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Current HIV Research Jan 2012Since the beginning of the AIDS pandemic, and following the discovery of the human immunodeficiency virus (HIV) as the etiological agent of the disease, it was clear... (Review)
Review
Since the beginning of the AIDS pandemic, and following the discovery of the human immunodeficiency virus (HIV) as the etiological agent of the disease, it was clear that the virus gains access to the human host predominantly through the mucosal tissue after sexual exposure. As a consequence, the female genital tract (vaginal and cervical), as well as the rectal, penile, and oral mucosae have been extensively studied over the last thirty years towards a better understanding of--and to develop strategies to prevent--sexual HIV transmission. This review seeks to describe the biology of the events leading to HIV infection through the human mucosa and introduce some of the approaches attempted to prevent the sexual transmission of HIV.
Topics: Anti-Retroviral Agents; Female; HIV Infections; Humans; Immunity, Innate; Immunity, Mucosal; Male; Mouth Mucosa; Mucous Membrane; Penis; Rectum; Vagina
PubMed: 22264040
DOI: 10.2174/157016212799304689 -
Future Medicinal Chemistry Dec 2011There is an urgent need control the spread of the global HIV pandemic. A microbicide, or topical drug applied to the mucosal environment to block transmission, is a... (Review)
Review
There is an urgent need control the spread of the global HIV pandemic. A microbicide, or topical drug applied to the mucosal environment to block transmission, is a promising HIV prevention strategy. The development of a safe and efficacious microbicide requires a thorough understanding of the mucosal environment and its role in HIV transmission. Knowledge of the key events in viral infection identifies points at which the virus might be most effectively targeted by a microbicide. The cervicovaginal and rectal mucosa play an important role in the innate defense against HIV, and microbicides must not interfere with these functions. In this review, we discuss the current research on HIV microbicide development.
Topics: Anti-HIV Agents; HIV Infections; Humans; Mucous Membrane
PubMed: 22098355
DOI: 10.4155/fmc.11.153 -
Digestion 2018Ulcerative proctitis, one of the disease types of ulcerative colitis, is considered one of the initial manifestations of ulcerative colitis. Prevention of aggravation of... (Review)
Review
BACKGROUND
Ulcerative proctitis, one of the disease types of ulcerative colitis, is considered one of the initial manifestations of ulcerative colitis. Prevention of aggravation of ulcerative proctitis is important for improving the prognosis of ulcerative colitis. Here we reviewed the epidemiology, diagnosis, and management of ulcerative proctitis.
SUMMARY
The number of patients with ulcerative proctitis is increasing. Disease extension occurs in many patients with ulcerative proctitis. Differential diagnosis from other chronic proctitis is important and should be performed based on the clinical history and endoscopical and histological features. Mesalazine suppository has been the first-line therapy for patients with ulcerative proctitis because of its high effectiveness and safety. Topical treatment of ulcerative proctitis, particularly using mesalazine suppository has been underused in clinical practice. Key Messages: Mesalazine suppositories are more effective than dose intensification of oral mesalazine for relapsed patients with maintenance dose of oral mesalazine. However, low adherence to rectal mesalazine has hindered remission in patients with ulcerative proctitis.
Topics: Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Consensus; Diagnosis, Differential; Disease Progression; Gastroenterology; Humans; Intestinal Mucosa; Mesalamine; Patient Compliance; Practice Guidelines as Topic; Proctitis; Proctoscopy; Rectum; Suppositories; Time Factors; Treatment Outcome
PubMed: 29393142
DOI: 10.1159/000484224 -
Journal of Acquired Immune Deficiency... Mar 2017The Population Council's microbicide gel MZC (also known as PC-1005) containing MIV-150 and zinc acetate dihydrate (ZA) in carrageenan (CG) has shown promise as a...
The Population Council's microbicide gel MZC (also known as PC-1005) containing MIV-150 and zinc acetate dihydrate (ZA) in carrageenan (CG) has shown promise as a broad-spectrum microbicide against HIV, herpes simplex virus (HSV), and human papillomavirus. Previous data show antiviral activity against these viruses in cell-based assays, prevention of vaginal and rectal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection, and reduction of vaginal HSV shedding in rhesus macaques and also excellent antiviral activity against HSV and human papillomavirus in murine models. Recently, we demonstrated that MZC is safe and effective against SHIV-RT in macaque vaginal explants. Here we established models of ex vivo SHIV-RT/HSV-2 coinfection of vaginal mucosa and SHIV-RT infection of rectal mucosa in macaques (challenge of rectal mucosa with HSV-2 did not result in reproducible tissue infection), evaluated antiviral activity of MZC, and compared quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay readouts for monitoring SHIV-RT infection. MZC (at nontoxic dilutions) significantly inhibited SHIV-RT in vaginal and rectal mucosas and HSV-2 in vaginal mucosa when present during viral challenge. Analysis of SHIV-RT infection and MZC activity by 1-step simian immunodeficiency virus gag quantitative RT-PCR and p27 enzyme-linked immunosorbent assay demonstrated similar virus growth dynamics and MZC activity by both methods and higher sensitivity of quantitative RT-PCR. Our data provide more evidence that MZC is a promising dual compartment multipurpose prevention technology candidate.
Topics: Animals; Antiviral Agents; Female; Gels; Herpesvirus 2, Human; Macaca; Microbial Sensitivity Tests; Models, Theoretical; Mucous Membrane; Organ Culture Techniques; Pyridines; RNA-Directed DNA Polymerase; Rectum; Simian Immunodeficiency Virus; Urea; Vagina
PubMed: 27552154
DOI: 10.1097/QAI.0000000000001167 -
Stem Cell Research & Therapy Jan 2021Radiation-induced rectal epithelial damage is a very common side effect of pelvic radiotherapy and often compromise the life quality and treatment outcome in patients...
BACKGROUND
Radiation-induced rectal epithelial damage is a very common side effect of pelvic radiotherapy and often compromise the life quality and treatment outcome in patients with pelvic malignancies. Unlike small bowel and colon, effect of radiation in rectal stem cells has not been explored extensively. Here we demonstrate that Lgr5-positive rectal stem cells are radiosensitive and organoid-based transplantation of rectal stem cells mitigates radiation damage in rectum.
METHODS
C57Bl6 male mice (JAX) at 24 h were exposed to pelvic irradiation (PIR) to determine the radiation effect in pelvic epithelium. Effect of PIR on Lgr5-positive rectal stem cells (RSCs) was determined in Lgr5-EGFP-Cre-ERT2 mice exposed to PIR. Effect of PIR or clinically relevant fractionated PIR on regenerative response of Lgr5-positive RSCs was examined by lineage tracing assay using Lgr5-eGFP-IRES-CreERT2; Rosa26-CAG-tdTomato mice with tamoxifen administration to activate Cre recombinase and thereby marking the ISC and their respective progeny. Ex vivo three-dimensional organoid cultures were developed from Lgr5-EGFP-Cre-ERT2 mice. Organoid growth was determined by quantifying the budding crypt/total crypt ratio. Organoids from Lgr5-EGFP-ires-CreERT2-TdT mice were transplanted in C57Bl6 male mice exposed to PIR. Engraftment and repopulation of Lgr5-positive RSCs were determined after tamoxifen administration to activate Cre recombinase in recipient mice. Statistical analysis was performed using Log-rank (Mantel-Cox) test and paired two-tail t test.
RESULT
Exposure to pelvic irradiation significantly damaged rectal epithelium with the loss of Lgr5+ve rectal stem cells. Radiosensitivity of rectal epithelium was also observed with exposure to clinically relevant fractionated pelvic irradiation. Regenerative capacity of Lgr5+ve rectal stem cells was compromised in response to fractionated pelvic irradiation. Ex vivo organoid study demonstrated that Lgr5+ve rectal stem cells are sensitive to both single and fractionated radiation. Organoid-based transplantation of Lgr5+ve rectal stem cells promotes repair and regeneration of rectal epithelium.
CONCLUSION
Lgr5-positive rectal stem cells are radiosensitive and contribute to radiation-induced rectal epithelial toxicity. Transplantation of Lgr5-positive rectal stem cells mitigates radiation-induced rectal injury and promotes repair and regeneration process in rectum.
Topics: Animals; Humans; Intestinal Mucosa; Male; Mice; Organoids; Radiation Injuries; Receptors, G-Protein-Coupled; Rectum; Stem Cells
PubMed: 33451351
DOI: 10.1186/s13287-020-02111-w -
Annals of Surgery Mar 1980Preservation of the rectum in chronic ulcerative colitis or familial polyposis conserves continence at the risk of recurrent disease or malignant change. Replacement of...
Preservation of the rectum in chronic ulcerative colitis or familial polyposis conserves continence at the risk of recurrent disease or malignant change. Replacement of rectal mucosa with a graft of ileum in these benign colonic mucosal diseases conserves fecal continence without the threat of continuing disease or the development of carcinoma. Rectal mucosal replacement with construction of a rectal reservoir includes total colectomy, removal of the rectal mucosa-submucosa and its replacement with an ileal graft. A rectal reservoir is constructed when intestinal continuity is restored. Twenty-nine patients have undergone rectal mucosal replacement; 12 for familial polyposis and 17 for ulcerative colitis. Twenty-five patients have had intestinal continuity restored. Patients have been followed from three months to seven years after the restoration of intestinal continuity. Twenty-three patients have a satisfactory result. Fecal continence has been preserved. Patients pass an average of six stools in a 24 hour period.
Topics: Adolescent; Adult; Child; Colectomy; Colitis, Ulcerative; Fecal Incontinence; Female; Humans; Ileostomy; Ileum; Intestinal Mucosa; Intestinal Polyps; Male; Middle Aged; Postoperative Complications; Rectal Neoplasms; Rectum; Transplantation, Autologous
PubMed: 7362295
DOI: 10.1097/00000658-198003000-00007 -
Journal of Immunological Methods Nov 2017The use of therapeutic antibodies, delivered by intravenous (IV) instillation, is a rapidly expanding area of biomedical treatment for a variety of conditions. However,...
The use of therapeutic antibodies, delivered by intravenous (IV) instillation, is a rapidly expanding area of biomedical treatment for a variety of conditions. However, little is known about how the antibodies are anatomically distributed following infusion and the underlying mechanism mediating therapeutic antibody distribution to specific anatomical sites remains to be elucidated. Current efforts utilize low resolution and sensitivity methods such as ELISA and indirect labeling imaging techniques, which often leads to high background and difficulty in assessing biodistribution. Here, using the in vivo non-human primate model, we demonstrate that it is possible to utilize the fluorophores Cy5 and Cy3 directly conjugated to antibodies for direct visualization and quantification of passively transferred antibodies in plasma, tissue, and in mucosal secretions. Antibodies were formulated with 1-2 fluorophores per antibody to minimally influence antibody function. Fluorophore conjugated Gamunex-C (pooled human IgG) were tested for binding to protein A, via surface plasmon resonance, and showed similar levels of binding when compared to unlabeled Gamunex-C. In order to assess the effect fluorophore labeling has on turnover and localization, rhesus macaques were IV infused with either labeled or unlabeled Gamunex-C. Plasma, vaginal Weck-Cel fluid, cervicovaginal mucus, and vaginal/rectal tissue biopsies were collected up to 8weeks. Similar turnover and biodistribution was observed between labeled and unlabeled antibodies, showing that the labeling process did not have an obvious deleterious effect on localization or turnover. Cy5 and Cy3 labeled antibodies were readily detected in the same pattern regardless of fluorophore. Tissue distribution was measured in macaque vaginal and rectal biopsies. The labeled antibody in macaque biopsies was found to have similar biodistribution pattern to endogenous antibodies in macaque and human tissues. In the vaginal and rectal mucosa, endogenous and infused antibodies were found primarily within the lamina propria. In the mucosal squamous epithelium of the vaginal vault, significant antibody was also observed in a striated pattern in the superficial, nonviable, stratum corneum. Endogenous antibody distribution in both human and macaque squamous tissues exhibited a similar pattern as seen with the labeled and unlabeled antibodies. This proof-of-principle study reveals that the labeled antibody is stable and physiologically similar relative to endogenous antibody setting the stage for future work to better understand the mechanisms of how antibodies reach unique anatomical sites. Direct visualization of fluorophore-conjugated antibodies following passive infusion can be utilized to assess the kinetics of biodistribution of infused antibodies and may be a useful approach to monitor and predict efficacy of therapeutic antibodies.
Topics: Animals; Carbocyanines; Cervix Mucus; Drug Stability; Female; Fluorescent Antibody Technique; Fluorescent Dyes; Humans; Immunoglobulins, Intravenous; Infusions, Intravenous; Macaca mulatta; Microscopy, Fluorescence; Models, Animal; Mucous Membrane; Plasma; Protein Stability; Rectum; Surface Plasmon Resonance; Tissue Distribution; Vagina
PubMed: 28780040
DOI: 10.1016/j.jim.2017.07.009 -
Scientific Reports May 2019A better understanding of the distribution and functional capacity of CD4 T helper (Th) and CD8 T cytotoxic (Tc) cell subsets in the rectal mucosa (RM), a major site for...
A better understanding of the distribution and functional capacity of CD4 T helper (Th) and CD8 T cytotoxic (Tc) cell subsets in the rectal mucosa (RM), a major site for HIV acquisition and replication, in adults is needed. In this study, we compared the distribution of Th and Tc cell subsets between blood and RM compartments in 62 HIV negative men, focusing primarily on IL-17-producing CD4 and CD8 T cells due to their importance in establishing and maintaining mucosal defenses, and examined associations between the frequencies of Th17 and Tc17 cell subsets and the availability of highly HIV-susceptible target cells in the RM. The RM exhibited a distinct immune cell composition comprised of higher frequencies of Th2, Th17, and Tc17 cells compared to the peripheral blood. The majority of Tc17 cells in RM were quadruple-cytokine producers (IL-17A, IFN-γ, TNF-α, and IL4), whereas most Th17 cells in blood and RM were single IL-17A producers or dual-cytokine producers (IL-17ATNF-α). In a separate cohort of 21 HIV positive men, we observed similar tissue distributions of Th and Tc cell subsets, although Tc17 cell frequencies in both blood and tissues were very low. Higher frequencies of multi-cytokine-producing Th17 and Tc17 cells in RM of HIV negative men positively correlated with increased mucosal HIV target cells, suggesting a need to further characterize the effector functions of these cells and their role in HIV acquisition and pathogenesis.
Topics: Adolescent; Adult; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Case-Control Studies; Cohort Studies; HIV; HIV Infections; Humans; Interleukin-17; Leukocytes, Mononuclear; Male; Middle Aged; Mucous Membrane; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Young Adult
PubMed: 31061442
DOI: 10.1038/s41598-019-43311-6 -
Journal of Cancer Research and... 2011Late rectal and sigmoid toxicities seen in cervical cancer patients are attributed to brachytherapy despite rectal doses within tolerance limits. The purpose of this...
BACKGROUND
Late rectal and sigmoid toxicities seen in cervical cancer patients are attributed to brachytherapy despite rectal doses within tolerance limits. The purpose of this study was to identify additional dosimetric points which may better forecast rectal complications.
MATERIALS AND METHODS
Fifteen high dose rate intracavitary brachytherapy (ICA-HDR) applications with conventional X-ray and computed tomography (CT) based planning were studied. In addition to International Commission on Radiation Units and Measurement (ICRU) rectal and bladder points, proximal and distal rectal and sigmoid points were digitized on CT scans and dose volume histograms' (DVHs') parameters were computed and correlated.
RESULTS
The mean ICRU, additional distal, proximal and sigmoid point doses were 486 ± 152 cGy, 527 ± 156 cGy, 401 ± 149 cGy and 838 ± 254 cGy, respectively, for a prescription of 700 cGy to point A. The mean sigmoid point dose was significantly higher than the ICRU rectal point doses (P=0.001). The high-dose sigmoid points were situated at a mean -8 mm (range -22.95 to 10.43 mm) lateral, 10 mm posterior (range -15.87 to 27.82 mm) and 31 mm (range 8.08-62.91 mm) cranial to the intracavitary applicator flange of central tandem.
CONCLUSIONS
Our dosimetric study suggests that sigmoid points and 0.1 cm 3 receive significantly higher doses than rectal points during ICA-HDR in carcinoma of the uterine cervix. No definite conclusion on reproducible spatial distribution on orthogonal X-rays could be achieved. To document and reduce sigmoid doses, some form of 3D image-based planning is necessary.
Topics: Brachytherapy; Colon, Sigmoid; Female; Humans; Intestinal Mucosa; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Rectum; Uterine Cervical Neoplasms
PubMed: 22044811
DOI: 10.4103/0973-1482.87027 -
Canadian Journal of Veterinary Research... Jan 2018The objectives of the study were to: i) determine baseline microvascular perfusion indices (MPI) and assess their repeatability in healthy horses under general... (Comparative Study)
Comparative Study
The objectives of the study were to: i) determine baseline microvascular perfusion indices (MPI) and assess their repeatability in healthy horses under general anesthesia, and ii) compare the MPIs of 3 microvascular beds (oral mucosa, colonic serosa, and rectal mucosa). Healthy adult horses were anesthetized and sidestream dark field microscopy was used to collect video loops of the oral mucosa, rectal mucosa, and colonic serosa under normotensive conditions without cardiovascular support drugs; videos were later analyzed to produce MPIs. Baseline MPI values were determined for each site, which included the total vessel density (TVD), perfused vessel density (PVD), portion perfused vessels (PPV), and microcirculatory flow index (MFI). Differences in MPIs between microvascular beds were not statistically significant. Repeatability of the measurements varied for each MPI. In particular, the site of sampling had a profound effect on the repeatability of the PPV measurements and should be considered in future studies.
Topics: Anesthesia, General; Animals; Blood Pressure; Colon; Female; Horses; Intestinal Mucosa; Male; Microcirculation; Mouth Mucosa; Rectum; Video Recording
PubMed: 29382969
DOI: No ID Found