Missed opportunities for HIV testing and sexual health-related challenges in an individual with intellectual disability: a case report.

BACKGROUND: HIV testing remains an important tool in identifying people living with HIV/AIDS (PLWHA). An early diagnosis of HIV can lead to a prolonged life expectancy if treatment is initiated promptly. Indicator conditions can be the first sign of an HIV infection and should therefore be recognised and consequently a HIV test should be carried out. Testing should occur in all individuals as sexuality can be experienced by everyone, and stigma can lead to the exclusion of vulnerable groups, leading to a gap in diagnosis and treatment [1, 2]. CASE PRESENTATION: A 63-year-old man, who identifies as bisexual and has had an intellectual disability since birth, presented at our health care centre for HIV testing. A decade ago, the patient was diagnosed with Stage III Diffuse Large B-cell Non-Hodgkin Lymphoma, an AIDS defining cancer. The patient presented at a Haematology and Oncology department 3 months prior, due to a weight loss of 10 kg over the past 5 months. Oral thrush, an HIV-indicator condition, had been diagnosed by the otolaryngologists shortly before. During this medical evaluation, pancytopenia was identified. Despite the presence of indicator conditions, the patient was never tested for HIV in the past. Staff members from the care facility for intellectually disabled suggested conducting a HIV test in our clinic through the public health department, where HIV positivity was revealed. The AIDS-defining diagnosis, along with a CD4 + cell count of 41/µl, suggests a prolonged period of HIV positivity. CONCLUSION: Due to the presence of existing indicator conditions, an earlier HIV diagnosis was possible. We contend that most of the recent illnesses could have been prevented if earlier testing had been carried out. Therefore, patients presenting with AIDS indicator conditions, including those with mental disabilities, should be given the opportunity to be tested for HIV. HIV/AIDS trainings should be made available to health care professionals as well as to personnel interacting with vulnerable groups.

Cholesterol-conjugated siRNAs silence gene expression in mucosal dendritic cells in cervicovaginal tissue in mice.

BACKGROUND: RNA interference (RNAi) provides a powerful way to investigate the role of genes in disease pathogenesis and modulate gene expression to treat disease. In 2018, the FDA approved patisiran, the first RNAi-based drug, hence paving the way for a novel class of RNAi therapeutics. Harnessing RNAi to inhibit vaginal HIV transmission requires effective gene silencing in immune cells, which remains difficult. Knockdown in accessible mucosal tissues may be easier than systemic gene silencing. Vaginally applied cholesterol-conjugated small interfering RNAs (chol-siRNAs) blocked herpes simplex virus transmission in mice without tissue damage or immunostimulation. OBJECTIVES AND METHODS: To investigate using flow cytometry, confocal microscopy, and quantitative imaging if chol-siRNAs silence gene expression in vaginal immune cells in mice. RESULTS: Although chol-siRNAs and lipoplexed-siRNAs silence gene expression in dendritic cells (DCs) in vitro, most internalized siRNAs concentrate within multivesicular bodies, where they are inaccessible to the cellular RNAi machinery. When applied intravaginally in vivo, chol-siRNAs penetrate the vaginal mucosa, including the lamina propria, and are efficiently internalized by intraepithelial (IE) and lamina propria (LP) DCs, and CD11b+ CD45+ cells, but not by T cells. Chol-siRNAs induce partial gene silencing in IE and LP DCs throughout the genital mucosa in vivo but are inactive in F4/80+ CD11b+ macrophages and T cells. CONCLUSION: As mucosal DCs play an essential role for mucosal viral entry and dissemination, chol-siRNAs could be harnessed to target various host factors that are critical for viral uptake, DC migration and trans-infection of virions to T cells, hence allowing the development of a preventive vaginal HIV microbicide. Furthermore, chol-siRNAs could help elucidate the pathways of HIV transmission and understand the immunologic function of DCs in the genital tract.

Changes in the user profiles of HIV pre-exposure prophylaxis (PrEP) before and after PrEP reimbursement.

BACKGROUND: In Germany, oral HIV pre-exposure prophylaxis (PrEP) was licensed in 2016. Health insurances have been covering the costs since 09/2019. This study compares the sociodemographic profiles of PrEP users before and after PrEP re-imbursement. METHODS: Participants were recruited in a cross-sectoral sexual health centre in Germany. baseline data were compared for 139 vs 138 individuals starting PrEP from 10/2017-12/2018 (pre-reimbursement cohort) and 09/2019-3/2020; respectively. The pre-reimbursement cohort was further analysed with respect to sexual behaviour and incident sexually transmitted infections (STIs). RESULTS: There were no significant differences in the sociodemographic characteristics between the two cohorts. Almost all PrEP users were men-who-have-sex-with-men (MSM). Before reimbursement, fewer individuals used PrEP on a daily base, and more had used PrEP prior to enrolment. During follow-up (pre-reimbursement cohort), the number of sexual and condomless intercourse partners increased, so did the proportion engaging in Chemsex. Incidences of infections with C.trachomatis, N.gonorrhoeae, M.genitalium, and T.pallidum were 45.2; 36.8; 30.1; and 9.2, respectively, per 100 person-years. CONCLUSION: The goal to make PrEP available to a broader range of people with the covering of costs was only partially reached. Medically supervised use is important to detect and treat STIs.

Online HIV/STI Risk Test (ORT): A prospective cross-sectional study among sexually active individuals in Germany.

BACKGROUND: Our goal was to develop and evaluate an anonymous self-administrable web-based test to determine risk for HIV/STI. METHODS: The Online HIV/STI Risk Test was developed and hosted since 12/2017. 11,529 participants completed the test and 10,668 were analyzed. The test included multiple choice questions about sociodemographic data, sexuality, sexual risk behavior, HIV/STI testing. Participant data was stratified by gender and sexuality and analyzed. RESULTS: 84.5 % were aged 18-39, 7.5 % < 18 and 8.1 % > 40. Males were 53.1 %, female 46.3 % and trans 0.6 %. 12.5 % were men who have sex with men (MSM). 59.1 % and 66.0 % of participants were vaccinated for hepatitis A and B respectively, but 75.1 % unvaccinated for HPV. Prior and repeated instances of HIV or other STI were higher among MSM. Yet, 61.4 % females, 70 % males and 55.4 % MSM had never tested for an STI. Although prevalence of > 3 sexual partners in the last twelve months was highest among MSM, condomless sex was greater among women. 34.5 % of males, 25.6 % of females, and 75 % of MSM engaged in anal sex respectively. CONCLUSIONS: The online HIV/STI Risk Test is a useful tool to acquire data on STI risk-behavior for strategizing STI prevention, testing, and vaccination, thus improving sexual health.

[Sexual behavior and prevention of sexually transmitted infections taking the SARS-CoV-2 pandemic into account. Data from a sexual healthcare and medicine center-WIR]. / Sexualverhalten und Prävention sexuell übertragbarer Infektionen unter Berücksichtigung der SARS-CoV-2-Pandemie. Daten aus einem Versorgungszentrum für sexuelle Gesundheit und Medizin ­ WIR.

BACKGROUND: Application-based data regarding sexual health and sexual behavior in various sexually active populations are scarce but at the same time relevant with regards to prevention and healthcare supply strategies. Given the structure of its attendees, the Walk In Ruhr (WIR) Center for Sexual Health and Medicine is able to obtain data from diverse living environments. OBJECTIVES: Based on the online HIV/STI risk test, questionnaires, and attendee data from the WIR, this study aims to deduce population-related findings with regards to age, gender, sexual orientation, and sexual and risk behavior as well as the respective needs for prevention. The influence of the SARS-CoV-19 pandemic on sexual behavior is examined by comparing various phases. METHODS: The analyzed data sources are the online HIV/STI risk test, the COWIR, and the PrEP study as well as the immunological outpatient clinic and the public health department at the WIR. RESULTS: Notwithstanding contact restrictions, sexually transmitted infections (STIs) have increased from 2019 to 2020. Apart from men having sex with men and females having sex with females, young people also have an increased risk of STIs based on sexual practices and the number of sexual contacts. A large number of bisexual and transsexual contacts was found. SARS-CoV­2 led to a decrease in sexual contacts; sexual practices continued. There was a growing proportion of STI tests and the treatment rate including partner treatment rose. DISCUSSION: Data from the WIR center show that young attendees with an active sexual life are being reached. The results from questionnaires and the online HIV/STI risk test are mirrored in increased positive STI test results. These results vary depending on sexual behavior and sexual preferences such that specific strategies for sexual education, prevention, testing, and therapy are required.

[Sexual health and medicine at the WIR-Walk In Ruhr: presentation of the center and results of the evaluation]. / Sexuelle Gesundheit und Medizin im WIR ­ Walk In Ruhr: Vorstellung des Zentrums und Ergebnisse der Evaluation.

BACKGROUND: Holistic sexual healthcare factors in diversity of social habitat and aims to improvise client outreach for prevention, testing, counseling, and treatment of STIs. Towards this goal, the immunology outpatient clinic, the public health department of Bochum, the AIDS Service Organization Bochum e. v., and other community-driven NGOs mutually cooperate under the umbrella of WIR - Walk In Ruhr, Centre for Sexual Health and Medicine. OBJECTIVES: WIR is an innovative concept for multi-professional in-house ambulatory healthcare with cross-sectoral and cross-legal reach. It has successfully improved accessibility, testing and treatment rates, and HIV/STI self-assessment. We present the results achieved at WIR. METHODS: A mixed-method design of qualitative and quantitative surveys. RESULTS: The WIR reaches more women (27.7%) and heterosexuals (56.4%) than other counseling/test centers. The rate of positive test results at the WIR increased from 9.3% in 2017 to 12.6% in 2018 and progress from prevention to medical care is a significant aspect of WIR. The Federal Ministry of Health has externally evaluated WIR for over three years. DISCUSSION: The integrative care model of WIR allows for early outreach and treatment of individuals with HIV/ST infections. Health advisors remain an important instrument facilitating outreach and psychosocial/psychotherapeutic counseling is administered frequently. Such a multi-layered approach in prevention, testing, and consultation, leads to improvement in both medical outcomes and the self-responsible attitude of patients towards their sexual health. Hence, expansion of integrative care models like WIR on a wider scale could arguably contribute to better health service and sexual health.

Numerical and structural chromosomal anomalies in undifferentiated pleomorphic sarcoma.

BACKGROUND: Malignant fibrous histiocytoma (MFH) or undifferentiated pleomorphic sarcoma (UPS) is the most common soft-tissue sarcoma of late adult life. Further advances in genetic characterization are warranted. The aim of this study was to search for numerical and structural chromosomal anomalies in UPS. MATERIALS AND METHODS: We investigated five sarcoma-specific chromosomal translocations, five oncogene amplifications as well as the numerical karyotype of 19 UPS samples and one UPS/MFH cell line (U2197) using FISH probes on interphase nuclei. RESULTS: Our results demonstrate that chromosomal translocations involving CHOP, SYT, EWS, FUS and FKHR genes are absent. Furthermore, amplification of ERBB2 (10.5%) and MDM2 (10.5%) was observed whereas the EGFR, C-MYC and N-MYC genes were not amplified. Interestingly, predominant aneuploidies were found in eight chromosomes. CONCLUSION: The data demonstrate rarity of sarcoma-specific chromosomal breaks and oncogene amplifications in UPS, yet polysomic chromosomes appear more characteristically in this condition.

Growth rate of late passage sarcoma cells is independent of epigenetic events but dependent on the amount of chromosomal aberrations.

Soft tissue sarcomas (STS) are characterized by co-participation of several epigenetic and genetic events during tumorigenesis. Having bypassed cellular senescence barriers during oncogenic transformation, the factors further affecting growth rate of STS cells remain poorly understood. Therefore, we investigated the role of gene silencing (DNA promoter methylation of LINE-1, PTEN), genetic aberrations (karyotype, KRAS and BRAF mutations) as well as their contribution to the proliferation rate and migratory potential that underlies "initial" and "final" passage sarcoma cells. Three different cell lines were used, SW982 (synovial sarcoma), U2197 (malignant fibrous histiocytoma (MFH)) and HT1080 (fibrosarcoma). Increased proliferative potential of final passage STS cells was not associated with significant differences in methylation (LINE-1, PTEN) and mutation status (KRAS, BRAF), but it was dependent on the amount of chromosomal aberrations. Collectively, our data demonstrate that these fairly differentiated/advanced cancer cell lines have still the potential to gain an additional spontaneous growth benefit without external influences and that maintenance of increased proliferative potential towards longevity of STS cells (having crossed senescence barriers) may be independent of overt epigenetic alterations.

Dento-Alveolar Distraction Osteogenesis for rapid Orthodontic Canine Retraction.

BACKGROUND: The objectives of this study were to evaluate the rate of canine distalization by segmental alveolar distraction method in first premolar extraction cases, to evaluate the displacement of the canine and first molar teeth, to assess the effects of the procedure on the pulpal vitality of the canines, and to determine the amount of root resorption in retracted canines. MATERIALS & METHODS: The sample of the study consisted of 20 teeth in 7 patients (five females and two males, mean age 18.5 years). After the osteotomy procedure distractor was fixed. After 3 days of consolidation period, the distractor was activated 3 quarter turns per day(0.75 mm/day) till the canines comes in contact with second premolar. An electrical vitality test was applied before and after the distraction procedure and during the follow-up period. RESULTS: The mean distal retraction of canines was 7.262 ± 0.4864 mm. The distal displacement of the canine was mainly a combination of tipping and translation. The mean distraction procedure was completed in 14.60 ±1.536 days. The duration of retraction was less for mandibular canine compared to maxillary canine. The mean posterior anchorage loss was mean 0.50±0.688 mm. The amount of root resorption that occurred during distraction was clinically insignificant. None of the teeth reacted negatively to the electrical vitality test that was performed 6 months after the completion of the distraction procedure. There was no clinical sign of discoloration or pulpal pain in any tooth. CONCLUSION: With dentoalveolar distraction, as canines can be fully retracted in 12 to 16 days, the non-compliance patients, patients with root-shape malformations, periodontal problems, or ankylosed teeth will benefit from this technique. The anchorage teeth can withstand the retraction forces better with no anchorage loss, and without clinical or radiographic evidence of root resorption, ankylosis, periodontal problems, and soft tissue dehiscence. This technique reduces orthodontic treatment duration by 6 to 9 months in patients who need extraction, with no need for any sort of anchorage reinforcement. How to cite this article: Kumar N, Prashantha GS, Raikar S, Ranganath K, Mathew S, Nambiar S. Dento-Alveolar Distraction Osteogenesis for rapid Orthodontic Canine Retraction. J Int Oral Health 2013; 5(6):31-41 .

Site- and grade-specific diversity of LINE1 methylation pattern in gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: Recent data indicate that gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have a hypomethylated long interspersed element (LINE1) promoter. To answer the question, of whether LINE1 may be of value in assessing the malignant potential of GEP-NETs, we analysed LINE1 methylation in different organs. MATERIALS AND METHODS: A total of 58 GEP-NETs of gastric (n=14), pancreatic (n=15), small intestine (n=17), appendix (n=8), colorectal (n=4) and non-neoplastic tissues were analysed using DNA isolation, bisulphite-treatment and pyrosequencing. RESULTS: LINE1 hypomethylation was detected in 50% of gastric, 100% pancreatic, 82% small intestine, 87.5% appendix and 100% colorectal NETs. G1 (p<0.001) and G2 (p<0.05) colorectal, and G1 (p<0.001) and G2 (p<0.001) pancreatic NETs exhibited significant LINE1 hypomethylation compared with non-neoplastic tissues. Higher rates of LINE1 hypomethylation in G2 pancreatic NETs than in G1 NETs (p<0.05) were observed. NETs exhibited a significantly lower frequency of hypomethylation in cases with lymph node metastases (p<0.05). CONCLUSION: LINE1 hypomethylation may serve as a marker of tumour grade and lymph node metastasis.

Kaposi's Sarcoma and Human Herpesvirus 8 in Cuba: evidence of subtype B expansion.

OBJECTIVE: To evaluate the temporal distribution (1991-2009) and associated variation of KSHV subtypes in Cuba. METHOD: Phylogenetic characterization based on the KSHV K1 gene was performed using 90 KSHV positive samples. RESULTS: Molecular characterization confirmed the prevalence of a wide range of KSHV subtypes (A: n=48 [A5=12]; C: n=15; B: n=22; and E: n=5). In the current study, we observed a significant increase in HHV-8 subtype B after 2004 (p=0.0063). This Subtype B in Cuba was associated with: heterosexual behaviour (OR: 3.63, CI: 1,2-10,98; p=0.03), with the antecedent of acquiring HIV/KSHV in Africa (p=0.0003), with nodular stage of KS lesions (OR 4.2, CI: 1.1 to 15.7; p=0.04). CONCLUSION: Our study is the first to report KSHV Subtype B expansion in Cuba, that might be reflective of a change in human behavioural pattern.

MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B.

MicroRNAs (miRNAs: short non-coding RNAs) are emerging as a class of potential novel tumor markers, as their dysregulation is being increasingly reported in various types of cancers. In the present study, we investigated the transcription status of miRNA-148a (miR-148a) in human pancreatic ductal adenocarcinoma (PDAC) and its role in the regulation of the dual specificity protein phosphatase CDC25B. We observed that miR-148a exhibited a significant 4-fold down-regulation in PDAC as opposed to normal pancreatic ductal cells. In addition, we observed that stable lentiviral-mediated overexpression of miR-148a in the pancreatic cancer cell line IMIM-PC2, inhibited tumor cell growth and colony formation. Furthermore, CDC25B was identified as a potential target of miR-148a by in silico analysis using PicTar, Targetscan and miRanda in conjunction with gene ontology analysis. The proposed interaction between miR-148a and the 3' untranslated region (UTR) of CDC25B was verified by in-vitro luciferase assays. We demonstrate that the activity of a luciferase reporter containing the 3'UTR of CDC25B was repressed in the presence of miR-148a mimics, confirming that miR-148a targets the 3'UTR of CDC25B. Finally, CDC25B was down-regulated at the protein level in miR-148a overexpressing IMIM-PC2-cells, and in transiently transfected pancreatic cell lines (as detected by Western blot analysis), as well as in patient tumor samples (as detected by immunohistochemistry). In summary, we identified CDC25B as a novel miR-148a target which may confer a proliferative advantage in PDAC.

Role of erythropoietin receptor expression in malignant melanoma.

Recombinant human erythropoietin (Epo) is used to prevent and treat tumor-related anemia and improve quality of life in cancer patients. Recent evidence suggested that Epo may adversely affect the survival of selected cancer patients by promoting tumor growth, inhibition of apoptosis, and induction of migration. Epo unfolds its effect on the Epo receptor (EpoR). We show--to the best of our knowledge for the first time--significantly increased EpoR expression in clinical melanoma metastases and primary melanomas in comparison with different sets of nevi by quantitative real-time reverse transcriptase-PCR, immunohistochemistry, and western blot analysis. When assessing the functionality of the EpoR-signaling pathway, recombinant human Epo led to the phosphorylation of JAK-2, signal transducers and activators of transcription 3 (STAT3), and ERK1/2 in several of the melanoma cell lines that were analyzed. Besides, Epo counteracted cisplatin-induced cell death in BLM and MV3 cells. Finally, Epo promoted cell migration of MV3 cells, whereas inhibition of the JAK/STAT and ERK1/2 pathways reduced Epo-mediated migration. In summary, we show the overexpression of functional EpoR expression in about half of the analyzed clinical melanoma metastasis specimens and show anti-apoptotic as well as pro-migratory effects of Epo, which is of importance for the treatment of anemia in advanced melanoma.

Induction of indoleamine 2, 3-dioxygenase by death receptor activation contributes to apoptosis of melanoma cells via mitochondrial damage-dependent ROS accumulation.

Although the induction of indoleamine 2, 3-dioxygenase (IDO) by several agents is well established, the mechanisms of its transcriptional regulation and those regulating its function as apoptotic mediator seem to be complex, agent-dependent, and cell type-specific. Besides their pro-apoptotic activity in melanoma cells, both anti-Fas agonist antibody (CH11) and the tumor necrosis factor (TNF)-alpha were found to induce IDO gene expression, the activation of apoptosis signal-regulating kinase (ASK1), and the activation of both c-Jun N-terminal kinase (JNK) and NF-kappaB pathways. In addition, the treatment of melanoma cells with CH11 or TNF-alpha induced the loss of mitochondrial membrane potential (Deltapsim), the accumulation of reactive oxygen species (ROS), the phosphorylation of Fas-associated domain (FADD), the cleavage of caspase-8, and truncation of Bid. Using RNA interference and pharmacological inhibitors, we could confirm the pro-apoptotic activity of IDO and address the mechanisms, which are responsible for its transcriptional regulation and the modulation of its pro-apoptotic activity during death receptor activation in melanoma cells. Thus, our data confirm the pro-apoptotic activity of IDO and provide an insight into the molecular mechanism of TNF-alpha and CH11-induced IDO expression, and the mechanism whereby IDO induces apoptosis of melanoma cells.

Transcriptional regulation of ASK/Dbf4 in cutaneous melanoma is dependent on E2F1.

BACKGROUND: Melanoma is a complex genetic disease, the management of which will require an in-depth understanding of the biology underlying its initiation and progression. Recently, we have reported the differential regulation of a novel gene, namely ASK/Dbf4, in melanoma and suggested upregulation of ASK/Dbf4 as a novel molecular determinant with prognostic relevance that confers a proliferative advantage in cutaneous melanoma. As trans-acting factor binding is fundamental to understand the regulation of gene expression, this study focuses on characterization of the specific transcriptional regulation of ASK/Dbf4 in melanoma. OBJECTIVE: We investigated whether ASK/Dbf4 is a transcriptional target of the important cell cycle regulator E2F1 in melanoma. RESULTS: As evidenced by gel supershift assays on nuclear extracts from various melanoma cell lines (SK-MEL-28, MV3, M13, A375 and BLM), E2F1 bound to the ASK/Dbf4 minimal promoter (MP). In addition, cisplatin-mediated abrogation of E2F1 binding to the ASK/Dbf4 MP resulted in a transcriptional decrease in ASK/Dbf4. Further, the current study also demonstrated that ASK/Dbf4 regulation was refractory to UVB, a well-known risk factor for melanoma. CONCLUSIONS: In summary, our study not only elucidated that ASK/Dbf4, a novel cell survival gene in melanoma was transcriptionally regulated by E2F1, but also that the induction of ASK/Dbf4 was refractory to UVB exposure suggesting that its upregulation was not an early event in melanomagenesis.

Cutaneous melanoma: fishing with chips.

DNA microarray technology is a versatile platform that allows rapid genetic analysis to take place on a genome-wide scale and has revolutionized the way cancers are studied. This platform has enabled researchers to characterize mechanisms central to tumorigenesis and understand important molecular events in the multi-step tumor progression model of cutaneous melanoma and other cancers. In melanoma, multiple global gene expression profiling studies using various DNA microarray platforms and various experimental designs have been performed. Each study has been able to capture and characterize either the involvement of a novel pathway or a novel cause-effect-relationship. The use of microarrays to define subclasses, to identify differentially regulated genes within a mutational context to analyze epigenetically regulated genes has resulted in an unprecedented understanding of the biology of cutaneous melanoma that may lead to more accurate diagnosis, more comprehensive prognosis, prediction and more effective therapeutic interventions. Related DNA microarray platforms like array-comparative genomic hybridization (CGH) have also been instrumental to identify many non-random chromosomal alterations; however, studies identifying validated targets as a result of CGH are limited. Thus, there exists significant opportunity to discover novel melanoma genes and translate such discoveries into meaningful clinical endpoints. In this review, we focus on various DNA microarray-based studies performed in cutaneous melanoma and summarize our current understanding of the genetics and biology of melanoma progression derived from accumulating genomic information.