| 1. |
- Mukanyangezi, Marie Francoise, et al.
(author)
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Screening for human papillomavirus, cervical cytological abnormalities and associated risk factors in HIV-positive and HIV-negative women in Rwanda.
- 2018
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In: HIV medicine. - : Wiley. - 1468-1293 .- 1464-2662. ; 19:2, s. 152-166
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Journal article (peer-reviewed)abstract
- Cervical cancer is the major cause of death from cancer in Africa. We wanted to assess the prevalence of human papillomavirus (HPV) infections and associated risk factors and to determine whether HPV testing could serve as a screening method for squamous intraepithelial lesions (SILs) in Rwanda. We also wanted to obtain a broader understanding of the underlying risk factors for the establishment of HPV infection in Rwanda.A total of 206 HIV-positive women, 172 HIV-negative women and 22 women with unknown HIV status were recruited at the University Teaching Hospitals of Kigali (UTHK) and of Butare (UTHB) in Rwanda. Participants underwent an interview, cervical sampling for a Thinprep Pap test and a screening test analysing 37 HPV strains.Only 27% of HIV-positive women and 7% of HIV-negative women had been screened for cervical cancer before. HPV16 and HPV52 were the most common HPV strains. HIV-positive women were more commonly infected with high-risk (HR) HPV and multitype HPV than HIV-negative women. The sensitivity was 78% and the specificity 87% to detect high-grade SIL (HSIL) with HPV screening. Among HIV-negative women, being divorced was positively associated with HR-HPV infection, while hepatitis B, Trichomonas vaginalis infection and HR-HPV infection were factors positively associated with SILs. Ever having had gonorrhoea was positively associated with HR-HPV infection among HIV-positive women. HR-HPV infection and the number of live births were positively associated with SILs.The currently used quadrivalent vaccine may be insufficient to give satisfactory HPV coverage in Rwanda. HPV Screening may be effective to identify women at risk of developing cervical cancer, particularly if provided to high-risk patients.
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| 2. |
- Ganesh, Divya, et al.
(author)
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Potentially Malignant Oral Disorders and Cancer Transformation
- 2018
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In: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 38:6, s. 3223-3229
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Research review (peer-reviewed)abstract
- Cancer in the oral cavity is often preceded by precursor lesions. Nine oral mucosal disorders are known to have an increased risk of malignant transformation. The etiology varies from disorders caused by exogenous factors such as tobacco and autoimmune inflammation to idiopathic or inherited genetic aberrations. In this review, these potentially malignant disorders (PMDs) are described regarding clinical presentation and histopathological architecture. Special attention is paid to the underlying etiologies of PMDs and the potential pathways leading to cancer. The clinical perspective focuses on the importance of accurate and timely diagnosis.
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| 3. |
- Giglio, Daniel, 1977, et al.
(author)
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Changes in the Neuronal Control of the Urinary Bladder in a Model of Radiation Cystitis.
- 2018
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In: The Journal of pharmacology and experimental therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103 .- 0022-3565. ; 365:2, s. 327-335
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Journal article (peer-reviewed)abstract
- Currently, we have assessed the neuronal control of the urinary bladder in radiation cystitis and whether interstitial cells contribute to the condition. Fourteen days after bladder irradiation (20 Gy), rats were sedated and the urinary bladder was cut into two sagittal halves where electrical field stimulation (EFS; 5-20 Hz) was applied on the pelvic nerve afferents or stretch (80 mN) on one-half of the bladder, while contractions were registered on the contralateral half of the bladder in the absence and presence of increasing doses of imatinib (1-10 mg/kg; inhibitor of c-kit-positive interstitial cells), atropine (1 mg/kg; to block muscarinic M3receptors), or pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (2 mg/kg; P2X1purinoceptor antagonist). Urinary bladders were also excised for organ bath experiments, Western blot, quantitative polymerase chain reaction, and immunohistochemistry. In vivo, EFS contractions were enhanced after irradiation, and imatinib (1-10 mg/mg) inhibited contractions by EFS and stretched dose-dependently in controls but not in irradiated bladders. In the irradiated bladder in vitro, atropine resistance was increased and imatinib (100µM) inhibited contractions by EFS and agonists (ATP, methacholine) in irradiated bladders and controls. The urinary bladder expressions of P2X1purinoceptors, muscarinic M3receptor, choline acetyltransferase, c-kit, and the agonist of c-kit, stem cell factor, were not changed by irradiation. In conclusion, bladder irradiation affects several levels of neuronal control of the urinary bladder. Interstitial cells may contribute to some of the symptoms associated with radiation cystitis.
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| 4. |
- Giglio, Daniel, 1977, et al.
(author)
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Downregulation of toll-like receptor 4 and IL-6 following irradiation of the rat urinary bladder
- 2016
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In: Clinical and Experimental Pharmacology and Physiology. - : Wiley. - 1440-1681 .- 0305-1870. ; 43:7, s. 698-705
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Journal article (peer-reviewed)abstract
- The pathophysiology behind radiation cystitis is poorly understood. Here we investigated whether bladder irradiation affects the immune system of the rat urinary bladder. Female rats were sedated and exposed to one single radiation dose of 20Gy or only sedated (controls) and killed 16h to 14days later. Rats were placed in a metabolic cage at 16h, 3days, 7days and 14days following bladder irradiation. The urinary bladders were harvested and analysed with qPCR, immunohistochemistry and/or Western blot for the expression of interferon (IFN)-, interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, nitric oxide synthases (eNOS, iNOS and nNOS), tumour necrosis factor (TNF)- and toll-like receptor 4 (TLR4). Urine was collected and analysed for IL-6 and nitrite (reflecting nitric oxide activity) with ELISA and the Griess reaction, respectively. Irradiation increased bladder frequency and decreased voiding volumes 14days following bladder irradiation. Bladder irradiation increased the expression of IL-10 and collagen in the bladder, while TLR4 and IL-6 expressions were decreased in the urothelium concomitantly with a decrease in mast cells in the submucosa and urine levels of IL-6 and nitrite. The present findings show that bladder irradiation leads to urodynamic changes in the bladder and may suppress important immunoregulatory pathways in the urinary bladder.
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| 5. |
- Mukanyangezi, Marie Francoise, et al.
(author)
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Persistence rate of cervical human papillomavirus infections and abnormal cytology in Rwanda
- 2019
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In: HIV Medicine. - : Wiley. - 1464-2662 .- 1468-1293. ; 20:7, s. 485-495
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Journal article (peer-reviewed)abstract
- Objectives In this study, we determined the incidence and persistence of human papillomavirus (HPV) strains and of squamous intraepithelial lesions (SIL) or worse cytology in 237 HIV-positive and HIV-negative Rwandan women and whether the interleukin (IL)-28B single nucleotide polymorphism (SNP) at rs12979860 correlated with susceptibility to and persistence of HPV infection. Methods Cervical samples were collected at baseline and after 9, 18 and 24 months for a 40-HPV DNA screening test and a ThinPrep Pap test. Genotyping of the IL-28B SNP rs12979860 was performed using real-time polymerase chain reaction (PCR). Results Chronic high-risk (HR) HPV infections occurred in 56% of HIV-positive women, while no HIV-negative women developed HPV chronicity. High-grade SIL (HSIL) or cancer was diagnosed in 38% of HIV-positive women with persistent HR-HPV infections. HIV and HR-HPV positivity at baseline were factors associated with an increased risk of HPV persistence. Additionally, HR-HPV positivity at baseline was associated with an increased risk of developing HSIL or worse cytology. The unfavourable T/x genotype at rs12979860 is common among Africans, and women with this genotype were found to be more commonly infected with HPV. Conclusions HPV screening in Rwanda may help to identify women at risk of developing cervical cancer and polymorphism in IL-28B may be associated with risk of contracting HPV infection.
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| 6. |
- Mukanyangezi, Marie Francoise, et al.
(author)
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Radiation induces changes in toll-like receptors of the uterine cervix of the rat
- 2019
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:4
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Journal article (peer-reviewed)abstract
- Radiotherapy is an important therapeutic approach against cervical cancer but associated with adverse effects including vaginal fibrosis and dyspareunia. We here assessed the immunological and oxidative responses to cervical irradiation in an animal model for radiation-induced cervicitis. Rats were sedated and either exposed to 20 Gy of ionising radiation given by a linear accelerator or only sedated (controls) and euthanized 1-14 days later. The expressions of toll-like receptors (TLRs) and coupled intracellular pathways in the cervix were assessed with immunohistofluorescence and western blot. Expression of cytokines were analysed with the Bio-Plex Suspension Array System (Bio-Rad). We showed that TLRs 2-9 were expressed in the rat cervix and cervical irradiation induced up-regulation of TLR5, TRIF and NF-kappa B. In the irradiated cervical epithelium, TLR5 and TRIF were increased in concert with an up-regulation of oxidative stress (8-OHdG) and antioxidant enzymes (SOD-1 and catalase). G-CSF, M-CSF, IL-10, IL-17A, IL-18 and RANTES expressions in the cervix decreased two weeks after cervical irradiation. In conclusion, the rat uterine cervix expresses the TLRs 2-9. Cervical irradiation induces immunological changes and oxidative stress, which could have importance in the development of adverse effects to radiotherapy.
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| 7. |
- Mukanyangezi, Marie Francoise, et al.
(author)
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Sexual risk behaviour in a cohort of HIV-negative and HIV-positive Rwandan women
- 2019
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In: Epidemiology and Infection. - : Cambridge University Press (CUP). - 0950-2688 .- 1469-4409. ; 147
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Journal article (peer-reviewed)abstract
- Here we wanted to assess whether sexual risk behaviour differs dependent by human immunodeficiency virus (HIV) status by following 100 HIV- and 137 HIV+ women recruited at two university teaching hospitals in Rwanda. Women were tested for sexually transmitted infections (STIs; trichomoniasis, syphilis, hepatitis B and C) and for reproductive tract infections (RTIs; candidiasis, bacterial vaginosis (BV)) and were interviewed at baseline and 9 months later. BV was the most prevalent infection, while syphilis was the most common STI with a 9-month incidence of 10.9% in HIV+ women. Only 24.5% of women positive for any RTI/STI contacted their health facility and got treatment. More HIV- women than HIV+ women had had more than one sexual partner and never used condoms during the follow-up period. The use of condoms was affected neither by marital status nor by concomitant STIs besides HIV. Our data highlight the importance of public education regarding condom use to protect against STIs in an era when HIV no longer is a death sentence.
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| 8. |
- Oscarsson, Nicklas, 1974, et al.
(author)
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Hyperbaric oxygen treatment reverses radiation induced pro-fibrotic and oxidative stress responses in a rat model
- 2017
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In: Free Radical Biology and Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 103, s. 248-255
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Journal article (peer-reviewed)abstract
- © 2017Purpose Radiotherapy is effective in the treatment of tumors in the pelvic area but is associated with side effects such as cystitis and proctitis. Hyperbaric Oxygen Therapy (HBOT) has emerged as a treatment modality for radiation-induced side effects. In a rat model for radiation cystitis, we studied the effects of HBOT on oxidative stress and pro-fibrotic factors. Materials and methods Sedated Sprague-Dawley rats underwent bladder irradiation of 20Gy with and without 20 sessions of HBOT during a fortnight. Control animals were treated with and without HBOT. All four groups of animals were euthanized 28 days later. Histopathological examinations, immunohistochemistry and quantitative polymerase chain reaction (qPCR) were used to analyze changes in oxidative stress (8-OHdG), anti-oxidative responses (SOD-1, SOD2, HO-1 and NRFα) and a panel of Th1-type and Th2-type cytokines (IL-1β, IL-4, IL-5, IL-6, IL-10, IL-13, TNF, TGF-β, IFN-γ) in the urinary bladder. Results Bladder irradiation increased the expression of 8-OHdG, SOD2, HO-1, NRFα, IL-10, TNF and tended to increase TGF-β. These changes were completely reversed by HBOT while HBOT in control animals had no effects on the studied markers for oxidative stress, anti-oxidative responses and Th1-type and Th2-type cytokines. Conclusions Radiation induced a significant elevation of oxidative stress, antioxidants and pro-fibrotic factors in our animal model for radiation cystitis that were completely reversed and normalized by HBOT. Our findings indicate that HBOT may prevent radiation-induced changes by affecting oxidative stress and inflammatory cascades induced by radiation. Summary Radiotherapy may cause the development of chronic inflammation and fibrosis, significantly impairing organ function. We hypothesized that bladder irradiation induces an oxidative stress reaction, thereby triggering the redox system and thus initiating an inflammatory and pro-fibrotic response. We aimed to assess whether these changes would be reversed by hyperbaric oxygen using an animal model for radiation cystitis. Our study show that hyperbaric oxygen may reverse oxidative stress and pro-inflammatory factors induced by radiation.
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| 9. |
- Oscarsson, Nicklas, 1974, et al.
(author)
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Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2–3 trial
- 2019
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In: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 20:11, s. 1602-1614
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Journal article (peer-reviewed)abstract
- © 2019 Elsevier Ltd Background: Late radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region. Symptoms of late radiation cystitis can be assessed with the Expanded Prostate Index Composite Score (EPIC). Previous reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomised and retrospective studies. We aimed to assess whether hyperbaric oxygen therapy would mitigate symptoms of late radiation cystitis. Methods: We did a randomised, controlled, phase 2–3 trial (RICH-ART [Radiation Induced Cystitis treated with Hyperbaric oxygen—A Randomised controlled Trial]) at five Nordic university hospitals. All patients aged 18–80 years, with pelvic radiotherapy completed at least 6 months previously, a score of less than 80 in the urinary domain of the Expanded Prostate Index Composite Score (EPIC), and referred to participating hyperbaric clinics due to symptoms of late radiation cystitis, were eligible for inclusion. Exclusion criteria were ongoing bleeding requiring blood transfusion exceeding 500 mL in the past 4 weeks, permanent urinary catheter, bladder capacity less than 100 mL, fistula in the urinary bladder, previous treatment with hyperbaric oxygen therapy for late radiation injuries, and contraindications to hyperbaric oxygen therapy. After computer-generated 1:1 randomisation with block sizes of four for each stratification group (sex, time from radiotherapy to inclusion, and previous invasive surgery in the pelvic area), patients received hyperbaric oxygen therapy (30–40 sessions, 100% oxygen, breathed at a pressure of 240–250 kPa, for 80–90 min daily) or standard care with no restrictions for other medications or interventions. No masking was applied. The primary outcome was change in patient-perceived urinary symptoms assessed with EPIC from inclusion to follow-up at visit 4 (6–8 months later), measured as absolute change in EPIC urinary total score. RICH-ART closed enrolment on Dec 31, 2017; the last follow-up data will be compiled in 2023. RICH-ART is registered with ClinicalTrials.gov, number NCT01659723, and with the European Medicines Agency, number EudraCT 2012-001381-15. Findings: Of 223 patients screened between May 9, 2012, and Dec 20, 2017, 87 patients were enrolled and randomly assigned to either hyperbaric oxygen therapy (n=42) or standard care (n=45). After excluding eight patients who withdrew consent directly after randomisation (one in the hyperbaric oxygen therapy group and seven in the standard care group), 79 were included in the intention-to-treat analyses (n=41 in the hyperbaric oxygen therapy group, n=38 in the standard care group). Median time from randomisation to visit 4 was 234 days (IQR 210–262) in the hyperbaric oxygen therapy group and 217 days (195–237) in the standard care group. The difference between change in group mean of EPIC urinary total score at visit 4 was 10·1 points (95% CI 2·2–18·1; p=0·013; 17·8 points [SD 18·4] in the hyperbaric oxygen therapy group vs 7·7 points [15·5] in the standard care group). 17 (41%) of 41 patients in the hyperbaric oxygen therapy group experienced transient grade 1–2 adverse events, related to sight and hearing, during the period of hyperbaric oxygen therapy. Interpretation: Our results suggest that hyperbaric oxygen therapy relieves symptoms of late radiation cystitis. We conclude that hyperbaric oxygen therapy is a safe and well tolerated treatment. Funding: The regional research fund of Region Västra Götaland, Sweden, the regional Health Technology Assessment Centre at Sahlgrenska University Hospital, Sweden, and Lions Cancer Research Fund of Western Sweden.
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| 10. |
- Podmolíková, Lucie, et al.
(author)
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Cholinergic regulation of proliferation of the urothelium in response to E. coli lipopolysaccharide exposition.
- 2018
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In: International immunopharmacology. - : Elsevier BV. - 1878-1705 .- 1567-5769. ; 56, s. 222-229
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Journal article (peer-reviewed)abstract
- How the proliferation of the urothelium is regulated is known to a little degree. E. coli lipopolysaccharide (LPS) activates the innate immune response of the urinary bladder via the Toll-like receptor 4 (TLR4) on the urothelium but induces also urothelial proliferation. We wanted to assess whether muscarinic receptors are involved in the regulation of urothelial proliferation triggered by LPS stimulation. Female Fischer 344 rats were instilled with LPS or saline (control) in the urinary bladder in the absence or presence of muscarinic receptor blockade with atropine and regeneration of the urothelium was assessed 4h and 24h later. In the Fischer 344 bladder, urothelial thinning and urothelial caspase 3 up-regulation occurred at 4h after LPS urinary bladder instillation, which were totally blocked in rats pre-treated with atropine. TLR4 was only expressed in blood vessels in the Fischer 344 bladder, while it was also expressed in umbrella cells in the Sprague-Dawley bladder. Proliferation (Ki67 incorporation) of the human urothelial cell line UROtsa was reduced in the presence of the muscarinic receptor antagonists methoctramine (M2/M4-selective) and pirenzepine (M1/M4-selective), while proliferation instead was enhanced in the presence of atropine. In UROtsa cells exposed to LPS for 24h, 4-DAMP (M3/M1/M5-selective) inhibited instead proliferation. In conclusion, muscarinic receptors regulate urothelial proliferation and LPS may induce urothelial apoptosis via muscarinic receptor-dependent pathways. Our findings also suggest that species differences exist in the expressional pattern of TLR4 in the urothelium.
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