Safety and Tolerability of KIO-101 Eye Drops in Healthy Volunteers and Patients with Ocular Surface Disease-A Phase I Study.

PURPOSE: Inhibitors of dihydroorotate dehydrogenase (DHODH) have been found to be potent anti-inflammatory agents. Recently, a topical formulation (KIO-101 eye drops) of a DHODH inhibitor has been developed. The aim of the present study was to evaluate the safety and tolerability of KIO-101 eye drops in Healthy Volunteers (HVs) and patients with conjunctival hyperemia. METHODS: The study was carried out in a double-masked, placebo-controlled, randomized, parallel-group design with two parts. In part I, HVs received single and multiple instillations (four times daily for 12 consecutive days) of KIO-101 eye drops in ascending doses of 0.05%, 0.15%, and 0.30%, respectively. Part II was conducted in patients with conjunctival hyperemia who received 0.15% KIO-101 eye drops twice daily for 12 consecutive days. Ophthalmic and systemic safety examinations were performed on all participants. In part II, ocular hyperemia grading and an ocular surface disease index (OSDI) questionnaire were performed. RESULTS: 24 HVs participated in part I and 21 patients in part II. KIO-101 eye drops were well tolerated in all subjects. No serious adverse events (SAEs) occurred, and all AEs that were reported were transient and considered mild to moderate. In the highest dose cohort (0.30%), epistaxis occurred in two subjects after multiple instillations. In part II, after 12 days treatment with 0.15% KIO-101, conjunctival hyperemia decreased by -1.1 ± 0.27 points in the treatment and -0.6 ± 0.79 points in the placebo group (p = 0.0385). OSDI decreased from 47.9 ± 18.7 to 27.6 ± 19.13 points in the treatment group, while in the placebo group, a change from 41.3 ± 12.08 to 27.3 ± 18.63 points occurred. CONCLUSIONS: A 12-day treatment regimen with topical KIO-101 eye drops at low and mid doses was safe and well tolerated in both HVs and patients with conjunctival hyperemia. The obtained results point towards an early sign of reduction in conjunctival hyperemia.

Ranpirnase (OKG-0301), a Novel Ribonuclease, Demonstrates Antiviral Activity against Adenovirus in the Ad5/NZW Rabbit Ocular Replication Model.

Adenovirus ocular infections are common ocular viral infections seen worldwide, for which there is no approved antiviral therapy available. Ranpirnase is a novel ribonuclease which preferentially degrades tRNA resulting in an inhibition of protein synthesis. The study goal was to determine the anti-adenoviral activity of topical formulations of ranpirnase (OKG-0301) on adenoviral replication in the Ad5/NZW rabbit ocular replication model. NZW rabbits were inoculated in both eyes with human adenovirus type 5 (HAdV5) after corneal scarification. A day later, topical therapy was initiated in both eyes with 0.03% OKG-0301, 0.003% OKG-0301, saline or 0.5% cidofovir. Eyes were cultured to determine HAdV5 eye titers over 2 weeks. OKG-0301 (0.03% and 0.003%) and 0.5% cidofovir decreased viral titers compared to saline. Furthermore, both OKG-0301 formulations and 0.5% cidofovir shortened the duration of the HAdV5 infection compared to saline. Both 0.03% OKG-0301 and 0.003% OKG-0301 demonstrated increased antiviral activity compared to saline in the Ad5/NZW rabbit ocular replication model. The antiviral activity of the OKG-0301 groups was similar to that of the positive antiviral control, 0.5% cidofovir. Ranpirnase (OKG-0301) may be a potential candidate for a topical antiviral for adenoviral eye infections. Further clinical development is warranted.

A mechanistic derivation of the Monod bioreaction equation for a limiting nutrient.

We present a quasi-steady state mechanistic derivation of the Monod bioreaction equation based upon a conceptual model involving aqueous phase diffusive transport of substrate towards a spherical microbe; transport of the substrate across its surface membrane; and reaction depleting the substrate within the microbe. The resulting Monod coefficients [Formula: see text] and [Formula: see text] are dependent upon substrate-species pairs and the mass transfer properties of the system. Two substrate transport scenarios are investigated: (1) a constant rate model that is a function of a constant flux across the surface of the microbe; and (2) a linear rate model that is the product of a constant transport velocity and the concentration of substrate in contact with the surface of the microbe. The model is verified and parameterized using benzene, toluene, and phenol depletion and biomass growth data obtained from Reardon et al. (Biotechnol Bioeng: 385-400, 2000). Calibration results indicate a normalized surface to bulk concentration ratio of nearly unity in all simulations for benzene, toluene, and phenol when paired with P. putida F1, implying that the process is not aqueous phase diffusion limited.

Cell Enriched Autologous Fat Grafts to Follicular Niche Improves Hair Regrowth in Early Androgenetic Alopecia.

BACKGROUND: Adipose and adipose derived regenerative cells (ADRCs) play an increasing role in androgenetic alopecia. OBJECTIVES: The authors sought to evaluate the safety and feasibility of fat grafts enriched with ADRCs in early androgenetic alopecia. METHODS: Seventy-one patients were treated: 16 with Puregraft fat and 1.0 × 106 ADRCs/cm2 scalp; 22 with Puregraft fat and 0.5 × 106 ADRCs/cm2 scalp, 24 with Puregraft fat alone, and 9 with saline control. Treatments were delivered into the skin and subcutaneous layer of the scalp. A total of 40 cm2 of scalp was treated and macrophotography and global photography were obtained at baseline and at 6, 24, and 52 weeks. RESULTS: A total of 71 patients tolerated the procedures well. No unanticipated associated adverse events were reported. When evaluating all patients at 24 weeks, there were no statistical differences between any of the treatment groups with respect to nonvellus (terminal) hair counts or width. There were increases (mean change from baseline) in terminal hair count for the low-dose ADRC group in the Norwood Hamilton 3 subgroup at week 6 (13.90 ±â€…16.68), week 12 (11.75 ±â€…19.42), week 24 (16.56 ±â€…14.68), and week 52 (2.78 ±â€…16.15). For this subgroup, the difference in hair count between the low-dose ADRC group and no-fat saline control was statistically significant (P = 0.0318) at week 24. CONCLUSIONS: Puregraft fat and ADRCs are safe and well tolerated. In early male hair loss, this therapy demonstrated a statistically significant increase in terminal hair counts relative to the control population at 24 weeks and represents a promising approach for early androgenetic alopecia.

The Gene Therapy Resource Program: A Decade of Dedication to Translational Research by the National Heart, Lung, and Blood Institute.

Over a 10-year period, the Gene Therapy Resource Program (GTRP) of the National Heart Lung and Blood Institute has provided a set of core services to investigators to facilitate the clinical translation of gene therapy. These services have included a preclinical (research-grade) vector production core; current Good Manufacturing Practice clinical-grade vector cores for recombinant adeno-associated virus and lentivirus vectors; a pharmacology and toxicology core; and a coordinating center to manage program logistics and to provide regulatory and financial support to early-phase clinical trials. In addition, the GTRP has utilized a Steering Committee and a Scientific Review Board to guide overall progress and effectiveness and to evaluate individual proposals. These resources have been deployed to assist 82 investigators with 172 approved service proposals. These efforts have assisted in clinical trial implementation across a wide range of genetic, cardiac, pulmonary, and blood diseases. Program outcomes and potential future directions of the program are discussed.

Hair follicle growth by stromal vascular fraction-enhanced adipose transplantation in baldness.

Great interest remains in finding new and emerging therapies for the treatment of male and female pattern hair loss. The autologous fat grafting technique is >100 years old, with a recent and dramatic increase in clinical experience over the past 10-15 years. Recently, in 2001, Zuk et al published the presence of adipose-derived stem cells, and abundant research has shown that adipose is a complex, biological active, and important tissue. Festa et al, in 2011, reported that adipocyte lineage cells support the stem cell niche and help drive the complex hair growth cycle. Adipose-derived regenerative cells (also known as stromal vascular fraction [SVF]) is a heterogeneous group of noncultured cells that can be reliably extracted from adipose by using automated systems, and these cells work largely by paracrine mechanisms to support adipocyte viability. While, today, autologous fat is transplanted primarily for esthetic and reconstructive volume, surgeons have previously reported positive skin and hair changes posttransplantation. This follicular regenerative approach is intriguing and raises the possibility that one can drive or restore the hair cycle in male and female pattern baldness by stimulating the niche with autologous fat enriched with SVF. In this first of a kind patient series, the authors report on the safety, tolerability, and quantitative, as well as photographic changes, in a group of patients with early genetic alopecia treated with subcutaneous scalp injection of enriched adipose tissue. The findings suggest that scalp stem cell-enriched fat grafting may represent a promising alternative approach to treating baldness in men and women.

Reduction of diffusive contaminant emissions from a dissolved source in a lower permeability layer by sodium persulfate treatment.

Residual contamination contained in lower permeability zones is difficult to remediate and can, through diffusive emissions to adjacent higher permeability zones, result in long-term impacts to groundwater. This work investigated the effectiveness of oxidant delivery for reducing diffusive emissions from lower permeability zones. The experiment was conducted in a 1.2 m tall × 1.2 m wide × 6 cm thick tank containing two soil layers having 3 orders of magnitude contrast in hydraulic conductivity. The lower permeability layer initially contained dissolved methyl tert-butyl ether (MTBE) and benzene, toluene, ethylbenzene, and p-xylenes (BTEX). The treatment involved delivery of 10% w/w nonactivated sodium persulfate (Na2S2O8) solution to the high permeability layer for 14 days. The subsequent diffusion into the lower permeability layer and contaminant emission response were monitored for about 240 days. The S2O8(2-) diffused about 14 cm at 1% w/w into the lower permeability layer during the 14 day delivery and continued diffusing deeper into the layer as well as back toward the higher-lower permeability interface after delivery ceased. Over 209 days, the S2O8(2-) diffused 60 cm into the lower permeability layer, the BTEX mass and emission rate were reduced by 95-99%, and the MTBE emission rate was reduced by 63%. The overall treatment efficiency was about 60-110 g-S2O8(2-)delivered/g-hydrocarbon oxidized, with a significant fraction of the oxidant delivered likely lost by back-diffusion and not involved in hydrocarbon destruction.

Submicrometer surface patterning using interfacial colloidal particle self-assembly.

Hexagonal noncontiguously packed (HNCP) arrays of submicrometer-sized particles trapped at an air-water interface are successfully transferred to solid substrates. The long-range order of the hexagonal arrays at the interface can be improved by compression-relaxation cycles. The interparticle distance (i.e., the periodicity of the hexagonal array) can be controlled by varying the degree of compression of the particle film. The critical characteristics of the substrate surface are hydrophobicity (advancing water contact angle of >70 degrees) and a charge complementary to the surface of the particles. Suitable silicon and glass substrates are easily prepared by treatment with commercially available organosilicon compounds. Two transfer processes have been developed. When the parallel transfer process is used, the HNCP arrays are deposited on the solid substrates with minimal pattern distortion. The vertical dipping transfer distorts the pattern and renders a sense of directionality perpendicular to the dipping direction. This surface patterning technique is applied to fabrication of subwavelength grating for antireflection in the visible region. Antireflective HNCP arrays comprising varied particle diameters and pattern periodicities are fabricated on glass substrates to demonstrate the effects of these parameters on the antireflection performance.

Hepatitis B virus and HIV coinfection: results of a survey on treatment practices and recommendations for therapy.

BACKGROUND: The management of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection is challenged by the selection of patients for therapy, options for antiviral medications, and inconsistency in published treatment guidelines. METHODS: A survey was sent to 161 sites in a multicenter HIV clinical trials group to assess HBV screening, criteria for initiation of therapy, and treatment choices for patients coinfected with HBV and HIV. RESULTS: Of 161 sites, 78 completed the survey (response rate, 48.4%). Of these sites, 98.7% screened for HBV infection, 86% vaccinated HIV-infected patients who were not immune to HBV infection, and 79% made treatment decisions without referral to a hepatologist or gastroenterologist. Treatment recommendations varied; 42% of the sites initiated therapy when patients' levels of alanine aminotransferase and aspartate aminotransferase were elevated and HBV DNA level was >10(5) copies/mL, whereas 49% of the sites initiated therapy in the presence of any detectable HBV DNA level. Antiviral treatment choices for patients who were not concurrently receiving antiretroviral therapy were lamivudine plus tenofovir, adefovir, or interferon. Patients concurrently receiving antiretroviral therapy received lamivudine plus tenofovir preferentially, followed by tenofovir plus emtricitabine, adefovir, or interferon. Ninety-one percent of the sites screened for hepatocellular carcinoma. CONCLUSIONS: The majority of HIV-infected patients were screened and vaccinated for HBV infection and underwent surveillance for hepatocellular carcinoma. Decisions regarding the performance of liver biopsy, threshold to initiate therapy, and criteria to discontinue therapy varied, reflecting inconsistencies in available treatment guidelines. Treatment decisions reflected concerns regarding future drug resistance in patients who are naive to antiretroviral therapy and the emergence of drug resistance in patients receiving antiretroviral therapy.

Cytori Therapeutics, Inc.

Cytori Therapeutics, Inc. develops stem and regenerative cell therapies that can be used in a 'real-time' treatment setting for cardiovascular disease, reconstructive surgery and many other serious, chronic and life-threatening conditions and disorders. Cytori uses adult stem cells from adipose tissue, which offers a rich, accessible and autologous source of adult stem cells, and maximizes these benefits to create a cost-effective and safe treatment option.

A comparison of factors associated with prevalent diabetes mellitus among HIV-Infected antiretroviral-naive individuals versus individuals in the National Health and Nutritional Examination Survey cohort.

BACKGROUND: In the general population, diabetes mellitus (DM) is associated with age, minority race/ethnicity, and obesity. Among HIV-infected persons, antiretroviral therapy (ART) use and hepatitis C virus (HCV) infection have been associated with DM. This study examined DM prevalence and its predictors in ART-naive HIV-infected patients. METHODS: A cross-sectional analysis of ART-naive HIV-infected adults enrolled in 3 Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) clinical trials versus adults enrolled in the National Health and Nutritional Examination Survey (NHANES). RESULTS: The prevalence of DM in the CPCRA clinical trials versus the NHANES was 3.3% versus 4.8%. The mean body mass index (BMI) was lower in the CPCRA trials versus the NHANES (25 kg/m vs. 28 kg/m). HCV was associated with DM only in univariate analyses in the CPCRA trials. In univariate and multivariate analyses, race/ethnicity, age, and BMI were associated with DM in both cohorts. Among women, age and BMI were associated with DM in both cohorts; race/ethnicity was associated with DM only in the NHANES. HCV was predictive of DM in blacks in the CPCRA trials (P = 0.004 before adjustment for multiple comparisons) but not in the full cohort. CONCLUSIONS: Our findings did not suggest an increased prevalence of DM in ART-naive HIV-infected patients. Although there was a trend toward increased prevalence of DM in HIV-HCV-coinfected patients, dominant risk factors associated with DM among ART-naive HIV-infected adults mirrored those of the general population.

The use of adult stem cells in regenerative medicine.

The cellular component of the tissue engineering paradigm is arguably the most important piece of the complex task of regenerating or repairing damaged or diseased tissue. Critical to the development of clinical strategies is the need for reliable sources of multipotent cells that can be obtained with limited morbidity. The adult stem cell population may be well suited for this task. The next several years will bring many phase I and II studies using adult stem cells as the cellular foundation for engineered tissue constructs. Future research should be directed toward better characterization of this cell population, including identifying unique markers and mapping out lineage development. For now, the ideal source of adult stem cells remains uncertain, but as questions are answered, adult stem cell biology will likely transition from bench top to clinical reality.

Transmission thresholds for dengue in terms of Aedes aegypti pupae per person with discussion of their utility in source reduction efforts

The expense and ineffectiveness of drift-based insecticide aerosols to control dengue epidemics has led to suppression strategies based on eliminating larval breeding sites. The present work attempts to estimate transmission thresholds for dengue based on an easily-derived statistic, the standing crop of Aedes aegypti pupae per person in the environment. We have developed these thresholds for use in the assessment of risk of transmission and to provide targets for the actual degree of suppression required to prevent or eliminate transmission in source reduction programs. The notion of thresholds is based on 2 concepts: the mass action principal- the course of an epidemic is dependent on the rate of contact between susceptible hosts and infectious vectors, and threshold theory - the introduction of a few infectious individuals into a community of susceptible individuals will not give rise to an outbreak unless the density of the vectors exceeds a certain critical level. We use validated transmission models to estimate thresholds as a function of levels of pre-existing antibody levels in human populations, ambient air temperatures, and the size and frequency of viral introduction. Threshold levels were estimated to range between about 0.5 and 1.5 Ae. aegypti pupae per person for ambient air temperatures of 28 degrees C and initial seroprevalences ranging between 0 percent to 67 percent. Suprisingly, the size of the viral introduction used in these studies, ranging between 1 and 12 infectious individuals per year was not seen to significantly influence the magnitude of the threshold. From a control perspective, these results are not particularly encouraging. The ratio of Ae. aegypti pupae to human density has been observed in limited field studies to range between 0.3 and >60 in 25 sites in dengue-epidemic of dengue-susceptible areas in the Caribbean, Central America, and South East Asia. If, for purposes of illustration, we assume an initial seroprevalence of 33 percent, the degree of suppression required to essentially eliminate the possibility of summertime transmission in Puerto Rico, Honduras, and Bangkok, Thailand was estimated to range between 10 percent and 83 percent; however in Mexico and Trinidad, reductions of >90 percent would be required.(AU)