Mucoadhesive carbamazepine gel for in situ olfactory delivery

Purpose: To formulate mucoadhesive carbamazepine gel for delivery to the brain via the olfactory mucosa. Methods: Carbamazepine transfersomes were formulated using Lipoid S 100 and sodium cholate. The transfersomes were evaluated for entrapment efficiency, in vitro release transmission electron microscopy, zeta potential, polydispersity index. The transfersomes were then incorporated into gellan gum gel, and the in situ gel formulation was evaluated for drug content, gel strength, in vitro release and mucoadhesive force. Transfersomes were also evaluated for bioanalytical study in rats. Result: TEM analysis showed good regular spheres. The negative zeta potential ensures resistance to aggregation. The gel strength of the formulations was in the range of 0.6 to 7.4 g. In vitro diffusion study of transfersomal gel showed Fickian diffusion mechanism. Formulation F6 was optimized depending for gel strength (6.4 g) , drug content (99.47 ± 0.25 %), and good mucoadhesive force (50.24 ± 0.76 dyne/cm2). Bioanalytical study of F6 showed increased drug concentration in brain. Conclusion: Mucoadhesive carbanmazepine gel can be used effectively to achieve increased concentration of drug in the brain via olfactory mucosal rout

ADF/cofilin-driven actin dynamics in early events of Leishmania cell division

ADF/cofilin is an actin-dynamics-regulating protein that is required for several actin-based cellular processes such as cell motility and cytokinesis. A homologue of this protein has recently been identified in the protozoan parasite Leishmania, which has been shown to be essentially required in flagellum assembly and cell motility. However, the role of this protein in cytokinesis remains largely unknown. We show here that deletion of the gene encoding ADF/cofilin in these organisms results in several aberrations in the process of cell division. These aberrations include delay in basal body and kinetoplast separation, cleavage furrow progression and flagellar pocket division. In addition to these changes, the intracellular trafficking and actin dynamics are also adversely affected. All these abnormalities are, however, reversed by episomal complementation. Together, these results indicate that actin dynamics regulates early events in Leishmania cell division

Trafficking activity of myosin XXI is required in assembly of Leishmania flagellum

Actin-based myosin motors have a pivotal role in intracellular trafficking in eukaryotic cells. The parasitic protozoan organism Leishmania expresses a novel class of myosin, myosin XXI (Myo21), which is preferentially localized at the proximal region of the flagellum. However, its function in this organism remains largely unknown. Here, we show that Myo21 interacts with actin, and its expression is dependent of the growth stage. We further reveal that depletion of Myo21 levels results in impairment of the flagellar assembly and intracellular trafficking. These defects are, however, reversed by episomal complementation. Additionally, it is shown that deletion of the Myo21 gene leads to generation of ploidy, suggesting an essential role of Myo21 in survival of Leishmania cells. Together, these results indicate that actin-dependent trafficking activity of Myo21 is essentially required during assembly of the Leishmania flagellum

Deletion analysis of BMI1 oncoprotein identifies its negative regulatory domain

<p>Abstract</p> <p>Background</p> <p>The polycomb group (PcG) protein BMI1 is an important regulator of development. Additionally, aberrant expression of BMI1 has been linked to cancer stem cell phenotype and oncogenesis. In particular, its overexpression has been found in several human malignancies including breast cancer. Despite its established role in stem cell maintenance, cancer and development, at present not much is known about the functional domains of BMI1 oncoprotein. In the present study, we carried out a deletion analysis of BMI1 to identify its negative regulatory domain.</p> <p>Results</p> <p>We report that deletion of the C-terminal domain of BMI1, which is rich in proline-serine (PS) residues and previously described as PEST-like domain, increased the stability of BMI1, and promoted its pro-oncogenic activities in human mammary epithelial cells (HMECs). Specifically, overexpression of a PS region deleted mutant of BMI1 increased proliferation of HMECs and promoted an epithelial-mesenchymal transition (EMT) phenotype in the HMECs. Furthermore, when compared to the wild type BMI1, exogenous expression of the mutant BMI1 led to a significant downregulation of p16INK4a and an efficient bypass of cellular senescence in human diploid fibroblasts.</p> <p>Conclusions</p> <p>In summary, our data suggest that the PS domain of BMI1 is involved in its stability and that it negatively regulates function of BMI1 oncoprotein. Our results also suggest that the PS domain of BMI1 could be targeted for the treatment of proliferative disorders such as cancer and aging.</p

Management of cryotherapy-ineligible women in a "screen-and-treat" cervical cancer prevention program targeting HIV-infected women in Zambia: Lessons from the field

Objective: We demonstrate the feasibility of implementing a referral and management system for cryotherapy-ineligible women in a "screen-and-treat" cervical cancer prevention program targeting HIV-infected women in Zambia. Methods: We established criteria for patient referral, developed a training program for loop electrosurgical excision procedure (LEEP) providers, and adapted LEEP to a resource-constrained setting. Results: We successfully trained 15 nurses to perform visual inspection with acetic acid (VIA) followed by immediate cryotherapy. Women with positive tests but ineligible for cryotherapy were referred for further evaluation. We trained four Zambian physicians to evaluate referrals, perform punch biopsy, LEEP, and manage intra-operative and post-operative complications. From January 2006 through October 2007, a total of 8823 women (41.5% HIV seropositive) were evaluated by nurses in outlying prevention clinics; of these, 1477 (16.7%) were referred for physician evaluation based on established criteria. Of the 875 (59.2% of 1147 referred) that presented for evaluation, 748 (8.4% of total screened) underwent histologic evaluation in the form of punch biopsy or LEEP. Complications associated with LEEP included anesthesia reaction (n = 2) which spontaneously resolved, intra-operative (n = 12) and post-operative (n = 2) bleeding managed by local measures, and post-operative infection (n = 12) managed with antibiotics. Conclusion: With adaptations for a resource-constrained environment, we have demonstrated that performing LEEP is feasible and safe, with low rates of complications that can be managed locally. It is important to establish referral and management systems using LEEP-based excisional evaluation for women with cryotherapy-ineligible lesions in VIA-based "screen-and-treat" protocols nested within HIV-care programs in resource-constrained settings

Temperature-dependent optical properties of titanium nitride

The refractory metal titanium nitride is promising for high-temperature nanophotonic and plasmonic applications, but its optical properties have not been studied at temperatures exceeding 400 °C. Here, we perform in-situ high-temperature ellipsometry to quantify the permittivity of TiN films from room temperature to 1258 °C. We find that the material becomes more absorptive at higher temperatures but maintains its metallic character throughout visible and near infrared frequencies. X-ray diffraction, atomic force microscopy, and mass spectrometry confirm that TiN retains its bulk crystal quality and that thermal cycling increases the surface roughness, reduces the lattice constant, and reduces the carbon and oxygen contaminant concentrations. The changes in the optical properties of the material are highly reproducible upon repeated heating and cooling, and the room-temperature properties are fully recoverable after cooling. Using the measured high-temperature permittivity, we compute the emissivity, surface plasmon polariton propagation length, and two localized surface plasmon resonance figures of merit as functions of temperature. Our results indicate that titanium nitride is a viable plasmonic material throughout the full temperature range explored

Infiltrating T-cell markers in cervical carcinogenesis: a systematic review and meta-analysis.

Funder: Intramural Research Program of the National Cancer Institute at the National Institutes of Health (Z01 CP010124-21).BACKGROUND: The host adaptive immune response helps determine which cervical HPV infections persist and progress to precancer and cancer, and systematic characterisation of T-cell infiltration would help inform key steps in cervical carcinogenesis. METHODS: A systematic review and meta-analysis were conducted of infiltrating T-cells in normal cervix, low-grade lesions, high-grade lesions, and invasive cancers including epithelial, stromal, and total tissue and the following markers: CD3, CD4, CD8, FoxP3, CD25, and the CD4:CD8 ratio. An additional qualitative review summarised longitudinal data on associations between infiltrating T-cells and cervical disease persistence, regression, progression, or prognosis. RESULTS: There were fewer CD3+, CD4+, and CD8+ cells in cervical lesions and more cells in cancers compared to normal epithelium. FoxP3 and CD25+ regulatory T-cell infiltration is high in persistent and precancerous lesions, and longitudinal data show improved outcomes with lower regulatory T-cell levels. CONCLUSIONS: Successful immune evasion may reduce T-cell infiltration in HPV infected and precancerous epithelium, while invasive cancers are highly immunogenic, and regulatory T-cell infiltration increases with cervical disease progression. Understanding these factors may have prognostic value and could aid in novel treatment development and clinical guidelines, but published data are highly heterogeneous and leave important gaps to be filled by future studies

Myths and misconceptions about cervical cancer among Zambian women: rapid assessment by peer educators.

OBJECTIVE: To make a rapid assessment of the common myths and misconceptions surrounding the causes of cervical cancer and lack of screening among unscreened low-income Zambian women. METHODS: We initiated a door-to-door community-based initiative, led by peer educators, to inform unscreened women about the existence of a new see-and-treat cervical cancer prevention program. During home visits peer educators posed the following two questions to women: 1. What do you think causes cervical cancer? 2. Why haven't you been screened for cervical cancer? The most frequent types of responses gathered in this exercise were analyzed thematically. RESULTS: Peer educators contacted over 1100 unscreened women over a period of two months. Their median age was 33 years, a large majority (58%) were not educated beyond primary school, over two-thirds (71%) did not have monthly incomes over 500,000 Zambian Kwacha (US$100) per month, and just over half (51%) were married and cohabiting with their spouses. Approximately 75% of the women engaged in discussions had heard of cervical cancer and had heard of the new cervical cancer prevention program in the local clinic. The responses of unscreened low-income Zambian women to questions posed by peer educators in urban Lusaka reflect the variety of prevalent 'folk' myths and misconceptions surrounding cervical cancer and its prevention methods. CONCLUSION: The information in our rapid assessment can serve as a basis for developing future educational and intervention campaigns for improving uptake of cervical cancer prevention services in Zambia. It also speaks to the necessity of ensuring that programs addressing women's reproductive health take into account societal inputs at the time they are being developed and implemented. Taking a community-based participatory approach to program development and implementation will help ensure sustainability and impact

Implementation of 'see-and-treat' cervical cancer prevention services linked to HIV care in Zambia

Greater than 80% of the world's new cases and deaths due to cervical cancer occur in the developing world. No more than 5% of women in these settings are screened for cervical cancer even once in their lifetimes. Earlier attempts to establish population-based cervical cancer prevention programs using cytology screening in resource-limited settings have inevitably fallen short or failed. Although many of the reasons for failure can be attributed to lack of resources and trained manpower, the multiple visit requirements of cytology-based screening programs jeopardizes success and sustainability