose of the study was to describe the clinical utilization of a novel Double-Balloon applicator for accelerated partial breast irradiation (APBI).

Methods And Materials: The Double-Balloon single-entry breast applicator contains a single central treatment catheter, as well as four peripheral catheters that can be differentially loaded to customize radiation dose coverage. An inner balloon is filled with up to 7-30 cm of saline to increase separation between the peripheral catheters, and an outer balloon is filled with up to 37-115 cm of saline to displace breast tissue from the peripheral catheters. Treatment planning objectives include coverage of the breast planning target volume to a minimum of V > 90%, limiting dose heterogeneity such that V < 10 cm and V < 50 cm, and limiting maximum dose to skin (<100% of prescription dose) and ribs (<145% of prescription dose).

Results: High-dose-rate APBI was delivered to 11 women using this device (34 Gy in 10 twice daily fractions). The mean V was 98.2% (range 94.2-99.4%). The mean skin D with the Double-Balloon applicator was 83.3% (range 75.6-99.5%). The mean breast V was 5.8 cm (range 2.3-10.2 cm), and the mean breast V was 32.9 cm (range 25.0-41.7 cm). Pretreatment quality assurance was performed using CT prior to each morning fraction and ultrasound prior to each afternoon fraction.

Conclusions: The Double-Balloon applicator can be easily introduced into a previously existing brachytherapy program. APBI plans created with this applicator achieve excellent planning target volume coverage, while limiting skin dose and maintaining breast V < 10 cm.
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http://dx.doi.org/10.1016/j.brachy.2017.07.015DOI Listing
June 2018

UriSwab: an effective transport medium for nucleic acid detection of Chlamydia trachomatis, Mycoplasma genitalium and Neisseria gonorrhoeae.

Sex Health 2017 11;14(6):502-506

Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Parkville, Vic. 3052, Australia.

Background Patient self-sampling allows for remote collection and return to clinic or laboratory by post. Urine samples, although convenient, are challenging to post. This study evaluated UriSwab (Copan, Brescia, Italy) as a collection and transport vessel for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Mycoplasma genitalium (MG) detection by polymerase chain reaction, compared with flocked swab and neat urine.

Methods: Five replicates of each specimen type were prepared from previously characterised urine samples (n=330), stored at room temperature (RT) or 37°C, then extracted on day 1, 3, 7, 10 and 16 (VERSANT kPCR Sample Prep System, Siemens, Munich, Germany). Crossing thresholds (Cq) from CT and NG detection (VERSANT CT/GC DNA 1.0 assay kit, Siemens) and MG detection (real-time polymerase chain reaction assay) were compared using logistic regression, stratified by sample type, temperature and analyte. Mixed-model statistical techniques were used to assess correlation between repeated observations.

Results: UriSwab showed an increasing trend in Cq values at RT and 37°C for CT and NG, and RT for MG (all P<0.01). UriSwab was not statistically significantly different to neat urine, except CT at RT (0.83, 95% confidence interval: 0.51-1.15). Flocked swab similarly showed increasing Cq values at 37°C for CT, a significant decreasing trend at RT for MG and increasing trend at 37°C for MG. Flocked swab was not statistically significantly different from neat urine at RT and 37°C for CT and MG.

Conclusion: UriSwab allows transport of urine for CT, NG and MG detection regardless of storage time or temperature, suggesting that CT and NG are stable for up to 16 days and MG up to 10 days.
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http://dx.doi.org/10.1071/SH16117DOI Listing
November 2017

Maternal high-fat diet leads to hippocampal and amygdala dendritic remodeling in adult male offspring.

Psychoneuroendocrinology 2017 Sep 31;83:49-57. Epub 2017 May 31.

INRA, Nutrition and Integrative Neurobiology, UMR 1286, Bordeaux, France; Université de Bordeaux, Nutrition and Integrative Neurobiology, UMR 1286, Bordeaux, France. Electronic address:

Early-life exposure to calorie-dense food, rich in fat and sugar, contributes to the increasing prevalence of obesity and its associated adverse cognitive and emotional outcomes at adulthood. It is thus critical to determine the impact of such nutritional environment on neurobehavioral development. In animals, maternal high-fat diet (HFD) consumption impairs hippocampal function in adult offspring, but its impact on hippocampal neuronal morphology is unknown. Moreover, the consequences of perinatal HFD exposure on the amygdala, another important structure for emotional and cognitive processes, remain to be established. In rats, we show that adult offspring from dams fed with HFD (45% from fat, throughout gestation and lactation) exhibit atrophy of pyramidal neuron dendrites in both the CA1 of the hippocampus and the basolateral amygdala (BLA). Perinatal HFD exposure also impairs conditioned odor aversion, a task highly dependent on BLA function, without affecting olfactory or malaise processing. Neuronal morphology and behavioral alterations elicited by perinatal HFD are not associated with body weight changes but with higher plasma leptin levels at postnatal day 15 and at adulthood. Taken together, our results suggest that perinatal HFD exposure alters hippocampal and amygdala neuronal morphology which could participate to memory alterations at adulthood.
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http://dx.doi.org/10.1016/j.psyneuen.2017.05.003DOI Listing
September 2017

Modulation of therapeutic sensitivity by human papillomavirus.

Radiother Oncol 2015 Sep 10;116(3):342-5. Epub 2015 Sep 10.

Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, USA; University of Wisconsin Carbone Comprehensive Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, USA. Electronic address:

Human papillomaviruses (HPVs) are small double-stranded DNA viruses that pose significant public health concerns as the causative agent of approximately 5% of worldwide cancers. The HPV oncogenes E6 and E7 play key roles in carcinogenesis. In the last 15years there has been a significant increase in the incidence of HPV-related head and neck cancers arising primarily in the oropharynx. Patients with HPV-positive head and neck cancers (HNCs) have a significantly improved prognosis compared to those with HPV-negative disease. In this review we will discuss data suggesting how HPV oncogenes modulate both the intrinsic radiation sensitivity of HNCs and also have important effects upon the tumor microenvironment. Together, these findings contribute to the improved outcomes seen in patients with HPV-positive HNC.
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http://dx.doi.org/10.1016/j.radonc.2015.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609293PMC
September 2015

Incorporating Patient Satisfaction Metrics in Assessing Multidisciplinary Breast Cancer Care Quality.

South Med J 2015 Jun;108(6):372-6

From the Department of Radiation Oncology and the College of Medicine, Medical University of South Carolina, Charleston, and the Biostatistics Shared Resource and the Department of Public Health Sciences, Hollings Cancer Center, Charleston, South Carolina.

Objectives: The Medical University of South Carolina implemented a patient-centered multidisciplinary breast clinic program (MDBC) in August 2012. In this study, patient satisfaction with the MDBC care delivery model and communication with healthcare providers was examined to inform the refinement of the MDBC program.

Methods: During the first 10 months of the MDBC, patients were asked to complete a 14-question postconsultation telephone survey. A statistical analysis was performed to explore potential associations between age, race, and stage with overall patient satisfaction scores.

Results: Overall, patients (N = 52, 56% white, 42% African American, 2% Hispanic; mean age 61 years) rated the quality of care highly (mean 4.7, range [1 = poor to 5 = excellent]) and felt comfortable with their plan of care (mean 1.63, range [1 = extremely comfortable to 5 = not at all comfortable]). No statistically significant differences in overall satisfaction were found by age, race, or stage; however, patient responses were commonly not optimal (ie, either "no" or "yes, but not as much as I would like") when asked if the care team addressed the impact of their diagnosis on personal relationships (40.4%) or emotional health (28.9%).

Conclusions: Patients were highly satisfied with the care they received in the MDBC program. Findings suggest that this model is well suited to a diverse patient population and have highlighted quality improvement targets such as increased emphasis on providers' communication about psychosocial issues.
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http://dx.doi.org/10.14423/SMJ.0000000000000300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470304PMC
June 2015

Opportunities and pitfalls of molecular testing for detecting sexually transmitted pathogens.

Pathology 2015 Apr;47(3):219-26

1Queensland Children's Medical Research Institute, The University of Queensland, Qld 2Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Melbourne 3Department of Microbiology, The Royal Children's Hospital, Melbourne 4Murdoch Childrens Research Institute, Melbourne 5Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Vic, Australia.

In the last 20 years, nucleic acid amplification tests (NAATs) have gradually replaced traditional methods for the detection of sexually transmitted infections. NAAT technology comes with some considerable benefits for diagnosis, including increased sensitivity, rapid result turnaround and suitability for high throughput screening of asymptomatic individuals using more-readily available specimens. However, the transition to NAAT has not come without its problems. False-negative and false-positive results have been reported owing to various technical issues. Furthermore, increased reliance on NAATs for diagnosis have created the need to develop NAAT-based methods to inform treatment, being an area that presents its own set of challenges. In this review article, we explore NAAT-based detection of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Trichomonas vaginalis. In doing so, we consider the benefits and limitations of NAAT-based technology and highlight areas where further research and development is in need.
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http://dx.doi.org/10.1097/PAT.0000000000000239DOI Listing
April 2015

The contrasting phylodynamics of human influenza B viruses.

Elife 2015 Jan 16;4:e05055. Epub 2015 Jan 16.

World Health Organisation Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.

A complex interplay of viral, host, and ecological factors shapes the spatio-temporal incidence and evolution of human influenza viruses. Although considerable attention has been paid to influenza A viruses, a lack of equivalent data means that an integrated evolutionary and epidemiological framework has until now not been available for influenza B viruses, despite their significant disease burden. Through the analysis of over 900 full genomes from an epidemiological collection of more than 26,000 strains from Australia and New Zealand, we reveal fundamental differences in the phylodynamics of the two co-circulating lineages of influenza B virus (Victoria and Yamagata), showing that their individual dynamics are determined by a complex relationship between virus transmission, age of infection, and receptor binding preference. In sum, this work identifies new factors that are important determinants of influenza B evolution and epidemiology.
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http://dx.doi.org/10.7554/eLife.05055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383373PMC
January 2015

An Inflammatory Cytokine Milieu is Prominent in Premalignant Oral Lesions, but Subsides when Lesions Progress to Squamous Cell Carcinoma.

J Clin Cell Immunol 2014 Jun;5(3)

Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA ; Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA.

While head and neck squamous cell carcinomas (HNSCC) are associated with profound immune suppression, less is known about the immunological milieu of premalignant oral lesions. The present study shows dynamic shifts in the immune milieu within premalignant oral lesions and when they have progressed to HNSCC. Specifically, this study showed that the premalignant lesion environment consists of inflammatory mediators and IL-17, but this inflammatory phenotype declines when premalignant oral lesions have progressed to HNSCC. The cytokine profiles of human tissues did not correspond with plasma cytokine profiles. A murine carcinogen-induced premalignant lesion model that progresses to HNSCC was used to examine cytokine profiles released from tissues as well as regional lymph nodes. As in human tissues, murine premalignant lesions and regional lymph nodes released high levels of inflammatory cytokines and, very prominently, IL-17. Also similar to human tissues, release of inflammatory cytokines declined in HNSCC tissues of mice and in the regional lymph nodes of mice with HNSCC. Studies focusing on IL-17 showed that mediators from premalignant lesions stimulated normal spleen cells to produce increased levels of IL-17, while mediators from HNSCC were less stimulatory toward IL-17 production. IL-17 production by Th17-skewed CD4+ cells was strongly inhibited by normal oral epithelium as well as HNSCC. In contrast, premalignant lesion-derived mediators further increased IL-17 production by Th17-skewed cells. The stimulation of IL-17 production by premalignant lesions was dependent on IL-23, which premalignant lesions released in higher amounts than control tissues or HNSCC. HNSCC tissues instead produced increased levels of TGF-β compared to premalignant lesions, and skewed normal spleen cells toward the Treg phenotype. This skewing was blocked by supplementation with IL-23. These studies suggest IL-23 to be a significant contributor to the inflammatory IL-17 phenotype in premalignant oral lesions and suggest the decline in IL-23 in HNSCC leads to a decline in Th17 cells.
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http://dx.doi.org/10.4172/2155-9899.1000230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240319PMC
June 2014

Effect of the premalignant and tumor microenvironment on immune cell cytokine production in head and neck cancer.

Cancers (Basel) 2014 Apr 2;6(2):756-70. Epub 2014 Apr 2.

Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC 29425, USA.

Head and neck squamous cell carcinoma (HNSCC) is marked by immunosuppression, a state in which the established tumor escapes immune attack. However, the impact of the premalignant and tumor microenvironments on immune reactivity has yet to be elucidated. The purpose of this study was to determine how soluble mediators from cells established from carcinogen-induced oral premalignant lesions and HNSCC modulate immune cell cytokine production. It was found that premalignant cells secrete significantly increased levels of G-CSF, RANTES, MCP-1, and PGE2 compared to HNSCC cells. Splenocytes incubated with premalignant supernatant secreted significantly increased levels of Th1-, Th2-, and Th17-associated cytokines compared to splenocytes incubated with HNSCC supernatant. These studies demonstrate that whereas the premalignant microenvironment elicits proinflammatory cytokine production, the tumor microenvironment is significantly less immune stimulatory and may contribute to immunosuppression in established HNSCC.
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http://dx.doi.org/10.3390/cancers6020756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074802PMC
April 2014

Administration of a vaccine composed of dendritic cells pulsed with premalignant oral lesion lysate to mice bearing carcinogen-induced premalignant oral lesions stimulates a protective immune response.

Int Immunopharmacol 2012 Jul 16;13(3):322-30. Epub 2012 May 16.

Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, United States.

The use of dendritic cell (DC) vaccines as treatment for malignancy is complicated by immune evasion tactics often employed by carcinomas such as head and neck squamous cell carcinoma (HNSCC). The present study aims to determine if an immune response can be elicited by administering a DC vaccine during the premalignant stages of HNSCC, prior to development of immune escape. Mice treated with the carcinogen 4-nitroquinoline 1-oxide (4NQO) in drinking water develop premalignant oral lesions that progress to HNSCC. As previous studies demonstrated that premalignant lesions and HNSCC overexpress common tumor antigens, bone marrow-derived DCs were pulsed with premalignant lesion lysate (DCpm) and administered to 4NQO-treated mice exhibiting premalignant lesions. Lesion progression was tracked through endoscopy, which revealed that DCpm vaccination and control vaccination with dendritic cells pulsed with normal tongue epithelium lysate (DCnt) significantly decreased lesion burden at 8weeks. Analysis of lymph node cells revealed that while DCnt vaccination resulted in a rapid increase in total lymphocyte count, levels of activated conventional CD4(+) T cells and Th1, Tc1, Th17, Tc17, and Th2 cells, DCpm vaccination results in a delayed, yet substantial, increase in these immune effector mechanisms. This suggests that dendritic cell vaccination may have a beneficial effect on clinical outcome regardless of type of antigenic stimulation. Also, pulsing DCs with premalignant lysate rather than normal tongue epithelium lysate affects the dendritic cells in a way that delays the immune effector response upon vaccination of premalignant lesion-bearing mice.
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http://dx.doi.org/10.1016/j.intimp.2012.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372686PMC
July 2012

Immunological modulation by 1α,25-dihydroxyvitamin D3 in patients with squamous cell carcinoma of the head and neck.

Cytokine 2012 Jun 24;58(3):448-54. Epub 2012 Mar 24.

Department of Otolaryngology, Medical University of South Carolina, Charleston, SC, USA.

Prior studies showing that treatment of head and neck squamous cell carcinoma (HNSCC) patients with 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] stimulated intratumoral immune infiltration were extended to analysis of cytokine profiles in the periphery and in oral tissues. Most prominent was the disparity between cytokine levels in plasma and in either pathologically normal oral tissue or HNSCC tissue from patients that were untreated or treated with 1,25(OH)(2)D(3). Levels of IL-6 and IL-10, but not IL-2, IFN-γ or TNF-α, tended to be increased in the plasma of HNSCC patients and 1,25(OH)(2)D(3) further increased plasma levels of all of these cytokines. While these cytokines tended to be increased in HNSCC tissue, 1,25(OH)(2)D(3) resulted in variable cytokine responses that showed a general tendency toward further increased levels. Levels of IL-8 and VEGF were increased in plasma and tissue of untreated HNSCC patients, and were further increased in plasma, but not in tissues, of patients treated with 1,25(OH)(2)D(3). Levels of IL-1α and IL-1β were similar in plasma of controls and HNSCC patients, but were increased in HNSCC tissues. In contrast to that seen in plasma where 1,25(OH)(2)D(3) increased levels of IL-1α and IL-1β, this was not seen in tissue following 1,25(OH)(2)D(3) treatment. These results show a discordant relationship between systemic and intratumoral cytokine profiles and suggest a tendency of 1,25(OH)(2)D(3)to increase a multitude of cytokines within tumor tissue.
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http://dx.doi.org/10.1016/j.cyto.2012.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340440PMC
June 2012

Characterization of the evolution of immune phenotype during the development and progression of squamous cell carcinoma of the head and neck.

Cancer Immunol Immunother 2012 Jun 25;61(6):927-39. Epub 2011 Nov 25.

Research Service (151), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA.

While studies have indicated that squamous cell carcinoma of the head and neck (HNSCC) is associated with immune suppression, these studies did not analyze the immune response at the dysplastic stage. The present study utilized a mouse model of 4-nitroquinoline 1-oxide-induced oral carcinogenesis to examine the alterations in immune phenotype at the premalignant and malignant stages of HNSCC. Cervical lymph nodes of HNSCC-bearing mice were found to contain a greater number of cells, including a greater number of conventional (Tconv) and regulatory (Treg) T cells, compared to cervical lymph nodes of control and premalignant lesion-bearing mice, though the Tconv cells appear to be less proliferative and the Treg cells appear to be less suppressive at the HNSCC stage. Premalignant lesion-bearing mouse lymph nodes consist of a greater percentage of Tconv cells expressing markers for activation, memory, and exhaustion compared to both control and HNSCC-bearing mice. Also, lymph nodes' cells from both premalignant lesion-bearing and HNSCC-bearing mice include increased levels of Th1, Tc1, and Th17 cells, with no differences in levels of Th2 cells, compared to control mice. The data show that while there is the expected increase in immunosuppressive Tregs in lymph nodes when HNSCC is present, there is also an unexpected increase in immune populations usually associated with a beneficial antitumor response, including Tconv cells and Th1 and Tc1 cells. In addition, the results demonstrate that the premalignant stage of HNSCC development is associated with a robust immune response involving an increase in inflammatory Th1, Tc1, and Th17 cells.
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http://dx.doi.org/10.1007/s00262-011-1154-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925419PMC
June 2012
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