Prevalence of high-risk human papilloma virus genotypes and associated risk of cervical precancerous lesions in a large U.S. screening population: Data from the ATHENA trial

Abstract Objective We assessed the age-related prevalence of high risk human papillomavirus (HR-HPV) genotypes and the genotype-associated risk for high-grade cervical intraepithelial neoplasia (CIN) in a large U.S. screening population. Methods A total of 40,901 women aged ≥25years were screened with liquid-based cytology and HPV testing in the ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial. Genotyping was performed using the LINEAR ARRAY HPV Genotyping Test. Results HPV16 was the most prevalent genotype in all age groups, ranging from 3.5% to 0.8% in women aged 25–29 and ≥50years, respectively. The next most prevalent genotypes were HPV52, HPV31 and HPV18. In the overall population, HPV16 conferred the greatest absolute risk of ≥CIN3 both in women aged 25–29 and ≥30years (14.2% and 15.1%, respectively) followed by HPV31 (8.0% and 7.9%), HPV52 (6.7% and 4.4%) and HPV18 (2.7% and 9.0%). Similar trends were seen in women with negative cytology. The percent positivity increased markedly with disease progression for HPV16 and HPV18 which were responsible for 45.6% and 8.4% of ≥CIN3, respectively. Of note, HPV 18 was responsible for 50% of adenocarcinoma in situ (AIS) and 50% of invasive cancer cases. Conclusions HPV16 played a major role in the development of ≥CIN3 irrespective of age, supporting the identification of HPV16 in primary screening for all women. Identification of HPV18 is also warranted, given its significant contribution to AIS and cancer. Identification of non-16/18 genotypes as a pool should provide sufficient information for screening

Liquid-based cytology for primary cervical cancer screening: a multi-centre study

The aim of this six-centre, split-sample study was to compare ThinPrep fluid-based cytology to the conventional Papanicolaou smear. Six cytopathology laboratories and 35 gynaecologists participated. 5428 patients met the inclusion criteria (age > 18 years old, intact cervix, informed consent). Each cervical sample was used first to prepare a conventional Pap smear, then the sampling device was rinsed into a PreservCyt vial, and a ThinPrep slide was made. Screening of slide pairs was blinded (n = 5428). All non-negative concordant cases (n = 101), all non-concordant cases (n = 206), and a 5% random sample of concordant negative cases (n = 272) underwent review by one independent pathologist then by the panel of 6 investigators. Initial (blinded) screening results for ThinPrep and conventional smears were correlated. Initial diagnoses were correlated with consensus cytological diagnoses. Differences in disease detection were evaluated using McNemar's test. On initial screening, 29% more ASCUS cases and 39% more low-grade squamous intraepithelial lesions (LSIL) and more severe lesions (LSIL+) were detected on the ThinPrep slides than on the conventional smears (P = 0.001), including 50% more LSIL and 18% more high-grade SIL (HSIL). The ASCUS:SIL ratio was lower for the ThinPrep method (115:132 = 0.87:1) than for the conventional smear method (89:94 = 0.95:1). The same trend was observed for the ASCUS/AGUS:LSIL ratio. Independent and consensus review confirmed 145 LSIL+ diagnoses; of these, 18% more had been detected initially on the ThinPrep slides than on the conventional smears (P = 0.041). The ThinPrep Pap Test is more accurate than the conventional Pap test and has the potential to optimize the effectiveness of primary cervical cancer screening. © 2001 Cancer Research Campaign http://www.bjcancer.co

Enhanced chondrogenic phenotype of primary bovine articular chondrocytes in Fibrin-Hyaluronan hydrogel by multi-axial mechanical loading and FGF18

Current treatments for cartilage lesions are often associated with fibrocartilage formation and donor site morbidity. Mechanical and biochemical stimuli play an important role in hyaline cartilage formation. Biocompatible scaffolds capable of transducing mechanical loads and delivering bioactive instructive factors may better support cartilage regeneration. In this study we aimed to test the interplay between mechanical and FGF-18 mediated biochemical signals on the proliferation and differentiation of primary bovine articular chondrocytes embedded in a chondro-conductive Fibrin-Hyaluronan (FB/HA) based hydrogel. Chondrocytes seeded in a Fibrin-HA hydrogel, with or without a chondro-inductive, FGFR3 selective FGF18 variant (FGF-18v) were loaded into a joint-mimicking bioreactor applying controlled, multi-axial movements, simulating the natural movements of articular joints. Samples were evaluated for DNA content, sulphated glycosaminoglycan (sGAG) accumulation, key chondrogenic gene expression markers and histology. Under moderate loading, samples produced particularly significant amounts of sGAG/DNA compared to unloaded controls. Interestingly there was no significant effect of FGF-18v on cartilage gene expression at rest. Following moderate multi-axial loading, FGF-18v upregulated the expression of Aggrecan (ACAN), Cartilage Oligomeric Matrix Protein (COMP), type II collagen (COL2) and Lubricin (PRG4). Moreover, the combination of load and FGF-18v, significantly downregulated Matrix Metalloproteinase-9 (MMP-9) and Matrix Metaloproteinase-13 (MMP-13), two of the most important factors contributing to joint destruction in OA. Biomimetic mechanical signals and FGF-18 may work in concert to support hyaline cartilage regeneration and repair. Statement of significance: Articular cartilage has very limited repair potential and focal cartilage lesions constitute a challenge for current standard clinical procedures. The aim of the present research was to explore novel procedures and constructs, based on biomaterials and biomechanical algorithms that can better mimic joints mechanical and biochemical stimulation to promote regeneration of damaged cartilage. Using a hydrogel-based platform for chondrocyte 3D culture revealed a synergy between mechanical forces and growth factors. Exploring the mechanisms underlying this mechano-biochemical interplay may enhance our understanding of cartilage remodeling and the development of new strategies for cartilage repair and regeneration

Cortical plasticity is associated with blood-brain barrier modulation.

Brain microvessels possess the unique properties of a blood-brain barrier (BBB), tightly regulating the passage of molecules from the blood to the brain neuropil and vice versa. In models of brain injury, BBB dysfunction and the associated leakage of serum albumin to the neuropil have been shown to induce pathological plasticity, neuronal hyper-excitability, and seizures. The effect of neuronal activity on BBB function and whether it plays a role in plasticity in the healthy brain remain unclear. Here we show that neuronal activity induces modulation of microvascular permeability in the healthy brain and that it has a role in local network reorganization. Combining simultaneous electrophysiological recording and vascular imaging with transcriptomic analysis in rats, and functional and BBB-mapping MRI in human subjects, we show that prolonged stimulation of the limb induces a focal increase in BBB permeability in the corresponding somatosensory cortex that is associated with long-term synaptic plasticity. We further show that the increased microvascular permeability depends on neuronal activity and involves caveolae-mediated transcytosis and transforming growth factor β signaling. Our results reveal a role of BBB modulation in cortical plasticity in the healthy brain, highlighting the importance of neurovascular interactions for sensory experience and learning

Sitting time, physical activity and cervical intraepithelial neoplasia in Australian women: A preliminary investigation

Issue addressed: Physical activity affects the immune system, which in turn may modify the risk of cervical intraepithelial neoplasia (CIN). The effect of sitting on CIN is unknown. This study investigated the relationship between sitting time, physical activity and the risk of CIN. Methods: Community-dwelling adult women within metropolitan Perth, Western Australia, who had had a Papanicolaou (Pap) smear test at any of five clinics and medical centres, were approached by their general practitioners. In total, 348 women were recruited and interviewed for information on sitting time, physical activity level and lifetime physical activity exposure using the International Physical Activity Questionnaire (IPAQ) – short form. Associations of exposure variables with CIN risk were assessed by unconditional logistic regression analyses. Results: The prevalence of abnormal Pap smear status indicating CIN was found to be 15.8%. Women with prolonged sitting duration (≥ 42 h per week) had significantly increased risk of CIN (adjusted OR 3.49, 95% CI 1.12–10.88) than women who sat less than 24.5 h per week. Although the effect of total physical activity level was non-significant (P = 0.408), being always involved in physical activity during the entire life appeared to be inversely associated with the CIN risk (P = 0.036). Conclusions: Prolonged sitting time was significantly associated with increased risk of abnormal Pap smear status indicating CIN. So what?: This preliminary investigation highlights a new prospect for health-promotion intervention to reduce the risk of CIN. Health practitioners should encourage women to reduce their sitting time and maintain physically active throughout their life course

Triage of women with equivocal or low-grade cervical cytology results: a meta-analysis of the HPV test positivity rate

Introduction Methods Results Discussion Conclusion Abstract Consistent evidence underlines the utility of human papillomavirus (HPV) DNA testing in the management of women with equivocal cervical cytological abnormalities, but not in case of low-grade lesions. We performed a meta-analysis including studies where the high-risk probe of the Hybrid Capture-II is used to triage these two cytological categories. The triage test-positivity rate reflects the colposcopy referral workload.Data were pooled on the HPV test positivity rate in women with atypical squamous cells of undetermined significance (ASCUS/ASC-US) or low-grade squamous intraepithelial lesions (LSIL), derived from different cytological classification systems. The meta-analysis was restricted to studies, published between 1991 and 2007. A random-effect model was applied for meta-analytical pooling and the influence of covariates on the HPV positivity rate was analyzed by meta-regression. The variation by age was assessed within individual studies since age strata were not defined uniformly. On an average, 43% (95% CI: 40-46%) of women with ASCUS/ASC-US were high-risk HPV positive (range 23-74%). In women with LSIL, the pooled positivity rate was 76% (95% CI: 71-81%; range 55-89%). In spite of considerable inter-study heterogeneity, the difference in HPV positivity between the two triage groups was large and highly significant: 32% (95% CI: 27-38%). HPV rates dropped tremendously as age and cutoffs of test positivity increased. Other factors (cytological classification system, country, continent, collection method and year of publication) had no statistically significant impact, except in LSIL triage where HPV positivity was significantly lower in European compared to American studies. Women with LSIL, especially younger women, have high HPV positivity rates suggesting limited utility of reflex HPV triaging these cases. Research is needed to identify more specific methods to triage women with low-grade squamous cervical lesions

T Cells Specifically Targeted to Amyloid Plaques Enhance Plaque Clearance in a Mouse Model of Alzheimer's Disease

Patients with Alzheimer's disease (AD) exhibit substantial accumulation of amyloid-β (Aβ) plaques in the brain. Here, we examine whether Aβ vaccination can facilitate the migration of T lymphocytes to specifically target Aβ plaques and consequently enhance their removal. Using a new mouse model of AD, we show that immunization with Aβ, but not with the encephalitogenic proteolipid protein (PLP), results in the accumulation of T cells at Aβ plaques in the brain. Although both Aβ-reactive and PLP-reactive T cells have a similar phenotype of Th1 cells secreting primarily IFN-γ, the encephalitogenic T cells penetrated the spinal cord and caused experimental autoimmune encephalomyelitis (EAE), whereas Aβ T cells accumulated primarily at Aβ plaques in the brain but not the spinal cord and induced almost complete clearance of Aβ. Furthermore, while a single vaccination with Aβ resulted in upregulation of the phagocytic markers triggering receptors expressed on myeloid cells-2 (TREM2) and signal regulatory protein-β1 (SIRPβ1) in the brain, it caused downregulation of the proinflammatory cytokines TNF-α and IL-6. We thus suggest that Aβ deposits in the hippocampus area prioritize the targeting of Aβ-reactive but not PLP-reactive T cells upon vaccination. The stimulation of Aβ-reactive T cells at sites of Aβ plaques resulted in IFN-γ-induced chemotaxis of leukocytes and therapeutic clearance of Aβ

Effect of the G375C and G346E Achondroplasia Mutations on FGFR3 Activation

Two mutations in FGFR3, G380R and G375C are known to cause achondroplasia, the most common form of human dwarfism. The G380R mutation accounts for 98% of the achondroplasia cases, and thus has been studied extensively. Here we study the effect of the G375C mutation on the phosphorylation and the cross-linking propensity of full-length FGFR3 in HEK 293 cells, and we compare the results to previously published results for the G380R mutant. We observe identical behavior of the two achondroplasia mutants in these experiments, a finding which supports a direct link between the severity of dwarfism phenotypes and the level and mechanism of FGFR3 over-activation. The mutations do not increase the cross-linking propensity of FGFR3, contrary to previous expectations that the achondroplasia mutations stabilize the FGFR3 dimers. Instead, the phosphorylation efficiency within un-liganded FGFR3 dimers is increased, and this increase is likely the underlying cause for pathogenesis in achondroplasia. We further investigate the G346E mutation, which has been reported to cause achondroplasia in one case. We find that this mutation does not increase FGFR3 phosphorylation and decreases FGFR3 cross-linking propensity, a finding which raises questions whether this mutation is indeed a genetic cause for human dwarfism

Psychological impact, support and information needs for women with an abnormal Pap smear: comparative results of a questionnaire in three European countries

<p>Abstract</p> <p>Background</p> <p>Extensive information on cervical cancer is currently available. Its effectiveness in reducing anxiety in women receiving abnormal Pap tests is not clear. We investigated current practices of communicating abnormal Pap results to evaluate women's reactions and determine the sources of information they use subsequently.</p> <p>Methods</p> <p>A self-administered questionnaire-based study was performed in 1475 women in France, Spain and Portugal who had received an abnormal Pap smear result in the 12 months prior to completing the questionnaire. Questions covered methods of communication of the result, emotional reactions, support received (from the physician and entourage), and information sources, using pre-specified check box options and rating scales. Data were analyzed by country.</p> <p>Results</p> <p>Pap test results were mostly communicated by phone to Spanish women (76%), while physician letters were common in France (59%) and Portugal (36%). Frequent reactions were anxiety, panic and stress, which were less common in Spanish women than their French and Portuguese counterparts. After discussing with their physician, half of the participants were worried, despite rating highly the psychological support received. Over 90% of women in each country discussed their results with family or friends. Partners provided a high level of support. Overall, the abnormal diagnosis and consequences had a low to medium impact on daily, professional and family life and their relationships with their partner. Impact was higher in Spanish women than the French or Portuguese. Information on the diagnosis and its treatment was rated average, and nearly 80% of participants wanted more information, notably French women. Preferred sources were the physician and the Internet.</p> <p>Conclusions</p> <p>Women expressed a strong wish for more information about cervical cancer and other HPV-related diseases, and that their physician play a major role in its provision and in support. There was a heavy reliance on the close entourage and the Internet for information, highlighting the need for dissemination of accurate material. Differences between countries suggest information management strategies may need to be tailored to different geographical regions.</p

Condom and Oral Contraceptive Use and Risk of Cervical Intraepithelial Neoplasia in Australian Women

Objective: To assess the association between condom use and oral contraceptive consumption and the risk of cervical intraepithelial neoplasia (CIN).Methods: A cross-sectional study was conducted in Perth clinics. A total of 348 women responded to the structured questionnaire. Information sought included demographic and lifestyle characteristics such as the use of condom for contraception, consumption of oral contraceptive, and duration of oral contraceptive usage. Crude and adjusted odds ratio (OR) and associated 95% confidence interval (CI) were calculated using unconditional logistic regression models and reported as estimates of the relative risk. Results: The prevalence of CIN was found to be 15.8%. The duration of oral contraceptive consumption among women with abnormal Papanicolaou (Pap) smear result indicating CIN was significantly shorter than those without abnormal Pap smear result (mean±SD, 5.6±5.2 years vs. 8.2±7.6 years; p=0.002). Comparing to =3 years usage, prolonged consumption of oral contraceptive for =10 years reduced the risk of CIN (p=0.012). However, use of condom for contraception might not be associated with a reduced risk of CIN after accounting for the effects of confounding factors (adjusted OR, 0.52; 95% CI, 0.05 to 5.11; p=0.577).Conclusion: Use of oral contraceptives, but not condoms, for contraception appeared to be inversely associated with CIN. Prolonged use of oral contraceptive demonstrated its benefits of reducing the risk of CIN