Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans

Factors influencing uptake of voluntary counselling and testing services for HIV/AIDS in the Lower Manya Krobo Municipality (LMKM) in the Eastern Region of Ghana: a cross-sectional household survey

Background Voluntary counselling and testing (VCT) is one of the nine strategies recommended for prevention and control of HIV globally. In this study, we assessed the awareness and utilisation of VCT services among residents of the Lower Manya Krobo Municipality (LMKM) in the Eastern Region of Ghana. Methods A population-based descriptive cross-sectional survey was conducted with 200 participants, aged between 18 and 55 years. Participants were recruited using cluster and simple random techniques to take part in the survey. Data was analysed descriptively, as well as using regression analysis approach. Results Ninety-one percent of the respondents surveyed were aware of VCT services for HIV/AIDS. Seventy percent (70 %) have used VCT service in the last 12 months prior to the survey. Of this proportion, 97 % were satisfied with the quality of VCT services offered and indicated their willingness to recommend the service to others. Participants desire to know their HIV status (40 %), referral by health workers (25 %), and participants who wanted to get married (11 %) were the main reasons for increased uptake. Participants who had formal education, primary (OR = 1.8 (95 % CI 1.25–2.84)), junior high school (OR = 2.3 (95 % CI 1.54–3.37)), senior high school (OR = 2.8 (95 % CI 1.73–4.78)), and tertiary (OR = 3.4 (95 % CI 1.98–8.42)), had increased chance of using VCT service compared with participants who had no education (p < 0.001). Reasons for non-utilisation of VCT service were lack of awareness of the VCT service in the area (32 %), fear of being stigmatised (53 %), and the belief that HIV/AIDS cannot be cured and therefore the lack of need (5 %). Conclusions Although awareness and utilisation of VCT service rates were reportedly high, more efforts need to be done in order to increase awareness and promote utilisation. HIV/AIDS educational campaign programmes need to be strongly pursued, with emphasis on the benefits of VCT services. This has the potential of reducing stigma and increase utilisation

Key stages of mammary gland development: Molecular mechanisms involved in the formation of the embryonic mammary gland

The development of the embryonic mammary gland involves communication between the epidermis and mesenchyme and is coordinated temporally and spatially by various signaling pathways. Although many more genes are likely to control mammary gland development, functional roles have been identified for Wnt, fibroblast growth factor, and parathyroid hormone-related protein signaling. This review describes what is known about the molecular mechanisms that regulate embryonic mammary gland development

Anabolic Therapies

The striking clinical benefits of intermittent parathyroid hormone in osteoporosis have begun a new era of skeletal anabolic agents. Recombinant human parathyroid hormone (rhPTH) (1–34) is the first US Food and Drug Administration–approved anabolic therapy. Its use has been limited by the need for subcutaneous injection. Newer delivery systems include transdermal and oral preparations. Newer anabolic therapies include monoclonal antibody to sclerostin, a potent inhibitor of osteoblastogenesis; and use of bone morphogenetic proteins and parathyroid hormone–related protein PTHrP, a calcium-regulating hormone similar to PTH

Interleukin-4 and 13 concentrations in infants at risk to develop Bronchopulmonary Dysplasia

BACKGROUND: An exaggerated inflammatory response occurs in the first few days of life in infants who subsequently develop bronchopulmonary dysplasia (BPD). The increase of inflammatory cytokines in many disease processes is generally balanced by a rise in anti-inflammatory cytokines. Interleukin-4 (IL-4) and interleukin-13 (IL-13) have been shown to inhibit production of several inflammatory cytokines important in the development of BPD. METHODS: We sought to determine if a correlation exists between the presence or absence of IL-4 and IL-13 in tracheal aspirates (TA) during the first 3 weeks of life and the development of BPD in premature infants. Serial TAs were prospectively obtained from 36 very low birth weight infants and IL-4 and IL-13 concentrations were determined by ELISA. RESULTS: Infants who developed BPD (n = 19) were less mature (25.3 ± 0.02 wks vs. 27.8 ± 0.05 wks; p < 0.001), and had lower birth weights (739 ± 27 g vs.1052 ± 41 g; p < 0.001). IL-4 and IL-13 were detectable in only 27 of 132 and 9 of 132 samples assayed respectively. Furthermore, the levels detected for IL-4 and IL-13 were very low and did not correlate with the development of BPD. CONCLUSIONS: TA concentrations of IL-4 and IL-13 do not increase significantly during acute lung injury in premature infants

Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells

MVA-BN®-HER2 is a new candidate immunotherapy designed for the treatment of HER-2-positive breast cancer. Here, we demonstrate that a single treatment with MVA-BN®-HER2 exerts potent anti-tumor efficacy in a murine model of experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a strong tumor-mediated immunosuppressive environment characterized by a high frequency of regulatory T cells (Treg) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN®-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN®-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells accompanied by a decrease in the frequency of Treg cells in the lung, resulting in a significantly increased ratio of effector T cells to Treg cells. In contrast, administration of HER2 protein formulated in Complete Freund’s Adjuvant (CFA) induced a strongly Th2-biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor-bearing lungs by CD8+ T cells or the decrease in the frequency of Treg cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8+ cells confirmed that CD8 T cells were required for the anti-tumor activity of MVA-BN®-HER2. Furthermore, depletion of CD4+ or CD25+ cells demonstrated that tumor-induced Treg cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN®-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN®-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression

Comparison of central corneal thickness and anterior chamber depth measurements using three imaging technologies in normal eyes and after phakic intraocular lens implantation

Contains fulltext : 81835.pdf (Publisher’s version ) (Open Access)BACKGROUND: The repeatability and interchangeability of imaging devices measuring central corneal thickness (CCT) and anterior chamber depth (ACD) are important in the assessment of patients considering refractive surgery. The purpose of this study was to investigate the agreement of CCT and ACD measurements using three imaging technologies in healthy eyes and in eyes after phakic intraocular lens implantation (pIOL). METHODS: In this comparative study, CCT and ACD were measured using anterior segment optical coherence tomography (AS-OCT), Orbscan II, and Pentacam in 33 healthy volunteers (66 eyes) and 22 patients (42 eyes) after pIOL implantation. Intraobserver repeatability was evaluated for all three devices in the healthy volunteer group. RESULTS: Pairwise comparison of CCT measurements showed significant differences between all devices (P < 0.001), except for the AS-OCT and Orbscan II in the healthy volunteer group (P = 0.422) and the Orbscan II and Pentacam in the pIOL group (P = 0.214). ACD measurements demonstrated significant differences between all pairwise comparisons in both groups (P < or = 0.001). Intraobserver reliability was high for CCT and ACD measurements in the healthy volunteer group, with coefficients of variation ranging from 0.6% to 1.2% and 0.4% to 0.5% respectively. CONCLUSIONS: CCT and ACD measurements using AS-OCT, Orbscan II, and Pentacam demonstrated high intraobserver reliability. However, these devices should not be used interchangeably for measurements of CCT and ACD in healthy subject and patients after pIOL implantation

Sociodemographic and geographic characteristics associated with patient visits to osteopathic physicians for primary care

<p>Abstract</p> <p>Background</p> <p>Health care reform promises to dramatically increase the number of Americans covered by health insurance. Osteopathic physicians (DOs) are recognized for primary care, including a "hands-on" style with an emphasis on patient-centered care. Thus, DOs may be well positioned to deliver primary care in this emerging health care environment.</p> <p>Methods</p> <p>We used data from the National Ambulatory Medical Care Survey (2002-2006) to study sociodemographic and geographic characteristics associated with patient visits to DOs for primary care. Descriptive analyses were initially performed to derive national population estimates (NPEs) for overall patient visits, primary care patient visits, and patient visits according to specialty status. Osteopathic and allopathic physician (MD) patient visits were compared using cross-tabulations and multiple logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) for DO patient visits. The latter analyses were also conducted separately for each geographic characteristic to assess the potential for effect modification based on these factors.</p> <p>Results</p> <p>Overall, 134,369 ambulatory medical care visits were surveyed, representing 4.6 billion (NPE) ± 220 million (SE) patient visits when patient visit weights were applied. Osteopathic physicians provided 336 million ± 30 million (7%) of these patient visits. Osteopathic physicians provided 217 million ± 21 million (10%) patient visits for primary care services; including 180 million ± 17 million (12%) primary care visits for adults (21 years of age or older) and 37 million ± 5 million (5%) primary care visits for minors. Osteopathic physicians were more likely than MDs to provide primary care visits in family and general medicine (OR, 6.03; 95% CI, 4.67-7.78), but were less likely to provide visits in internal medicine (OR, 0.37; 95% CI, 0.24-0.58) or pediatrics (OR, 0.21; 95% CI, 0.11-0.40). Overall, patients in the pediatric and geriatric ages, Blacks, Hispanics, and persons in the South and West were less likely to utilize DOs, although there was some evidence of effect modification according to United States Census region.</p> <p>Conclusions</p> <p>Health care reform provides unprecedented opportunities for DOs to reach historically underserved populations and to overcome the "pediatric primary-care paradox."</p

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

Adoptive T cell therapy involving the use of ex vivo generated antigen-specific cytotoxic T lymphocytes provides a promising approach to immunotherapy. It has become increasingly apparent that anti-tumor efficacy using adoptively transferred T cells is linked to their duration of in vivo persistence and can only be achieved when combined with some form of pre-infusion patient conditioning regimen. An optimal conditioning regimen that provides a positive benefit without serious toxicities has yet to be defined. We have established a unique clinical model that allows for evaluation of a given conditioning regimen on adoptively transferred T cells in humans. In this first-in-human study (FHCRC #1796), we evaluate the use of fludarabine, an FDA-approved reagent with predictable lymphodepleting kinetics and duration of action, as a conditioning regimen that promotes homeostatic upregulation of cytokines and growth signals contributing to in vivo T cell persistence.We conducted a phase I study in patients with refractory metastatic melanoma. Patients received two infusions of a single tumor-reactive antigen-specific CTL clone expanded to 10(10)/m(2); the first infusion was given without fludarabine conditioning, and the second CTL infusion was given after a course of fludarabine (25 mg/m(2)/dayx5 days). This design permits intra-patient comparison of in vivo T cell persistence pre- and post-fludarabine. Nineteen CTL infusions were administered to ten patients. No serious toxicities were observed. Three of nine evaluable patients experienced minor response or stable disease for periods of 5.8-11.0 months with two additional patients demonstrating delayed disease stabilization. The median overall survival in this heavily pre-treated population was 9.7 months. Fludarabine led to a 2.9 fold improvement in the in vivo persistence of transferred CTL clones from a median of 4.5 days (range 0-38+) to 13.0 days (range 2-63+) (p<0.05). Fludarabine lymphodepletion increased plasma levels of the homeostatic cytokines IL-7 and IL-15. Surprisingly, fludarabine also increased the relative percentage of CD4+ T cells expressing the regulatory protein Foxp3.Lymphodepletion with fludarabine enhances transferred T cell persistence but suggest that additional improvements to optimize T cell survival and address regulatory T cells are critical in providing anti-tumor efficacy.ClinicalTrials.gov NCT00317759

Epidemiology of fractures in Armenia: development of a country-specific FRAX model and comparison to its surrogate

Summary: Fracture probabilities derived from the surrogate FRAX model for Armenia were compared to those from the model based on regional estimates of the incidence of hip fracture. Disparities between the surrogate and authentic FRAX models indicate the importance of developing country-specific FRAX models. Despite large differences between models, differences in the rank order of fracture probabilities were minimal. Objective: Armenia has relied on a surrogate FRAX model based on the fracture epidemiology of Romania. This paper describes the epidemiology of fragility fractures in Armenia used to create an Armenia-specific FRAX model with an aim of comparing this new model with the surrogate model. Methods: We carried out a population-based study in two regions of Armenia (Ararat and Vayots Dzor representing approximately 11% of the country’s population). We aimed to identify all low-energy fractures: retrospectively from hospital registers in 2011–2012 and prospectively in 2013 with the inclusion of primary care sources. Results: The differences in incidence between the surveys with and without data from primary care suggested that 44% of patients sustaining a hip fracture did not receive specialized medical care. A similar proportion of forearm and humeral fractures did not come to hospital attention (48 and 49%, respectively). Only 57.7% of patients sustaining a hip fracture were hospitalized. In 2013, hip fracture incidence at the age of 50 years or more was 201/100,000 for women and 136/100,000 for men, and age- and sex-specific rates were incorporated into the new “authentic” FRAX model for Armenia. Compared to the surrogate model, the authentic model gave lower 10-year fracture probabilities in men and women aged less than 70 years but substantially higher above this age. Notwithstanding, there were very close correlations in fracture probabilities between the surrogate and authentic models ( >  0.99) so that the revisions had little impact on the rank order of risk. Conclusion: A substantial proportion of major osteoporotic fractures in Armenia do not come to hospital attention. The disparities between surrogate and authentic FRAX models indicate the importance of developing country-specific FRAX models. Despite large differences between models, differences in the rank order of fracture probabilities were minimal