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Zika virus (ZIKV) has emerged as a significant health threat worldwide. Although typically mosquito-borne, recent evidence suggests that ZIKV is also a sexually transmitted virus. While persistent ZIKV infections in male reproductive tissues have been identified, little is understood regarding the outcomes of primary sexual transmission in females. We investigated how the route of infection affects vaginal ZIKV shedding and dissemination. In two mouse models, vaginal infection resulted in prolonged ZIKV shedding in the vaginal mucosa with delayed systemic infection. Furthermore, heightened vaginal inflammation did not influence ZIKV replication or dissemination, in contrast to previous studies of mosquito-borne infection. Thus, vaginal infection significantly alters ZIKV infection kinetics and must be considered when developing novel treatments.

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists boost antiviral immunity, decrease viral titers and ameliorate Zika-induced pathology in vivo. Here we report that AHR is activated by infection with different coronaviruses, potentially impacting antiviral immunity and lung epithelial cells. Indeed, the analysis of single-cell RNA-seq from lung tissue detected increased expression of AHR and AHR transcriptional targets, suggesting AHR signaling activation in SARS-CoV-2-infected epithelial cells from COVID-19 patients. Moreover, we detected an association between AHR expression and viral load in SARS-CoV-2 infected patients. Finally, we found that the pharmacological inhibition of AHR suppressed the replication in vitro of one of the causative agents of the common cold, HCoV-229E, and the causative agent of the COVID-19 pandemic, SARS-CoV-2. Taken together, these findings suggest that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology. Future studies should further evaluate the potential of AHR as a target for host-directed antiviral therapy., RNA viruses, such as Zika and Dengue, activate the aryl hydrocarbon receptor (AHR) signaling to restrict the antiviral response. Here, the authors report that coronaviruses also activate AHR signaling, potentially allowing them to escape the immune response, and show that AHR antagonism limits SARS-CoV-2 replication in vitro, suggesting that AHR could be targeted for antiviral therapy.

The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency Virus (HIV-1). Therefore understanding how DMPA increases susceptibility to HIV-1 is an important public health issue. Using C57BL/6 mice and our previously optimized humanized mouse model (NOD-Rag1tm1Mom Il2rgtm1Wjl transplanted with hCD34-enriched hematopoietic stem cells; Hu-mice) where peripheral blood and tissues are reconstituted by human immune cells, we assessed how DMPA affected mucosal barrier function, HIV-1 susceptibility, viral titres, and target cells compared to mice in the diestrus phase of the estrous cycle, when endogenous progesterone is highest. We found that DMPA enhanced FITC-dextran dye leakage from the vaginal tract into the systemic circulation, enhanced target cells (hCD68+ macrophages, hCD4+ T cells) in the vaginal tract and peripheral blood (hCD45+hCD3+hCD4+hCCR5+ T cells), increased the rate of intravaginal HIV-1 infection, extended the window of vulnerability, and lowered vaginal viral titres following infection. These findings suggest DMPA may enhance susceptibility to HIV-1 in Hu-mice by impairing the vaginal epithelial barrier, increasing vaginal target cells (including macrophages), and extending the period of time during which Hu-mice are susceptible to infection; mechanisms that might also affect HIV-1 susceptibility in women.

Introduction Although normal epithelial cells do not show human epidermal growth factor receptor-2 (HER2) gene amplification and should lack membrane staining by HER2 immunohistochemistry (IHC), HER2 staining in benign breast epithelium is occasionally encountered. The significance of this occurrence has not yet been adequately studied, and its associated American Society of Clinical Oncology/College of American Pathologists recommendations are vague. Our objective is to assess the correlation between HER2 IHC 3+ breast cancer cases with normal epithelium staining (NES) and their corresponding fluorescence in situ hybridization (FISH) results, and to suggest recommendations for interpretation. Materials and Methods A total of 154 breast cancer cases with HER2 IHC 3+ were reviewed. NES, along with other clinicopathologic characteristics, were recorded. NES was scored as present or absent. All study cases were sent for FISH testing. All cases, and particularly those that showed false positivity for IHC (positive IHC, negative FISH) were examined for NES. Results Of the 154 cases, 146 cases were FISH-positive (94.8%) and 2 failed FISH testing (1.3%). Conversely, 22% (34/154) of the cases showed NES for HER2. Of these 34 cases, 23 (67%) were FISH-amplified, 9 (26%) were FISH not amplified, and 2 failed FISH testing. Notably, all of the false-positive (FISH-negative) breast cancer cases showed some degree of positivity in normal breast epithelium. Conclusions Our findings, though descriptive, show a very strong association between NES and false-positive HER2 IHC. This confirms the need to carefully evaluate IHC-positive breast cancers for NES, and to have a low threshold for confirmatory testing by FISH.

The Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) has been widely used for ASD assessment. While prior studies investigated sensitivity and specificity of ADOS-2 Modules 1-3, there has been limited research addressing algorithm cut-off scores to optimize ADOS-2 classification. The goal of this study was to assess algorithm cut-off scores for diagnosing ASD with Modules 1-3, and to evaluate alignment of the ADOS-2 classification with the best estimate clinical diagnosis. Participants included 3144 children aged 31 months or older who received ADOS-2 Modules 1-3, as well as the best estimate clinical diagnosis. Five classification statistics were reported for each module: sensitivity, specificity, positive predictive value, negative predictive value, and accuracy (i.e., Receiver Operator Classification Statistic), and these statistics were calculated for the optimal cut-off score. Frequency tables were used to compare ADOS-2 classification and the best estimate clinical diagnosis. Half of the sample received Module 3, 21% received Module 2, and 29% received Module 1. The overall prevalence of ASD was 60%; the male-to-female ratio was 4:1, and half of the sample was non-White. Across all modules, the autism spectrum cut-off score from the ADOS-2 manual resulted in high sensitivity (95%+) and low specificity (63%-73%). The autism cut-off score resulted in better specificity (76%-86%) with favorable sensitivity (81%-94%). The optimal cut-off scores for all modules based on the current sample were within the autism spectrum classification range except Module 2 Algorithm 2. In the No ASD group, 29% had false positives (ADOS-2 autism spectrum classification or autism classification). The ADOS-2 autism spectrum classification did not indicate directionality for diagnostic outcome (ASD 56% vs. No ASD 44%). While cut-off scores of ADOS-2 Modules 1-3 in the manual yielded good clinical utility in ASD assessment, false positives and low predictability of the autism spectrum classification remain challenging for clinicians.

Patients with cancer are at significantly greater risk of COVID-19 and its complications than the general population. Since IgG antibodies remain detectable well after infection with the SARS-CoV-2 virus, seroprevalence can be used to estimate the proportion of the cancer population previously infected and potentially immune to SARS-CoV-2. The current study is a multi-center, prospective observational study to assess the seroprevalence of SARS-CoV-2 IgG antibody in a cancer population referred for vaccination between April and June 2021. Of a total of 270 adult patients with cancer accrued, 16% reported a history of COVID-19 more than four weeks previously confirmed by PCR. At the same time, serologic positivity for SARSCoV2 IgG was found in 29% of patients prior to vaccination including nearly 20% of patients without a history of confirmed COVID-19. Seropositivity was significantly greater in females consistent with higher rates in patients with breast cancer and gynecologic cancers. A seroconversion rate of 79.5% was observed in cancer patients with a history of PCR confirmed COVID-19, less than observed in the general population. In multivariable analysis, gender and prior history of COVID-19 were both independently associated with seropositivity prior to vaccination. Follow-up is continuing of this cohort of patients with cancer following vaccination to assess antibody and clinical outcomes.

Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent sexually transmitted infections that disproportionately impacts women worldwide. Currently, there are no vaccines or curative treatments, resulting in life-long infection. The mucosal environment of the female reproductive tract (FRT) is home to a complex array of local immune defenses that must be carefully coordinated to protect against genital HSV-2 infection, while preventing excessive inflammation to prevent disease symptoms. Crucial to the defense against HSV-2 infection in the FRT are three classes of highly related and integrated cytokines, type I, II, and III interferons (IFN). These three classes of cytokines control HSV-2 infection and reduce tissue damage through a combination of directly inhibiting viral replication, as well as regulating the function of resident immune cells. In this review, we will examine how interferons are induced and their critical role in how they shape the local immune response to HSV-2 infection in the FRT.

BackgroundCD-30 is highly expressed in some patients with non-seminomatous germ-cell tumors. Brentuximab vedotin is an antibody-drug conjugate directed to CD-30. We report a phase 2 trial of brentuximab vedotin in patients with chemo-refractory GCT.Patients and Methods This is a single arm, two cohort phase 2 trial investigating brentuximab vedotin 1.8 mg/kg IV every 3 weeks until disease progression or intolerable toxicities in patients with relapsed GCT who have no curative options. Patients with mGCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (high-dose or standard-dose chemotherapy) were eligible. CD30 expression was assessed and two cohorts defined: CD30 positive and CD30 negative/unknown.Results18 patients were enrolled. Median age 34.7 (range, 23-56). All patients had non-seminoma. Median AFP 4.9 (range, 1-219,345) and hCG 282 (range, 0.6-172,064). Five patients had late relapse (>2years). Median number of previous chemotherapy regimens was 3 (range, 2-7). Ten patients received prior high-dose chemotherapy. Seven patients had positive CD30 staining. There were two grade 3 treatment-related adverse events. No partial or complete responses were observed. 6 patients achieved radiographic stable disease (range, 9-14.9 weeks), 5 had elevated AFP or hCG at trial entry and all 5 had transient >50% decline in baseline AFP/hCG: 4 had CD30 -ve and 2 had CD30 +ve staining; 10 patients had progression of disease as their best response; 2 were not evaluable for response.ConclusionBrentuximab vedotin does not appear to have clinically meaningful single-agent activity in patients with refractory GCT. Trial Registration Number: NCT02689219Date of registration: February 12, 2016

Only in 2005 was a product labeling law passed in Israel that requires food companies to mark a choking hazard. We wished to investigate the influence of the hazard warning on the number of foreign body aspirations (FBA) in Israel, as well as the racial differences in the prevalence of and death rates from FBA. All the medical records of patients under the age of 14 who arrived at our center’s emergency department between the years 2007 and 2015 with suspected FBA were retrospectively reviewed. Population data was extracted from the Central Bureau of Statistics. Overall, 90 children arrived at the hospital with suspected FBA during 2007–2015. Forty-six (51%) of the patients were males, the mean age was 3.5 years. Seventy-one bronchoscopies were performed due to high suspicious presence of a foreign body. The most common objects aspirated were different types of nuts and seeds. In all cases, the patient's parents witnessed the aspiration of the foreign body. Most children (77, 86%) were of Arab ethnicity. The yearly prevalence of FBA in children 0–4 years of Arab ethnicity was 16.6:100,000 compared to 6.0:100,000 in the non-Arab population (p

Objective This study compared the effectiveness of regenerative injection therapy (RIT), i.e. prolotherapy, and repetitive transcranial magnetic stimulation (rTMS) in the treatment of fibromyalgia syndrome. Patients and methods This study included 120 female, age-matched fibromyalgia patients. All patients underwent a clinical examination, pain assessment by VAS, assessment of tender points, psychiatric and functional assessment using the Beck Depression Inventory (BDI), Fibromyalgia Impact Questionnaire Revised (RFIQ), and measurement of cortical auditory evoked potentials CAEPs elicited at 1000 Hz. Patients were divided into two equal groups; Group 1 received prolotherapy three times, two weeks apart, and Group 2 received rTMS sessions every other day for one month. Assessment was performed before treatment, immediately after treatment, and one month later. Results A significant improvement of pain measured by the mean score of VAS was remarked in Group 1 compared to Group 2 immediately after treatment and one month later. There was statistically significant difference of mean scores for the number of tender points in Group 1 compared to Group 2 after treatment and one month later. The patients improved functionally, with a statistically significant difference in mean score of RFIQ, in Group 1 compared to Group 2 one month after treatment. However, there was a significant difference in mean score of BDI in Group 2 compared to Group 1 after treatment and one month later. Further, CAEPs showed better improvement, with a significant difference in Group 2, one month after treatment. Conclusion RIT had the advantage in clinical and functional improvement in fibromyalgia patients, while rTMS had better results regarding depression and the cortical component of AEPs. These results might draw attention to the evaluability of a combination of both techniques for a better therapeutic response.

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells., Vito et al. investigated the effects of combination therapy in a TNBC tumor model and reported increased tumor-infiltrating lymphocytes that contributed to an improved response to immune checkpoint blockade. By depletion of circulating B cells prior to therapy, the authors showed a loss of therapeutic efficacy and simultaneous expansion of myeloid-derived suppressor cells.

Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1−blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients’ tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1− patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.

Background Domestic violence (DV) damages health and requires a global public health response and engagement of clinical services. Recent surveys show that 27% of married Palestinian women experienced some form of violence from their husbands over a 12 months' period, but only 5% had sought formal help, and rarely from health services. Across the globe, barriers to disclosure of DV have been recorded, including self-blame, fear of the consequences and lack of knowledge of services. This is the first qualitative study to address barriers to disclosure within health services for Palestinian women. Methods In-depth interviews were carried out with 20 women who had experienced DV. They were recruited from a non-governmental organisation offering social and legal support. Interviews were recorded, transcribed and translated into English and the data were analysed thematically. Results Women encountered barriers at individual, health care service and societal levels. Lack of knowledge of available services, concern about the health care primary focus on physical issues, lack of privacy in health consultations, lack of trust in confidentiality, fear of being labelled ‘mentally ill’ and losing access to their children were all highlighted. Women wished for health professionals to take the initiative in enquiring about DV. Wider issues concerned women’s social and economic dependency on their husbands which led to fears about transgressing social and cultural norms by speaking out. Women feared being blamed and ostracised by family members and others, or experiencing an escalation of violence. Conclusions Palestinian women’s agency to be proactive in help-seeking for DV is clearly limited. Our findings can inform training of health professionals in Palestine to address these barriers, to increase awareness of the link between DV and many common presentations such as depression, to ask sensitively about DV in private, reassure women about confidentiality, and increase awareness among women of the role that health services can play in DV.

Background Breast cancer is the most commonly occurring cancer in women worldwide. S100A14 is a novel important member of S100 proteins family. Its importance is due to its role in tumorigenesis and metastasis process. In this study, we aimed to determine serum levels of S100A14 protein in breast cancer patients and healthy individuals to know if it can be suggested as a new biomarker for breast cancer and to reveal whether it is correlated with cancer pathological features. Methods This cross-sectional study was performed in two groups: study group contains 46 breast cancer patients (29 metastatic and 17 non-metastatic) and control group contains 22 healthy women. Enzyme-linked immunoabsorbent assay was performed to determine S100A14 protein levels in samples. Pathological data were obtained for each patient. The data were statistically analyzed using Kruskal-Wallis H, Mann-Whitney U, and Spearman correlation tests. Results S100A14 serum levels were elevated in study group compared with control group (P < 0.05). S100A14 serum levels were significantly increased in distant breast cancer patients compared with regional breast cancer patients (P = 0.001). There was a strong positive correlation between serum S100A14 level and tumor grade (rs = 0.713, P < 0.001). Conclusion Our study indicated that S100A14 serum levels are elevated in breast cancer patients compared with control individuals. High S100A14 serum levels were correlated with poor tumor differentiation so it might have a prognostic significance for breast cancer tumors. The elevation of S100A14 levels in distant breast cancer patients suggests the ability of using serum S100A14 as a biomarker for detection of breast cancer metastasis.

Summary NK cells are central to anti-tumor immunity and recently showed efficacy for treating hematologic malignancies. However, their dysfunction in the hostile tumor microenvironment remains a pivotal barrier for cancer immunotherapies against solid tumors. Using cancer patient samples and proteomics, we found that human NK cell dysfunction in the tumor microenvironment is due to suppression of glucose metabolism via lipid peroxidation-associated oxidative stress. Activation of the Nrf2 antioxidant pathway restored NK cell metabolism and function and resulted in greater anti-tumor activity in vivo. Strikingly, expanded NK cells reprogrammed with complete metabolic substrate flexibility not only sustained metabolic fitness but paradoxically augmented their tumor killing in the tumor microenvironment and in response to nutrient deprivation. Our results uncover that metabolic flexibility enables a cytotoxic immune cell to exploit the metabolic hostility of tumors for their advantage, addressing a critical hurdle for cancer immunotherapy.

Background Adolescents rarely present with breast lumps, and such lumps are usually due to benign causes. Foreign bodies in the breast are an uncommon finding and could be detected incidentally during imaging or be symptomatic and present as a painful mass. Sometimes they cause diagnostic dilemmas as they mimic malignancies. To the best of our knowledge, this is the second case reported in the literature about an abscess caused by a migrating retained temporary epicardial pacing wire. Case presentation A 13-year-old girl of African ancestry was referred to our clinic with a left breast mass that had been gradually increasing in size for 2 years. The mass was tender but was not associated with skin changes, nipple discharge, or fever. She had a history of rheumatic heart disease and had undergone mitral and tricuspid valve repair more than 2 years ago. Blood work and biochemistry were within normal ranges. An ultrasound of her left breast showed a large, irregular, complex, heterogeneous mass measuring 4.3 × 2.7 × 3.5 cm at 6 o’clock position with central cystic changes but no significant intrinsic vascular flow. There was significant associated skin and subcutaneous edema. Given the echogenicity of the mass, an infectious cause was considered likely, and malignancy was less likely but could not be excluded. An ultrasound-guided biopsy was performed and revealed cores of breast tissue heavily infiltrated with mixed acute and chronic inflammatory cells, consistent with a chronic abscess. She received a 10-day course of antibiotics. However, she remained symptomatic, and the mass did not decrease in size. Therefore, we proceeded to surgical excision. The breast mass was excised. It was fixed to the underlying rib, and a thin, long, metallic wire that moved with her heartbeat was observed protruding from a small opening above the rib. This was a migrated retained epicardial pacing wire from the previous valve repair surgery. The histopathology of the mass revealed mammary tissue with acute and chronic inflammatory cells. Conclusion Temporary epicardial pacing wires should be removed completely by cardiothoracic surgeons after surgery to avoid migration that might lead to unexpected complications.

The hormonal contraceptive medroxyprogesterone acetate (MPA) is associated with increased risk of human immunodeficiency virus (HIV), via incompletely understood mechanisms. Increased diversity in the vaginal microbiota modulates genital inflammation and is associated with increased HIV-1 acquisition. However, the effect of MPA on diversity of the vaginal microbiota is relatively unknown. In a cohort of female Kenyan sex workers, negative for sexually transmitted infections (STIs), with Nugent scores, Summary: MPA may increase susceptibility to HIV-1 in sex workers through the suppression of endogenous estrogen, reducing vaginal glycogen and α-amylase levels, which increases bacterial diversity, potentially reducing protective bacterial species such as lactobacilli.

More than 40% of HIV infections occur via female reproductive tract (FRT) through heterosexual transmission. Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexually transmitted pathogens. These sentient cells recognize and respond to external stimuli by induction of a range of carefully balanced innate immune responses. Previously, we have shown that in response to HIV-1 gp120, the genital epithelial cells (GECs) from upper reproductive tract induce an inflammatory response that may facilitate HIV-1 translocation and infection. In this study, we report that the endometrial and endocervical GECs simultaneously induce biologically active interferon-β (IFNβ) antiviral responses following exposure to HIV-1 that act to protect the epithelial tight junction barrier. The innate antiviral response was directly induced by HIV-1 envelope glycoprotein gp120 and addition of gp120 neutralizing antibody inhibited IFNβ production. Interferon-β was induced by gp120 in upper GECs through Toll-like receptor 2 signaling and required presence of heparan sulfate on epithelial cell surface. The induction of IFNβ was dependent upon activation of transcription factor IRF3 (interferon regulatory factor 3). The IFNβ was biologically active, had a protective effect on epithelial tight junction barrier and was able to inhibit HIV-1 infection in TZM-bl indicator cells and HIV-1 replication in T cells. This is the first report that recognition of HIV-1 by upper GECs leads to induction of innate antiviral pathways. This could explain the overall low infectivity of HIV-1 in the FRT and could be exploited for HIV-1 prophylaxis.

Ovarian cancer (OC) is the leading cause of gynecological cancer-related death in North America. Most ovarian cancer patients (OCPs) experience disease recurrence after first-line surgery and chemotherapy; thus, there is a need for novel second-line treatments to improve the prognosis of OC. Although peripheral blood-derived NK cells are known for their ability to spontaneously lyse tumour cells without prior sensitization, ascites-derived NK cells (ascites-NK cells) isolated from OCPs exhibit inhibitory phenotypes, impaired cytotoxicity and may play a pro-tumourigenic role in cancer progression. Therefore, it is of interest to improve the cytotoxic effector function of impaired OCP ascites-NK cells at the tumour environment. We investigated the efficacy of using an artificial APC-based ex vivo expansion technique to generate cytotoxic, expanded NK cells from previously impaired OCP ascites-NK cells, for use in an autologous model of NK cell immunotherapy. We are the first to obtain a log-scale expansion of OCP ascites-NK cells that upregulate the surface expression of activating receptors NKG2D, NKp30, NKp44, produce robust amounts of anti-tumour cytokines in the presence of OC cells and mediate direct tumour cytotoxicity against ascites-derived, primary OC cells obtained from autologous patients. Our findings demonstrate that it is possible to generate cytotoxic OCP ascites-NK cells from previously impaired OCP ascites-NK cells, which presents a promising immunotherapeutic target for the second-line treatment of OC. Future work should focus on evaluating the in vivo efficacy of autologous NK cell immunotherapy through the intraperitoneal delivery of NK cell expansion factors to a preclinical xenograft mouse model of human OC.

Following the recent outbreak of Zika virus (ZIKV) infections in Latin America, ZIKV has emerged as a global health threat due to its ability to induce neurological disease in both adults and the developing fetus. ZIKV is largely mosquito-borne and is now endemic in many parts of Africa, Asia, and South America. However, several reports have demonstrated persistent ZIKV infection of the male reproductive tract and evidence of male-to-female sexual transmission of ZIKV. Sexual transmission may broaden the reach of ZIKV infections beyond its current geographical limits, presenting a significant threat worldwide. Several mouse models of ZIKV infection have been developed to investigate ZIKV pathogenesis and develop effective vaccines and therapeutics. However, the majority of these models focus on mosquito-borne infection, while few have considered the impact of sexual transmission on immunity and pathogenesis. This review will examine the advantages and disadvantages of current models of mosquito-borne and sexually transmitted ZIKV and provide recommendations for the effective use of ZIKV mouse models.

Objectives: To determine the association of different factors in the mammography related pain perception of women who attended their screening and diagnostic mammography appointments and whether the pain perceived was equal to the pain experienced. Methods : This prospective study was conducted at the Breast Unit of King Abdulaziz University (KAU) Hospital, Jeddah, Kingdom of Saudi Arabia (KSA), in the period between April and May 2015. A structured questionnaire with close-ended questions was given to a sample of 100 women before and after their mammogram, asking about their pain perception and whether it had changed. Results : The factors that affected anticipated mammography pain for the surveyed women were past mammography experiences, previous breast procedures, and the knowledge that was gathered beforehand about mammography. After the mammography, the women who thought the procedure was going to be painful experienced what they expected. The majority of the women who did not expect the mammography to be painful experienced pain during their mammogram. Most of the women who did not know whether it would be painful or not experienced the mammography as painful. Conclusion : Pain expectation can be approached in various ways to make the mammography experience much more tolerable for women, encouraging them to attend and return for their scans. Saudi Med J 2017; Vol. 38 (7): 768-771 doi: 10.15537/smj.2017.7.19298 How to cite this article: Ashkar LK, Zaki YH. Female patients' perception of pain caused by mammography in the Western Region of Saudi Arabia. Saudi Med J . 2017 Jul;38(7):768-771. doi: 10.15537/smj.2017.7.19298.

Background: Intraparenchymal thyroid Doppler measurements might be considered a useful index of the thyroid status as well as micro-circulation elsewhere in the body among sickle cell disea...

From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define genetic-epigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and whole-genome coverage will have multiple mechanistic and practical implications. By producing and analyzing DNA sequence variation (n = 303), DNA methylation (n = 303) and mRNA expression data (n = 80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations. These findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions., Author summary The placenta is a critical organ playing multiple roles including oxygen and metabolite transfer from mother to fetus, hormone production, and vascular perfusion. With this study, we aimed to deliver a placenta-specific regulatory map based on a combination of publicly available and newly generated data. To complete this reference, we obtained genotype information (n = 303), DNA methylation (n = 303) and expression data (n = 80) for placentas from healthy women. Our analysis of methylation and expression quantitative trait loci (QTLs) and correlations between methylation and expression data were designed to identify fundamental associations between genome, transcriptome, and epigenome in this key fetal organ. The results provide high-resolution genetic and epigenetic maps specific to the placenta based on a representative ethnically diverse cohort. As interest and efforts are growing to better understand the etiology of placental disease and the impact of the environment on placental function these data will provide a reference and enhance future investigations.

Chlamydia trachomatis infections in women are often asymptomatic and if left untreated can lead to significant late sequelae including pelvic inflammatory disease and tubal factor infertility. Vaccine development efforts over the past three decades have been unproductive and there is no vaccine approved for use in humans. The existence of serologically distinct strains or serovars of C. trachomatis mandates a vaccine that will provide protection against multiple serovars. Chlamydia spp. use a highly conserved type III secretion system (T3SS) composed of both structural and effector proteins which is an essential virulence factor for infection and intracellular replication. In this study we evaluated a novel fusion protein antigen (BD584) which consists of three T3SS proteins from C. trachomatis (CopB, CopD, and CT584) as a potential chlamydial vaccine candidate. Intranasal immunization with BD584 elicited serum neutralizing antibodies that inhibited C. trachomatis infection in vitro. Following intravaginal challenge with C. muridarum, immunized mice had a 95% reduction in chlamydial shedding from the vagina at the peak of infection and cleared the infection sooner than control mice. Immunization with BD584 also reduced the rate of hydrosalpinx by 87.5% compared to control mice. Together, these results suggest that highly conserved proteins of the chlamydial T3SS may represent good candidates for a Chlamydia vaccine.

Cell-based therapy is emerging as a promising therapeutic approach for a wide range of liver diseases. This study aimed to investigate the regenerative and antifibrotic therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in an early and late experimental hepatic schistosomiasis model. BM-MSCs were isolated from 6-wk-old BALB/c donor male mice, then grown and propagated in culture until cell count was 5-8 × 10(6)/ml. MSCs were then separated and injected into Schistosoma mansoni -infected female BALB/c mice on their 6, 10, 14, and 18 wk post-infection. Mice were sacrificed on the fourth and eighth week after BM-MSCs transplantation in each group. Homing of BM-MSCs was confirmed by PCR detection of male Y-chromosome gene (sry) in the liver tissue of the recipient female mice. The regenerative and antifibrotic potential of BM-MSCs was assessed by histopathological examination, morphometric analysis, electron microscopy, and liver function tests. Schistosoma-infected mice, which were treated with BM-MSCs, showed a decrease in the granuloma size, percentage and density of the fibrotic area, formation of new hepatocytes, and improvement of the liver function tests. Immunohistochemical examination of alpha-smooth muscle actin revealed a significant decrease in the immunoreactive hepatic stellate cells in mice treated with MSCs. Early granulomas (acute infection) showed better response to MSC injection than did later granulomas (chronic infection). Dosing and timing of MSCs transplantation should undergo more investigations in long-term experiments before application to the clinical field. This study is the first to assess and compare the effect of MSCs treatment on early and late granulomas.

To report a case of ruptured uterus in the first trimester with the use of misoprostol for early pregnancy tailure in a woman with unrecognized cesarean section scar pregnancy.A 27-year-old woman, gravida 5 para 3+1, presented with abdominal pain and vaginal bleeding. Transvaginal ultrasonography revealed a fetus without fetal heart activity at nine weeks gestation, making the diagnosis of early pregnancy failure. Her previous deliveries were by cesarean section. She was managed medically with misoprostol. Seven hours after misoprostol administration, she developed sudden onset of severe abdominal pain. Repeat transvaginal ultrasonography diagnosed cesarean section scar pregnancy. Laparotomy revealed hemoperitoneum with rupture of cesarean section scar pregnancy. Subtotal hysterectomy was performed.Failure to recognize cesarean section scar pregnancy can result in a ruptured uterus in the first trimester with the use of misoprostol for early pregnancy failure. Increased awareness of the unexpected consequences of cesarean section is of paramount importance.

Natural killer (NK) cells are useful for cancer immunotherapy and have proven clinically effective against hematologic malignancies. However, immunotherapies for poor prognosis solid malignancies, including ovarian cancer, have not been as successful due to immunosuppression by solid tumors. Although rearming patients' own NK cells to treat cancer is an attractive option, success of that strategy is limited by the impaired function of NK cells from cancer patients and by inhibition by self-MHC. In this study, we show that expansion converts healthy donor and immunosuppressed ovarian cancer patient NK cells to a cytotoxic CD56

To determine the types and to assess the role of auditory evoked potentials and otoacoustic emissions in early detection of hearing abnormalities in Behçet's disease (BD) patients. Their correlations with disease activity were also considered.Thirty patients with BD and thirty apparently sex- and age-matched healthy volunteers were included in this study. Auditory evaluation included pure tone audiometry (PTA), otoacoustic emissions (TEOAEs, DPOAE), auditory brainstem response test (ABR) and cortical auditory evoked potentials (tone and speech CAEPs) for all patients and control.The highest abnormality of CAEP latencies elicited by (500Hz and 1000 Hz) as well as speech stimuli (da and ga) among our BD patients was delayed P1 and N1 waves at 80 dB with greater bilateral affection, as well as significant differences between patients and controls. All our BD patients had a smaller amplitude of distortion product OAE (DPOAE) and S/N ratio at 1, 2, 4, 6 kHZ compared with controls and the differences were highly statistically significant (p=0.0001).Being one of the autoimmune inner ear diseases (AIED), BD has a definite hearing impairment, even in the presence of normal hearing sensitivity, as evidenced by PTA. BD patients had a sub-clinical cochlear pathology which was not affected by disease activity or different organ affection. DPOAE (S/N ratio) proved to be a sensitive test in detecting minimal changes in cochlear pathology and the latencies of CAEPs (tone and speech) measures were considered as sensitive indicators (100%) of early detection of hearing impairment in BD patients.

Approximately 40% of HIV-1 infections occur in the female genital tract (FGT), primarily through heterosexual transmission. FGT factors determining outcome of HIV-1 exposure are incompletely understood, limiting prevention strategies. Here, humanized NOD-Rag1−/− γc−/− mice differentially reconstituted with human CD34+ -enriched hematopoietic stem cells (Hu-mice), were used to assess target cell frequency and viral inoculation dose as determinants of HIV-1 infection following intravaginal (IVAG) challenge. Results revealed a significant correlation between HIV-1 susceptibility and hCD45+ target cells in the blood, which correlated with presence of target cells in the FGT, in the absence of local inflammation. HIV-1 plasma load was associated with viral dose at inoculation and frequency of target cells. Events following IVAG HIV-1 infection; viral dissemination and CD4 depletion, were not affected by these parameters. Following IVAG inoculation, HIV-1 titres peaked, then declined in vaginal lavage while plasma showed a reciprocal pattern. The greatest frequency of HIV-1-infected (p24+) cells were found one week post-infection in the FGT versus blood and spleen, suggesting local viral amplification. Five weeks post-infection, HIV-1 disseminated into systemic tissues, in a dose-dependent manner, followed by depletion of hCD45+ CD3+ CD4+ cells. Results indicate target cell frequency in the Hu-mouse FGT is a key determinant of HIV-1 infection, which might provide a useful target for prophylaxis in women.

NK cells play a vital role in innate anti-tumor immunity. Crosstalk between NK cells and dendritic cells (DCs) has come to the forefront in protection against tumors in the context of DC vaccines. We previously discovered that NK cell activation mediates the anti-tumor activity elicited by DC vaccines in response to melanoma tumor challenge in a murine lung metastasis model. In this study, we sought to explore the mechanism behind this NK–DC communication, specifically looking at the involvement of IL-15 and type I IFN signaling. Using DCs from IL-15–/– and IL-15Rα–/– mice, we found that the anti-tumor effect of the vaccine remained comparable with DCs from wild type mice. Moreover, DCs derived from IFN-α/βR–/– mice also maintained their anti-tumor effect. Interestingly, endogenous DCs were found to accumulate in the draining lymph nodes post-immunization and their depletion abolished the anti-tumor effect of the vaccine. Our findings suggest the important role that type I IFN signaling and endogenous DCs play in DC vaccine-mediated anti-tumor protection. Our data suggest that type I IFNs from vaccine DCs activate host DCs to provide NK cell-mediated anti-tumor immunity.

IL-15 is a cytokine that can affect many immune cells, including NK cells and CD8 T cells. In several tumor models, IL-15 delays primary tumor formation and can prevent or reduce metastasis. In this study, we have employed a model of breast cancer metastasis to examine the mechanism by which IL-15 affects metastasis. When breast tumor cells were injected i.v. into IL-15−/−, C57BL/6, IL-15 transgenic (TG) and IL-15/IL-15Rα–treated C57BL/6 mice, there were high levels of metastasis in IL-15−/− mice and virtually no metastasis in IL-15 TG or IL-15–treated mice. In fact, IL-15−/− mice were 10 times more susceptible to metastasis, whereas IL-15 TG mice were at least 10 times more resistant to metastasis when compared with control C57BL/6 mice. Depletion of NK cells from IL-15 TG mice revealed that these cells were important for protection from metastasis. When NK cells were depleted from control C57BL/6 mice, these mice did not form as many metastatic foci as IL-15−/− mice, suggesting that other cell types may be contributing to metastasis in the absence of IL-15. We then examined the role of CD4 T cells and macrophages. In IL-15−/− mice, in vivo depletion of CD4 T cells decreased metastasis. The lack of IL-15 in IL-15−/− mice, and possibly the Th2-polarized CD4 T cells, was found to promote the formation of M2 macrophages that are thought to contribute to metastasis formation. This study reveals that whereas IL-15 effects on NK cells are important, it also has effects on other immune cells that contribute to metastasis.

Background Natural killer (NK) cells play a critical role in cancer immunosurveillance. Recent developments in NK cell ex-vivo expansion makes it possible to generate millions of activated NK cells from a small volume of peripheral blood. We tested the functionality of ex vivo expanded NK cells in vitro against breast cancer cell lines and in vivo using a xenograft mouse model. The study aim was to assess functionality and phenotype of expanded NK cells from breast cancer patients against breast cancer cell lines and autologous primary tumours. Methods We used a well-established NK cell co-culture system to expand NK cells ex vivo from healthy donors and breast cancer patients and examined their surface marker expression. Moreover, we tested the ability of expanded NK cells to lyse the triple negative breast cancer and HER2-positive breast cancer cell lines MDA-MB-231 and MDA-MB-453, respectively. We also tested their ability to prevent tumour growth in vivo using a xenograft mouse model. Finally, we tested the cytotoxicity of expanded NK cells against autologous and allogeneic primary breast cancer tumours in vitro. Results After 3 weeks of culture we observed over 1000-fold expansion of NK cells isolated from either breast cancer patients or healthy donors. We also showed that the phenotype of expanded NK cells is comparable between those from healthy donors and cancer patients. Moreover, our results confirm the ability of ex vivo expanded NK cells to lyse tumour cell lines in vitro. While the cell lines examined had differential sensitivity to NK cell killing we found this was correlated with level of major histocompatibility complex (MHC) class I expression. In our in vivo model, NK cells prevented tumour establishment and growth in immunocompromised mice. Finally, we showed that NK cells expanded from the peripheral blood of breast cancer patients show high cytotoxicity against allogeneic and autologous patient-derived tumour cells in vitro. Conclusion NK cells from breast cancer patients can be expanded similarly to those from healthy donors, have a high cytotoxic ability against breast cancer cell lines and patient-derived tumour cells, and can be compatible with current cancer treatments to restore NK cell function in cancer patients.

This retrospective cohort study of 2051 consecutive fresh non-donor intracytoplasmic sperm injection (ICSI) cycles investigated whether time from oocyte retrieval to denudation, precisely measured and recorded by an operator-independent automated radiofrequency-based system, affected cycle outcome. ICSI cycles were divided into two groups: group I (denudation within

In present study, blood samples were collected randomly from 439 cows at three main regions of Egypt (northern, central and southern). Molecular diagnosis of Babesia and Theileria infections by PCR amplification of DNA (gene) fragments, then cloning and sequencing of the positive samples were conducted. A questionnaire was created to imply the assumed risk factors and logistic regression statistical analysis was carried out to appraise the potential factors on the animal level. The results revealed that 49 (11.16%) and 45 (10.25%) cattle were infected with Babesia and Theileria parasites, respectively. B. bigemina (7.97%) and T. annulata (9.56%) were the most prevalent parasites. For Babesia sp., final multivariate logistic regression analysis showed a significant association between the infection and irregular use of antiprotozoal drugs (P = 0.003; OR: 0.28; 95% CI: 0.12-0.65), management practice (P = 0.029; OR: 6.66; 95% CI: 1.21-36.59) and ecology area (P = 0.006; OR: 5.62; 95% CI: 1.63-19.31). However, for Theileria sp. infection, animal breed (P = 0.003; OR: 0.44; 95% CI: .45-1.00) and irregular use of antiprotozoal drugs (P

To create a diagnostic document describing the utilization of pre-implantation genetic testing (PGT) in the absence of monitoring and regulation. Retrospective cohort study of couples undergoing PGT between 2004 and 2007 in Lebanon. The clinical indications for 192 PGT cycles performed during the study period were gender selection (96.3%), chromosomal aneuploidy (3.1%), and balanced translocation (0.5%). When gender selection was sought, the selection of a son was desired in 94.1% of cases. Of couples undergoing PGT for sex selection, 16.2% were childless, 8.6% had one child of the opposite gender, 28.1% had two same-gender children, 29.7% had three same-gender children, and 11.9% had four or more. Our findings demonstrate the morally questionable consequences of self-regulated systems in which physicians are the sole gatekeepers of norms and ethics.

Volatile organic compound (VOC) testing in breath has potential in gastric cancer (GC) detection. Our objective was to assess the reproducibility of VOCs in GC, and the effects of conditions modifying gut microbiome on the test results. Ten patients with GC were sampled for VOC over three consecutive days; 17 patients were sampled before and after H. pylori eradication therapy combined with a yeast probiotic; 61 patients were sampled before and after bowel cleansing (interventions affecting the microbiome). The samples were analyzed by: (1) gas chromatography linked to mass spectrometry (GC-MS), applying the non-parametric Wilcoxon test (level of significance p 0.05); (2) by cross-reactive nanoarrays combined with pattern recognition. Discriminant function analysis (DFA) was used to build the classification models; and leave-one-out cross-validation analysis was used to classify the findings. Exhaled VOCs profiles were stable for GC patients over a three day period. Alpha pinene (p = 0.028) and ethyl acetate (p = 0.030) increased after the antibiotic containing eradication regimen; acetone (p = 0.0001) increased following bowel cleansing prior to colonoscopy. We further hypothesize that S. boulardii given with the standard eradication regimen to re-establish the gut microbiome was the source for long-term ethyl acetate production. Differences between the initial and the follow-up sample were also revealed in the DFA analysis of the sensor data. VOC measurement results are well-reproducible in GC patients indicating a useful basis for potential disease diagnostics. However, interventions with a potential effect on the gut microbiome may have an effect upon the VOC results, and therefore should be considered for diagnostic accuracy.

Natural killer (NK) cells have an important role in mounting protective innate responses against genital herpes simplex virus type 2 (HSV-2) infections. However their role as effectors in adaptive immune responses against HSV-2 is unclear. Here, we demonstrate that NK cells from C57BL/6 mice in an ex vivo splenocyte culture produce significantly more interferon γ (IFN-γ) upon re-exposure to HSV-2 antigens in a mouse model of genital HSV-2 immunization. We find that naïve NK cells do not require any prior stimulation or priming to be activated to produce IFN-γ. Our results demonstrate that HSV-2-experienced CD4

Surgery, the usual treatment option for vesicouterine fistula (VUF), is often delayed to allow involution of the uterus. The authors report a case of successful treatment with urinary catheterization. A 39-year-old, gravida 7, para 6, woman presented at term with obstructed labor. She had one previous cesarean section followed by a vaginal birth before. She underwent emergency cesarean section. She was readmitted after one week because of pelvic collection. Aspiration revealed pus and urine. Retrograde cystogram and pelvic MRI confirmed the presence of VHF. Urinary bladder catheterization for six weeks resulted in the successful treatment of the fistula. Urinary catheterization in the early postpartum period can result in resolution of post-cesarean section VUF, without delaying surgical intervention if it becomes necessary.

Background: The proportion of patients with advanced chronic kidney disease (CKD) initiating dialysis therapy at a higher glomerular filtration rate (GFR) has increased during the past decade. Recent data suggest that higher GFR may be associated with increased mortality. Study Design: A meta-analysis of cohort studies and trials. Setting & Population: Patients with advanced CKD. Selection Criteria for Studies: We performed a systematic literature search in MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, American Society of Nephrology abstracts, and bibliographies of retrieved articles to identify studies reporting on GFR at dialysis therapy initiation and mortality. Predictor: Estimated or calculated GFR at dialysis therapy initiation. Outcome: Pooled adjusted hazard ratio (HR) of continuous GFR for all-cause mortality. Results: 16 cohort studies and 1 randomized controlled trial were identified (n = 1,081,116). By meta-analysis restricted to 15 cohorts (n = 1,079,917), higher GFR at dialysis therapy initiation was associated with a higher pooled adjusted HR for all-cause mortality (1.04; 95% CI, 1.03-1.05; P

When examining gene expression profiles for the purposes of assessing embryo quality, it is imperative that sex be considered, because many embryonic transcripts have sex-related expression patterns. The objective of this study was to systematically examine eight Y chromosome linked genes (DDX3Y, EIF1AY, HSFY, SRY, TSPY, USP9Y, ZFY, and ZRSR2Y) to characterize their expression in bovine blastocysts and to examine the usefulness of this expression for the purpose of RNA-based embryo sexing. In order to examine the expression of these genes, pools of blastocysts (groups of 10 and 20) as well as single embryos (N = 50) were analyzed with reverse transcriptase polymerase chain reaction (RT-PCR) and reverse transcriptase quantitative PCR (RT-qPCR). Of the 50 single embryos, 32 were concurrently sexed with DNA-based methods. Transcripts of DDX3Y, EIF1AY, TSPY, USP9Y, ZFY and ZRSR2Y were detected in the pooled and single blastocysts, but no transcripts were detected for HSFY or SRY. After performing DNA-based sexing experiments, we concluded that this expression was restricted to the male embryos. The consistency of the expression varied according to the gene as well as the specific primer set. Three genes were expressed in the full set of male embryos, DDX3Y, USP9Y, and ZRSR2Y and therefore represent good candidates for RNA-based sexing methods.

Uterine natural killer (NK) cells are pivotal for successful mammalian reproduction. However, insights on functionally distinct subpopulations of uterine NK cells are largely elusive. Furthermore, translation of findings from murine into human pregnancy has been overshadowed by the limited number of mutual phenotypic NK cell markers. We here provide evidence that a subset of murine mature NK (mNK) cells present at the feto-maternal interface, identified as CD27(low)DX5(+)CD3(neg), is pivotal in maintaining pregnancy. This mNK subset has low cytotoxic capacity, produces higher amounts of interferon (IFN)-γ, and expresses functional homologs of human NK cell immunoglobulin-like receptors. We further show that bone marrow-derived CD27(low) mNK cells are selectively recruited to the uterus and ameliorate the rate of fetal loss when adoptively transferred into alymphoid RAG2(-/-)/γc(-/-) mice. Additionally, expression of CD27 is down-modulated on mNK cells upon migration to the uterus. Hence, we propose the existence of a regulatory mNK cell subset, which is licensed toward successful pregnancy maintenance at the fetomaternal interface in mice. As CD27(low) NK cells are also present in human decidua, the CD27(low) NK subset may provide a tool to foster translational research in reproduction, aiming to improve pregnancy outcome in humans.

Herpes simplex virus (HSV)-2 is the predominant cause of genital herpes and has been implicated in HIV infection and transmission. Thus far, vaccines developed against HSV-2 have been clinically ineffective in preventing infection. This review aims to summarize the innate and adaptive immune responses against HSV-2 and examines the current status of vaccine development.Both innate and adaptive immune responses are essential for an effective primary immune response and the generation of immunity. The innate response involves Toll-like receptors, natural killer cells, plasmacytoid dendritic cells, and type I, II, and III interferons. The adaptive response requires a balance between CD4+ and CD8+ T-cells for optimal viral clearance. T-regulatory cells may be involved, although their exact function has yet to be determined. Current vaccine development involves the use of HSV-2 peptides or attenuated/replication-defective HSV-2 to generate adaptive anti-HSV-2 immune responses, however the generation of innate responses may also be an important consideration.Although vaccine development has primarily focused on the adaptive response, arguments for innate involvement are emerging. A greater understanding of the innate and adaptive processes underlying the response to HSV-2 infection will provide the foundation for the development of an effective vaccine.

Diabetes mellitus disrupts all phases of the wound repair cascade and leads to development of chronic wounds. We previously showed that topical erythropoietin (EPO) can promote wound repair in diabetic rats. Fibronectin (FN) has a critical role throughout the process of wound healing, yet it is deficient in wound tissues of diabetic patients. Therefore, we investigated the effect of topical treatment of both EPO and FN (EPO/FN) on wound repair in diabetic mice. Full-thickness excisional skin wounds in diabetic and nondiabetic mice were treated with a cream containing vehicle, EPO, FN, or EPO/FN. We assessed the rate of wound closure, angiogenesis, apoptosis, and expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS) and β1-integrin, in the wound tissues. We also investigated the effect of EPO, FN, and EPO/FN on human dermal microvascular endothelial cells and fibroblasts cultured on fibrin-coated plates, or in high glucose concentrations. EPO/FN treatment significantly increased the rate of wound closure and this effect was associated with increased angiogenesis, increased eNOS and β1-integrin expression, and reduced expression of inflammatory cytokines and apoptosis. Our findings show that EPO and FN have an additive effect on wound repair in diabetic mice.

There is increasing evidence that natural killer (NK) cells play an important role in antitumor immunity following dendritic cell (DC) vaccination. Little is known, however, about the optimal stimulation of DCs that favors NK activation in tumor-bearing hosts. In this study, we demonstrate that treatment with toll-like receptor (TLR) ligands and infection with a mutant vesicular stomatitis virus (VSV-ΔM51) both induced DC maturation. Further, inoculation of these DCs led to robust NK-mediated protection against tumor challenge. Strikingly, only VSV-ΔM51-infected DCs were capable of suppressing the growth of established tumors, suggesting that additional signals provided by viral infection may be required to activate tumoricidal NK cells in tumor-bearing hosts. VSV-ΔM51 infection of DCs induced greater type I interferon (IFN I) production than TLR ligand treatment, and disruption of the IFN I pathway in DCs eliminated their ability to induce NK activation and tumor protection. However, further studies indicated that IFN I alone was not sufficient to activate NK cells, especially in the presence of a tumor, and DC-derived IL-15 was additionally required for tumoricidal NK activation. These results suggest that induction of IFN I by VSV-ΔM51 allows DCs to overcome tumor-associated immunosuppression and facilitate IL-15–mediated priming of tumoricidal NK cells. Thus, the mode of DC maturation should be carefully considered when designing DC-based cancer immunotherapies. Cancer Res; 71(7); 2497–506. ©2011 AACR.

Innate antiviral immunity, particularly at mucosal surfaces, has a critical role in early control of viral infections. Both type I interferons (IFNs) and interleukin-15 (IL-15) are essential components of innate antiviral immunity. It has been shown that toll-like receptor (TLR) ligand-induced innate antiviral immunity requires IFN-α/β and -λ receptor signaling. However, it is not known if IL-15 has a role in TLR ligand-mediated antiviral responses. Here, we report that ligands for TLR-3 and TLR-9 cannot confer protection against genital herpes simplex virus-2 (HSV-2) in the absence of IL-15 in vivo. Interestingly, wild-type mice depleted of natural killer (NK) cells and treated with TLR ligands are protected upon HSV-2 challenge, suggesting that the critical role of IL-15 is independent of NK cell-mediated activity. To examine the cytokine response in the absence of IL-15, we investigated TLR ligand-induced IFN-β and -λ production in the vaginal washes, but found no impairment in IL-15(-/-) mice. Finally, we report no impairment in the expression of the IFN-stimulated genes in IL-15(-/-) mice. Collectively, the data suggest that TLR ligands induce an IFN-mediated response in the vaginal tract of both wild-type and IL-15(-/-) mice, but its induction is insufficient for providing protection against HSV-2 in the absence of IL-15.

Objective:To investigate the short term effect of hubble-bubble smoking on voice.Study design:Prospective study.Material:Eighteen non-dysphonic subjects (seven men and 11 women) with a history of hubble-bubble smoking and no history of cigarette smoking underwent acoustic analysis and laryngeal video-stroboscopic examination before and 30 minutes after hubble-bubble smoking.Results:On laryngeal video-stroboscopy, none of the subjects had vocal fold erythema either before or after smoking. Five patients had mild vocal fold oedema both before and after smoking. After smoking, there was a slight increase in the number of subjects with thick mucus between the vocal folds (six, vs four before smoking) and with vocal fold vessel dilation (two, vs one before smoking). Acoustic analysis indicated a drop in habitual pitch, fundamental frequency and voice turbulence index after smoking, and an increase in noise-to-harmonics ratio.Conclusion:Even 30 minutes of hubble-bubble smoking can cause a drop in vocal pitch and an increase in laryngeal secretions and vocal fold vasodilation.

Type I interferon (IFN) signalling, NK cells and NK cell-derived IFN-γ are critical in the early control of genital HSV-2 infection. We have recently reported that NK cells are the source of early IFN-γ in the genital tract in response to HSV-2. However, the response of NK cells to genital HSV-2 infection is not well defined in the context of type I IFN signalling. Here we show that HSV-2 replication was significantly higher in mice deficient in the type I IFN receptor or NK cells compared to wild type controls. There was no detectable IFN-γ production in the genital washes from IFN-α/βR(-/-) mice or NK cell depleted mice in response to HSV-2 infection compared to control mice. Absence of the type I IFN receptor does not alter homing of NK cells to the genital mucosa. Moreover, the absence of IL-12 had no significant effect on NK cell-derived IFN-γ. Surprisingly, IFN-α/βR(-/-) mice had more IL-15 positive cells in the genital mucosa in response to HSV-2 infection compared to control mice. We then examined the expression of IL-15 receptors on NK cells. There was no significant differences in the levels of IL-15 receptor expression on NK cells from IFN-α/βR(-/-) or control mice. Our data clearly suggest that type I IFN receptor signalling is essential for NK cell activation in response to genital HSV-2 infection, and propose that NK cell activation by IL-15 may involve type I IFNs.

Objectives: To look at the incidence of arytenoid asymmetry in a group of healthy singers and to investigate whether the asymmetry correlates with posture, neck tension and glottal attack. Materials and Method: The medical records and video recordings of 42 singers were reviewed retrospectively. Posture, neck tension and glottal attack were evaluated in relation to arytenoid asymmetry during adduction. Results: The number of singers was 42, with a male-to-female ratio of 2:1. The age range was 16–38 years, with a mean of 24 ± 4.13 years. The total prevalence of arytenoid asymmetry was 50%, with a predominance in males and on the right side. The most common asymmetry was that of the cuneiform cartilages, accounting for 40.5% of the total sample and 81% of the total asymmetries. There was no correlation between arytenoid asymmetry and either posture, neck tension or glottal attack (p = 0.343, 0.489 and 0.945, respectively). Conclusion: One out of 2 singers is likely to have arytenoid asymmetry during adduction. The presence of asymmetry does not correlate with posture, neck tension or glottal attack.

Objectives:(1) To assess the prevalence of arytenoid asymmetry during adduction, and (2) to correlate arytenoid asymmetry with vocal symptoms.Materials and method:The medical records and video recordings of 116 patients who presented to the voice clinic were reviewed for the presence of arytenoid asymmetry, as regards sharpening of the aryepiglottic fold angle and altered positioning of the cuneiform and corniculate cartilages.Results:There were 61 males and 55 females, with a mean age of 39 years and a standard deviation of 15 years. Almost one-third had a history of reflux, 25 per cent had a history of smoking and 9.6 per cent had a history of allergy. Hoarseness was the most common symptom, occurring in 42.2 per cent of patients, followed by vocal fatigue (25 per cent) and inability to project the voice. The most common type of asymmetry was corniculate asymmetry, present in 27.6 per cent of the cases and accounting for 74.39 per cent of cases. This was followed by cuneiform cartilage asymmetry, present in 15.5 per cent of cases. There was no correlation between arytenoid asymmetry and vocal symptoms, except for vocal fatigue (p = 0.038).Conclusion:The prevalence of arytenoid asymmetry during adduction is common. The presence of vocal symptoms such as hoarseness, breathiness, inability to project the voice and straining does not generally seem to correlate with the prevalence of arytenoid asymmetry. However, subjects with vocal fatigue are more likely to have cuneiform asymmetry.